The influence of aspirin on postoperative platelet kinetics and venous thrombosis. Several parameters of platelet kinetics were followed in 105 middle-aged and elderly postoperative patients, half of whom were randomly allocated to receive aspirin. A significantly lower incidence of venous thrombosis, as detected by 125I-fibrinogen scanning, was found among patients receiving aspirin when compared with the control group. Platelet survival was shortened in the postoperative state, an effect that was inhibited by aspirin. The development of deep vein thrombosis did not shorten platelet survival, nor did fibrinogen survival discriminate patients with venous thrombosis. Treatment with aspirin reduced urinary excretion of 5-hydroxy indole acetic acid--presumably by inhibiting in vivo platelet release of serotonin, reduced postoperative consumption of platelets, and reduced the mean corpuscular volume of the platelet population. These studies suggest that platelet function is important in the pathogenesis of postoperative venous thrombosis.


Extravascular fibrinogen degradation in experimental burn wounds: a source of fibrin split products. Utilizing a 40 percent flame-burned canine model, serial aliquots of burn-wound edema and simultaneous plasma samples were collected for 26 hours after burn, following the injection of 100 muc of 125I-tagged fibrinogen. Both edema fluid and plasma samples were analyzed for radioactivity. In addition, radioactivity in the supernatant was reassayed after sequential in vitro addition of thrombin, protamine sulfate (PS), and trichloroacetic acid (TCA) to each sample. Plasma and edema fibrinogen and fibrin split product concentrations were measured directly. PS and TCA precipitable protein concentrations were calculated. Early post-burn edema radioactivity appeared primarily in the fibrinogen fractions where edema fibrinogen concentration was measured at almost 30 percent of the simultaneous plasma concentration. Late post-burn edema radioactivity (24 to 27 hours) was associated with the PS precipitable protein fraction (soluble fibrin monomer). Fibrin split product concentration increased in both plasma and edema during the study period. These observations allowed construction of a hypothesis to explain the post-burn elevation in plasma fibrin split product concentration noted in burned patients and strongly suggested that the abnormally elevated plasma fibrin split concentrations resulted from extravascular plasmin digestion of fibrinogen.


Pylorus-preserving gastrectomy for gastric ulcer--one- to nine-year follow-up study. Of 100 patients subjected to pylorus-preserving gastrectomy for surgical treatment of gastric ulcer, 60 were available for follow-up for periods of from one to 9 years. Questionnaires and personal interviews of these 60 and additional laboratory examinations of 40 of them showed results tending to favor the procedure as a highly recommendable technique of gastrectomy. Questions about body weight gain, return to preoperative occupation, and satisfaction with the operation all were answered favorably. In the follow-up laboratory examinations, reduction rates of 57.2 percent for maximal acid concentration, 81.6 percent for maximal acid output, and 70.8 percent for peak acid output. Sphincteric function was generally well preserved on the pyloric ring. Gastric emptying times, ranging from 30 to 180 minutes in 79 percent of the cases, were nearly compatible with the control figures. The results of fat and protein absorption tests performed on some of these patients showed their rates to be within normal ranges. No instances of dumping syndrome, recurrence of ulcer, or other significant postgastrectomy sequelae were recognized. The results indicate pylorus-preserving gastrectomy to be preferable for the surgical treatment of gastric ulcer and other benign lesions of the stomach.


Psychological antecedents to conception among abortion seekers. At a university hospital, 642 women seeking induced abortion for an unwanted pregnancy were surveyed before the procedure regarding their perception of what psychological and behavioral factors, if any, played a role in their becoming pregnant: 35 percent said they had had intercourse during what they believed was a "safe period"; 33 percent believed that they had experienced a contraceptive failure; 29 percent indicated fear of side effects influenced their use of a contraceptive method; 27 percent and 21 percent, respectively, indicated that they had thought pregnancy "couldn't happen to me" or had "put the thought of pregnancy out of my mind." The women's responses indicated that a number of additional attitudes, beliefs, and behaviors were also important and that for any individual woman at least three or four factors had often combined in a dynamic sequence to greatly increase her risk of pregnancy. The implications of the findings for educational and counseling programs are discussed.


Management of parkinson's disease--combined therapy with levodopa and thalamotomy. An increasing number of parkinsonian patients in whom levodopa fails to relieve tremor are being referred for thalamotomy. The literature suggests that in as many as 50 percent of patients treated with levodopa, there is no relief of tremor because of refractoriness to the medication or intractable side effects which limit dosage. Thalamotomy abolishes contralateral tremor in 90 percent of patients, with an associated mortality rate of 1 to 2 percent and morbidity of 6 percent. The relative merits and complications of levodopa and thalamotomy were reviewed and a therapeutic regimen designed in which the two approaches to treatment are combined to most effectively deal with all the symptoms of parkinsonism.


Diuretic-induced hypokalemia.

Diuretic-induced hypokalemia. Among patients receiving thiazides for hypertension, there was no reliable predictor of those who would develop significant hypokalemia (a decrease in serum potassium of at least 0.5 mEq. per L). Eighty percent of patients required 60 mEq. of potassium chloride 10 percent elixir daily for successful treatment of thiazide-induced hypokalemia. Foods containing potassium or organic anion compounds of potassium are not useful in this potentially dangerous situation.


Febrile seizures in children.

Febrile seizures in children. Benign febrile convulsions occur early in the course of fever of extracranial origin in children six months to five years old. The first seizure always calls for a spinal tap to exclude meningitis, as well as appropriate studies to exclude other causes of seizure activity. An EEG one week later is indicated but more extensive studies are usually nonproductive. The question of whether to employ long-term phenobarbital therapy has not been resolved.


Perils and pitfalls of open tibial fractures. The status of the fibula is an index of the severity of injury. Open tibial fracture with associated fractured fibula is more likely to develop complications. Antibiotics should be started promptly. Judicious debridement is essential but bone fragments should be left whenever possible. When there is any question about contamination, the wound is best left open. Rigid occlusive dressings promote epithelial ingrowth. Fracture distraction and plate fixation are associated with a high incidence of complications.


Direct arterial pressure, heart rate, and electrocardiogram during cigarette smoking in unrestricted patients. Direct arterial pressure, heart rate, and ECG have been recorded over a 24-hour period in nine individuals who were completely unrestricted throughout the study. Forty-nine separate cigarette smoking episodes were clearly indicated and analyzed. The results of our study confirm a significant increase in arterial pressure five minutes after smoking a cigarette. The systolic rise in pressure (mean 10.7 mm. Hg, P less than 0.001) was approximately twice that of the diastolic rise (5.3 mm. Hg, P less than 0.001) and was present under different conditions of everyday life with notable exception of lying in bed before sleep, We found no quantitative difference between normotensive and hypertensive subjects. There was no certain change in heart rate (mean increase +0.8 beats per minute, t equals 0.59, NS) in the group as a whole. Smoking also had a short-term action consisting of a brief fall in arterial pressure and heart rate occuring over eight to ten heart beats following immediately after the first inhalation of tobacco smoke, followed by a rebound rise in arterial pressure to a level greater than the presmoking level; this is probably a vagal effect. Cigarette smoking caused angina pectoris in one individual and the records showed ST-segment depression in the ECG before the subjective appreciation of pain.


The incidence of typical and atypical A-V Wenckebach periodicity. The classic pattern of the typical WP's consists of (1) progressive lengthening of the P-R intervals with the largest increment occuring in the second conducted beat, (2) progressive decrease in P-R increment which accounts for the progressive shortening of successive R-R intervals, and (3) the pause produced by the nonconducted P-wave is less than two P-P intervals. In 45 patients with atrial pacing-induced Wendkebach periods of A-V conduction, the structure of these was studied with His bundle recordings. Of the 128 periods analyzed exceeding 3:2 A-V conduction ratios, 66 per cent were atypical. In 24 patients with spontaneous WP's of A-V conduction, the electrocardiographic records were studied. Of the 98 periods analyzed exceeding 3:2 A-V conduction ratios, 86 per cent were atypical. WP's with A-V conduction ratios greater than 6:5 were all atypical. Five categories of atypical WP's are described.


The development of cardiac myxomas and papillary endocardial lesions from mural thrombus. A morphologic study of 466 cardiac mural thrombi, 66 examples of nonbacterial thrombotic endocarditis, 25 myxomas, and 12 papillary endocardial lesions was performed. It appeared that three different sequences of organization of endocardial thrombi are possible. (1) Ordinary mural thrombi are converted into a flat, fibrous scar by fibroblast proliferation and collagen and elastic fiber deposition. (2) Papillary endocardial lesions develop from non bacterial thrombotic endocarditis as additional thrombus material is acquired in some foci and lost in others. No ingrowth of granulation tissue occurs at the base of these lesions. The thrombus material of the papillae is gradually replaced by fibrous tissue, and the lesion eventually is identical to a large Lambl's excrescence. (3) Myxomas enlarge in part as do the papillary endocardial lesions. In addition, their size increases as a result of influx into the myxoma of fluid from the basal granulation tissue. Although myxomas cannot be differentiated from ordinary mural thrombi on the basis of the cellular and ground substance components, their mode of development results in a distinctive appearance. The mature lesion is composed of three zones: a basal layer of small vascular channels, undifferentiated mesenchymal cells, and ground substance; a middle, acellular zone of ground substance; and a cortical layer of mesenchymal cells. The peculiar arrangement of endothelial cells and undifferentiated mesenchymal cells, the examples of apparent atrial wall invasion, and the cases of embolic "metastases" provide no conclusive evidence of neoplasia, since these features may also be seen with ordinary mural thrombi.


Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. In a patient affected by the "long Q-T" syndrome we observed episodes of alternation of the T-wave associated with emotional or physical stresses. In anesthetized and vagotomized cats, we could reproduce both the lengthening of the Q-T interval and episodes of alternation of the T-wave by electrical stimulation of the left stellate ganglion. Our experiments provide further support on the relationships between the "long Q-T" syndrome and the sympathetic nervous system and indicate that alternation of the T-wave may depend on abrupt increases in the sympathetic discharge.


Influence of perfusion pressure and heart rate on local myocardial flow in the collateralized heart with chronic coronary occlusion. We studied the influence of controlled changes in perfusion pressure and heart rate on the regional distribution of myocardial flow in normal dogs and in dogs with multiple chronic coronary artery occlusions but without infarctions. Local myocardial blood flow was determined with the tracer microsphere technique. By stepwise altering of systemic blood pressure during maximal vasodilation classical pressure flow relations were obtained. One week after complete chronic occlusion a functionally and anatomically well-defined compartmentation of blood flow was found. The dilatory reserve is clearly compromised not only in the collateral-dependent myocardium but also in the apparently normal myocardium which delivers collateral flow. An "arterio-arterial shunting" mechanism is shown to exist. Several months after coronary occlusion, regional mycoardial flow is still nonhomogeneous. Although the coronary dilatory capacity of the collateralized myocardium is nearly normal, that of the normal myocardium is found to be higher than normal. Vessel growth in both areas is discussed as being responsible for this phenomenon. Right ventricular pacing during maximal vasodilation produces a flow decrease to the endocardial muscle layers in normal dogs, while the epicardial flow is unchanged. One week after complete chronic coronary occlusion pacing during maximal vasocilation reduces the dilatory capacity in the collateralized areas to such an extent that the supplementary increase in myocardial oxygen demand will induce ischemia because of the compromised oxygen supply.


Mechanism of the effect of coronary artery stenosis on coronary flow in the dog. The hemodynamic mechanism of the effect of coronary artery stenosis on coronary flow was studied in the circumflex artery of 10 open-chest dogs by simultaneously measuring coronary flow, aortic pressure, and coronary artery pressure distal to an adjustable constrictor; while the distal coronary bed was intermittently maximally vasodilated by intracoronary injections of angiographic contrast media (Hypaque-M, 75 per cent). For each stenosis, the pressure gradient across the stenosis varied directly with the flow through the stenosis (r equals 0.99), the slope of the regression indicating the severity of the stenosis. An important observation was that this regression line did not intercept the flow axis at zero flow, but at a positive flow, meaning that for a given regression line slope the pressure gradient was much less than expected. At rest, distal bed resistance decreased as progressive stenosis lowered the distal bed pressure, maintaining flow at control level until the distal bed pressure dropped below 60 mm. HG. However, at maximum hyperemia, distal bed resistance was at a fixed minimum value such that flow was directly proportional to distal bed pressure. Hence, progressive stenosis decreased the ratio of hyperemic to resting flow by: (1) causing the vasodilatory reserve to be used to maintain resting flow, decreasing that available for hyperemia, and (2) dropping the distal bed pressure relatively more for smaller increases in flow. This study provides a hemodynamic explanation for the known fact that progressive stenosis initially limits the maximum hyperemic flow, and only after this flow is decreased almost to resting level, does resting flow fall.


Effect of stimulation site on ventricular threshold in dogs with heart block. Ventricular pacing thresholds were measured in barbiturate-anesthetized dogs with complete heart block using an oscilloscope and current probe. All electrode and physiologic variables were carefully controlled in order to compare the effects of stimulus duration and site of ventricular threshold energy requirements. Left ventricular intramyocardial stimulation, at all stimulus durations under 5 msec., required less current and energy, and at all stimulus durations under 2 msec. less voltage, than either right ventricular endocardial or right ventricular intramyocardial stimulation. Chronaxy and polarization losses were lowest and impedance highest with left ventricular intramyocardial stimulation. The two right ventricular sites were almost equivalent electrically. Earlier studies which reported lower thresholds with endocardial stimulation than with intramyocardial stimulation were biased in favor of the endocardial site by lack of control of electrode variables including: material, configuration, cross-sectional area, and epicardial versus intramyocardial location.


Serum digoxin levels using an 125I-labelled antigen: Validation of method and observations on cardiac patients. 1. Determinations of serum digoxin levels utilizing commercially available kits with an 125I-labelled antigen were precise and not materially different from results obtained with a 3H-labelled antigen. 2. In order to approximate the steady state level, serum digoxin levels should be drawn either before or at least six hours following the administration of an oral tablet. 3. Concomitantly given thiazide diuretics did not interfere with the absorption of a tablet of digoxin. 4. In the digitalized patient, slow alterations in serum levels after oral administration appeared well correlated with, at least, the negative chronotropic effects of the drug. 5. Maximal exercise testing, a maneuver often applied to cardiac patients, does not significantly alter the serum digoxin level.


Variant angina pectoris.

Variant angina pectoris. A patient with variant angina pectoris due to a pedunculated calcific mass extending from the aortic valve and resulting in intermittent obstruction of the left coronary ostia is reported. No atherosclerotic disease was demonstrated by coronary angiography. During attacks, marked ST segment elevation and episodes of tachycardia were associated with a moderate rise in pulmonary artery pressure. Replacement of the calcified aortic valve resulted in total relief of symptomatology.


Thymoma masquerading as congenital partial absence of the left pericardium. Interpretation of irregularities of the left heart border on routine posterior-anterior and lateral roentgenograms may be quite challenging. Partial absence of the left pericardium provides a characteristic abnormality of the left heart border. Described is a case of a thymoma which mimicked partial absence of the left pericardium on routine roentgenography. The importance of including both partial absence of the left pericardium and thymoma in the differential diagnosis of irregularities of the left heart border is discussed.


The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. The role of the monocyte/macrophage in wound repair has been investigated by studying the healing process in wounds depleted of this cell and/or its phagocytic activity. Hydrocortisone acetate (0.6 mg/g body weight) administered as a subcutaneous depot was used to induce a prolonged monocytopenia in guinea pigs, and antimacrophage serum (AMS) was used for local elimination of tissue macrophages. In vitro, the presence of complement, macrophages are rapidly lysed and used killed by AMS. In the absence of complement, AMS is not cytotoxic but potently inhibits adherence to and phagocytosis of opsonized erythrocytes by macrophages. AMS titers were obtained by observation of adherence and phagocytosis of opsonized erythrocytes in serial dilutions of AMS. Six groups of animals were studied: a) untreated animals, b)animals receiving daily subcutaneous injections of normal rabbit serum (NRS) around each wound, c)animals receiving daily subcutaneous AMS around each wound, d)animals receiving systemic hydrocortisone, e)animals receiving systemic hydrocortisone and daily injections of NRS around each wound, and f)animals receiving systemic hydrocortisone and daily AMS around each wound. Wounds consisted of a series of six linear incisions in the dorsal skin. Subcutaneous AMS alone has no effect on the number of circulating monocytes, nor was there any observable effect on the number or the phagocytic ability of wound macrophages. Fibrosis in these wounds was unaffected. Systemic hydrocortisone induced a prolonged monocytopenia. The macrophage level in the wounds of these monocytopenic animals was reduced to approximately one-third that of controls; the phagocytic activity of the monocytes/macrophages that did appear in these wounds was, however, similar to that of controls. Some inhibition of wound debridement was observed in these wounds, but fibrosis was virtually unaffected. Collagen synthesis, as judged morphometrically, was similar to that of control wounds at all stages of repair. Conjoint systemic hydrocortisone and subcutaneous AMS around each wound resulted in the almost complete disappearance of macrophages from the wounds. Wound fibrin levels were elevated, and clearance of fibrin, neutrophils, erythrocytes and other miscellaneous debris from these wounds was delayed. Fibroblasts, which in control wounds first appear by 3 days postwounding and reach maximal levels by day 5, did not appear in these wounds until day 5, and their subsequent rate of proliferation was slower than that of controls. Continued.


The fine structure and innervation of the cushion veins of the human nasal respiratory mucosa. Cushion veins of the human nasal lining were studied in eight patients of both sexes ranging in age from 11 to 59 years. It was found that the subendothelial cushions were part of the tunica media and consisted of smooth muscle cells, collagen and elastic fibers and occasional fibrocytes. The muscle fibers of the cushion nearest to the endothelium were circular. They extended processes towards the endothelium through gaps in the endothelial basement membrane and formed appositional junctions with the endothelial cells. The rest of the cushion consisted of longitudinal muscle fibers. The sacoplasm of the muscle cells was characterized by large areas filled with vesicles of various sizes. In addition, these cells possessed cytoplasmic processes which were devoid of a basement membrane and which did not show the regular structure of sarcoplasm. The subendothelial cushion possessed a rich, intrinsic nerve supply of adrenergic and cholinergic axons. It is suggested that the cushion veins regulate the drainage of the cavernous tissue and are under nervous and humoral control. The increase in girth of the subendothelial cushion is effected by contraction of the longitudinal muscle cells and probably by uptake of extracellular fluid by means of the specialized cytoplasmic processes. The single layer of circular muscle cells situated between the endothelial lining and the longitudinal musculature, may provide protection to the endothelium against distension when the cushion expands.


Hormonal influences on the morphogenesis of the preputial gland of embryonic mice. Fetal preputial glands from 14- to 17-day old mouse embryos undergo comparable growth, branching, and display similar degrees of cytodifferentiation when cultured in vitro on medium lacking hormones, on this medium in the presence of either of the fetal gondas, and on medium supplemented with testosterone dipropionate. Conversely, morphogenesis of these analgen is markedly suppressed by estrogen and an anti-androgen, Cyproterone acetate. These observations demonstrate that acquisition of androgen-sensitivity is a late event in the morphogenesis of the preputial gland and correlate with the developmental properties of preputial mesenchyme as demonstrated in earlier studies on the epithelio-mesenchymal interaction.


The repair of fractured membrane bones in the newly hatched chick. Repair of a fractured membrane bone, the quadratojugal (QJ), has been studied in the newly hatched chick. Complete open fractures never united by bony fusion, even in birds maintained for six months post-fracture. Extraperiosteal connective tissue invaded the fracture gap and formed thick fibrous bundles which stabilised the fracture. Cartilage of two types formed on these bones. One was derived from periosteal cells and the other from osteoblasts or osteocytes. Considerably more cartilage formed in bones partially fractured than in those completely fractured. The "periosteal" cartilage did not form if the periosteum was removed at the time the bone was fractured. This was because, although the fibrous layer of the periosteum regenerated, the cambial layer did not. Metaplastic cartilage did form in the absence of the periosteum. Isolating fractured bones within polyethlene or glass tubes prevented accumulation of a blastema between the bony fragments. Cartilage did not form inside the tubes but did form where the ends of the tubes abutted onto the bones. Large defects in the bones (4 mm gaps, 4 mm of bone in the place of the QJ) healed via fibrous union with minimal osteogenesis and no chondrogenesis. Severing M. depressor mandibulae at the time the bone was fractured inhibited chondrogenesis, favoured osteogenesis and resulted in development of a pseudarthrosis. The potential for differentiation of the cells of the QJ and the role of the adjacent tissues as they related to repair of the fracture was discussed, and the ability of cells from membrane bones to become chondrogenic emphasized.


Alterations in the fine structure of hepatocytes in hyperthyroid rats. Ultrastructural investigation of liver from ten radiothyroidectomized adult male albino rats, made hyperthyroid by administration of desiccated thyroid for eight to ten weeks, revealed changes in hepatic organelles, but no differences between centrilobular, midzonal and periportal hepatocytes of a single lobule. The mitochondria were enlarged with an increase in matrix density, but no increase in number of mitochondria or alterations in membranes or cristae was observed. The smooth endoplasmic reticulum appeared slightly increased and dilated in treated rats, while stacked cisternae of the rough endoplasmic reticulum were seldom seen. Large vacuoles, which often contained follicular material and frequently opened into the spaces of Disse, were observed at the periphery of hepatocytes. The vacuoles may arise from invaginations of the cell membrane along these spaces to increase the surface area and to act as channels for liver metabolites. Moreover, in hyperthyroid rats hepatic glycogen was uniformly depleted. Whether these changes were a primary effect of thyroid hormone or secondary to metabolic alterations is unclear.


Effect of acylation with eleostearic acids on the monoamine oxidase inhibitory potency of some hydrazine antidepressants in mice. The effect of incorporation of an eleostearoyl group into molecules of aralkylhydrazines on their monoamine oxidase inhibitory potency was investigated in vitro and in vivo. The results showed that on a molar basis the hydrazides possessed an in vitro potency lower than and an in vivo potency and acute toxicity comparable to those of the corresponding aralkylhydrazines. The sequence of the relative potency of aralkylhydrazines and their hydrazides was similar. The overall pharmacological profile indicated that these aralkylhydrazines retained their monoamine oxidase inhibitory properties when the free hydrazine nitrogen was acylated with an eleostearoyl group.


The charge-transfer constant. A new substituent constant for structure-activity relationships. A new, versatile constant accounting for the pi-complex formation ability of aromatic systems is proposed. The constant is derived from charge-transfer complex data of aromatic species (charge-transfer constant, CT). The applicability of CT in structure-reactivity relations is demonstrated. It is shown that the affinity of various inhibitors (32) and acetylcholinesterase is a function of CT and pi (Hansch hydrophobicity constant).


Studies on antianaphylactic agents. 4. Synthesis and structure-activity relationships of 3-(4-oxo-4H-1-benzopyran-3)acrylic acids, a new series of antiallergic substances, and some related compounds. The syntheses of trans-3-(4-oxo-4H-1-benzypyran-3)acrylic acid and a number of analogs shown to be highly active in antiallergic bioassays are described. These compounds are of possible value in the treatment of asthma. The structural requirements for biological activity are discussed with reference to the type of the substituents on the chromone ring or positions of linkage of the acrylic acid on the pyrone ring.


Synthesis and absolute stereochemistry of 5-alkyl-5-(3'-hydroxy-1'-methylbutyl)barbituric acid and 5-alkyl-5-(3'-hydroxy-1'-methylbutyl)-2-thiobarbituric acids. 5-Alkyl-5-(3-hydroxy-1-methylbutyl) barbituric acid (2) and 5-alkyl-5-(3-hydroxy-1-methylbutyl)-2-thiobarbituric acids (3) are matabolites of 5-alkyl-5-(2-pentyl) barbituric acid and 5-alkyl-5-(2-pantyl)-2-thiobarbituric acid, respectively. We have synthesized the four possible optical isomers of 2 and 3 by a procedure which established the absolute stereochemistry of each isomer. The two racemic pairs in each case were also prepared. The properties of these synthetic samples of 2 and 3 of known stereochemistry are compared to the properties of 2 and 3 which have been isolated from metabolism studies.


Aminobenzoic acid diuretics. 7. 3-Substituted 4-phenyl-, 4-arylcarbonyl-, and 4-arylmethyl-5-sulfamoylbenzoic acids and related compounds. Various 4-substituted 3-alkylamino-, 3-alkoxy-, 3-alkylthio-, and 3-alkyl-5-sulfamoylbenzoic acids related to known aminobenzoic acid diuretics were synthesized and screened for their diuretic properties in dogs. The tabulated results from a 3-hr test period revealed that generally the diuretic profile and potency could be retained when 3-alkoxy, 3-alkylthio, and 3-phenethyl were substituted for the 3-alkylamino moiety. The high potency of several 3-alkoxy-, 3-alkylthio-, and 3-phenethyl-4-benzoyl-5-sulfamoylbenzoic acids confirmed previous suggestions that the apparent diuretic effect of 4- and 5-alkylamino-6-carboxy-3-phenyl-1,2-benzisothiazole 1,1-dioxides originates from the corresponding 4-benzoyl-5-sulfamoylbenzoic acid derivatives due to an existing equilibrium in plasma. 4-Benzoyl-5-sulfamoyl-3-(3-thenyloxy) benzoic acid (118) is among the most potent benzoic acid diuretics hitherto synthesized and shows significant diuretic activity in dogs at 1 mug/kg. The results obtained with different 3-substituted 4-phenyl-5-sulfamoylbenzoic acids supported the earlier concept regarding the steric influence of the 4-substituent on the diuretic potency of sulfamoylbenzoic acid diuretics.


2-aryl-5-benzoxazolealkanoic acid derivatives with notable antiinflammatory activity. The synthesis and antiinflammatory activity of 5-substituted 2-arylbenzoxazoles are described. Initial screening on carrageenin-induced rat paw edema showed that alpha-methylacetic substitution in the 5 position was preferable to substitutions with the equivalent esters, amides, alcohols, amines or tetrazoles. Halogen substitution in the aryl ring led to the most active compounds which were 2-(4-chlorophenyl)-alpha-methyl-5-benzoxazoleacetic acid (14) and 2-(4-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid (29). These compounds were three to five times more active than phenylbutazone as assessed from ED30 values determined on rat paw edema 5 hr after single oral doses.


Antitumor agents. 11. Synthesis and cytotoxic activity of epoxides of helenalin related derivatives. Several epoxides of helenalin related derivatives have been synthesized in an effort to evaluate the potential significance of the epoxycyclopentanone moiety for cytotoxic activity against the growth of tissue culture cells originating from human epidermoid carcinoma of larynx (H.Ep-2). Helenalin (1) was converted to the monoepoxy derivative 2 and the diepoxy derivative 3 by alkaline hydrogen peroxide at different temperatures. Alternative synthesis of 2 was achieved by a convenient method of protecting the alpha-methylene grouping of the gamma-lactone, i.e., epoxidation of helenalin dimethylamine adduct 4, followed by treatment of the reaction product 5 with m-chloroperbenzoic acid. 2,3-Epoxy-11,13-dihydrohelenalin (8) was prepared by direct epoxidation of 11,13-dihydrohelenalin (7). Treatment of mexicanin A (9) with m-chloroperbenzoic acid gave, in addition to the 1,2-epoxy derivative 10, 1-alpha-hydroxyhelenalin (11) which furnished an acetate (12) upon acetylation. Catalytic hydrogenation of 10 yielded the dihydroepoxide 13. Treatment of 1 or acetylhelenalin (15) with Ac2O-p-TsOH gave the same acetyl dienol acetate (14). Epoxidation of 14 with m-chloroperbenzoic acid gave 1,beta hydroxyhelenalin (19) and a mixture of monoepoxides (17 and 18) which yielded 19 and 11 upon silica gel chromatography. The results of the cytotoxicity test of the compounds studied indicate that either an alpha- or a beta-epoxycyclopentanone moiety in helenalin related derivatives contributes significantly to the cytotoxicity. Furthermore, this cytotoxicity appears to be independent of the presence or absence of an alpha-epoxy-gamma-lactonic moiety.


Preparation and antitumor activity of a rearranged ester of cephalotaxine. For further evaluation of structure-activity relationships among the Cephalotaxus alkaloids, a "rearranged" ester (2b) of cephalotaxine was prepared, one which is an isomer of deoxyharringtonine (5a). The parent alkaloid, cephalotaxine (1a), was allowed to react with thionyl chloride to replace its hydroxyl group with chlorine. The resulting chloro compound 1b, on treatment with the silver salt of half ester 6, yielded 2b via an allylic rearrangement followed by further double bond migration. The new "rearranged" deoxyharringtonine isomer 2b proved to be inactive in the P-388 lymphocytic leukemia system and thus further delineated the structural requirements for antitumor activity in this series of alkaloids.


Preparation and antileukemic activity of some alkoxybenzo(c)phenanthridinium salts and corresponding dihydro derivatives. Salts of 2,3,8,9-tetrasubstituted alkoxy-, hydroxy-, and acetoxybenzo(c)phenanthridines as well as the corresponding 6-methoxy-5,6-dihydrobenzo(c)phenanthridines were prepared from appropriate chalcones through the tetralone and the 4b,10b,11,12-tetrahydrobenzo(c)phenanthridine intermediates. Complete O-demethylation of the tetramethoxybenzophenanthridine was achieved by fusion with pyridine hydrochloride at elevated temperature. The title compounds are active against leukemias L1210 and P388 in mice and some are curative against Lewis lung carcinoma. The importance of the nature of the environment about the nitrogen atom of these compounds and the substituents is discussed. 3,4-Dimethoxy-3,4-methylenedioxychalcone possesses activity against leukemia P388.


Carbocyclic prostaglandin analogs. 1. Steroid carboxylic acids. Certain structural similarities between prostaglandins with close-packed side chains and the perhydrocyclopentanophenanthrene nucleus of steroids prompted the synthesis and biological evaluation of 6beta, 17 beta-dihydroxy-5alpha-androstane-2alpha-carboxylic acid (30), its 6-deoxy derivative 28, and the corresponding 6-deoxy-2beta derivative 29 in an attempt to evaluate carbocyclic acids as potential prostaglandin analogs. Preliminary in vitro studies on isolated guinea pig ileum have shown weakly specific, prostaglandin-stimulated smooth muscle antagonism for 28 when compared with antagonism of bradykinin- and acetylcholine-induced contractions. Complete dose-response curves for 28 on prostaglandin-stimulated guinea pig ileum have shown a reduction in the maxium response and a decrease in the slope of the curve, indicating a noncompetitive type of inhibition for this type of derivative.


Active site titration and aminoacyl adenylate binding stoichiometry of aminoacyl-tRNA synthetases. A simple, rapid, and economical procedure is described for the determination of the number of catalytically competent active sites on aminoacyl-tRNA synthetases based on the stoichiometry of aminoacyl adenylate formation. On mixing tRNA synthetase, cognate amino acid, (gamma-32P)ATP, and inorganic pyrophosphatase under suitable conditions there is an initial rapid stoichiometric "burst" (rate constant k1) of depletion of ATP as enzyme bound aminoacyl adenylate is formed. There is then an initially linear decrease in ATP concentration as the complex hydrolyzes (with rate constant k2) releasing enzyme to form further adenylate. Provided k2 less than k1 the initial burst gives the stoichiometry of aminoacyl adenylate formation. Complexes which are too unstable to be isolated by the usual gel or nitrocellulose disk filtration procedure may be assayed in this way. This technique has been applied to five highly purified aminoacyl-tRNA synthetases. The tyrosyl-tRNA synthetase from Bacillus stearothermophilus is shown to bind only one aminoacyl adenylate per dimer.


Binding of calcium to phosphatidylcholines as determined by proton magnetic resonance and infrared spectroscopy. The interactions of calcium, magnesium, and the rare earth cations, cerium, neodymium, and praseodymium, with phosphatidylcholines were studied by proton magnetic resonance and infared spectroscopy. The calcium-induced chemical shifts for the various protons of phosphatidylcholine were C alpha choline greater than C beta choline greater than N(CH3)3 greater than C3 glycerol. No significant chemical shifts were observed for the C1 and C2 glycerol protons. None of the acyl chain protons were affected by the presence of calcium. Analysis of the salt-induced chemical shifts yielded binding curves with an excellent fit with the theoretical. The vicinal coupling constants for the various protons of phosphatidylcholine did not appear to change in the presence of calcium. The lanthanide-induced isotropic shifts for the protons of phosphatidylcholines followed the order Cbeta choline greater than C3 glycerol greater than Calpha choline greater than N(CH3)3. Examination of the P=O stretching band (1150-1300 cm-1) of phosphatidylcholines by differential infrared spectroscopy showed that this band shifted to shorter wavelengths in the presence of calcium. The site of calcium binding to phosphatidylcholines as deduced from the proton magnetic resonance and infrared data is discussed in light of the high specificity for calcium in enhancing the amino-catalyzed methanolysis of phosphatidylcholines.


The effect of succinate on the translational diffusion coefficient of aspartate transcarbamylase. Employing a differential optical mixing spectrometer, we have determined that the translational diffusion coefficient (DT) of aspartate transcarbamylase (AT-Case) decreases by (4.1 plus or minus 0.6)% in the presence of succinate and carbamyl phosphate. This result, combined with the change in the sedimentation coefficient determined by Gerhart and Schachman (1968) and repeated by us in the present work indicates that ATCase experiences an increase in frictional coefficient of approximately 4% due to succinate and carbamyl phosphate, and that any change in the enzyme's partial specific volume (v) under these conditions is less than about 0.3%. We have also measured (DT)20,w for ATCase as (3.75 plus of minus 0.11) x 10-7 cm2/sec. Combining this with our measured value of s20,2-o for ATCase of (11.7 plus or minus 0.2) x 10-13 sec and the calculated value of v of 0.738 cm3/g (Rosenbusch and Weber, 1971), we have determined the molecular weight of ATCase as (2.9 plus of minus 0.1) x 10-5. We have also observed the ATCase dimer and find that at a dimer concentration of 0.6 mg/ml the value of s20,w for the dimer is 15.8 x 10-13 sec and that this value decreases by (4.0 plus or minus 0.5)% upon the addition of succinate and carbamyl phosphate, a behavior essentially identical with that of the monomer.


Studies of specificity of deoxyribonuclease from salmon testes. A limited digest of thymus DNA with salmon testes DNase was composed of fragments larger than tetranucleotides. With exhaustive digestion mono-, di-, and trinucleotides were formed. At the (3') omega terminus G predominated, its frequency ranged from approximately 35 to 72% and increased with decreasing size of fragments. The error caused by the ribose-containing contaminants of DNA is significant, and should not be neglected in the evaluation of nucleoside frequency at the terminal positions of fragments.


Demonstration of two active sites on a monomeric aminoacyl-tRNA synthetase. Possible roles of negative cooperativity and half-of-the-sites reactivity in oligomeric enzymes. The dimeric tyrosyl-tRNA synthetase from Bacillus stearothermophilus which binds (tightly) only one tyrosyl adenylate or tyrosine per dimer is shown from kinetic, equilibrium dialysis, and gel filtration methods to have a second active site. ATP and tyrosine bind strongly and synergistically to the tyrosyl-tRNA synthetase tyrosyl adenylate complex, [E with Tyr similar to AMP], to give the complex [E with Tyr similar to AMP,ATP,Tyr]. This complex probably slowly forms an [E with (Tyr similar to AMP)2] complex which hydrolyses rapidly and does not accumulate. Similarly, the monomeric valyl-enzyme is shown to have two active sites. An [E with Val similar AMP,ATP,Val] complex is formed which probably slowly gives an unstable [E with Val similar AMP)2] complex. In view of this and the recent demonstrations that several aminoacyl-tRNA synthetases are composed of repeating sequences it is suggested that all of these enzymes have at least two active sites. The second site is difficult to detect by normal steady-state kinetic measurements and binding assays as these enzymes exhibit negative cooperativity of substrate binding hand half-of-the sites reactivity. A mechanism based on interacting sites is proposed that could account for these observations: changes in binding energy at one site may be coupled with catalysis at the other to give large rate enhancements. Howeever, this cannot account for the high specificity in the acylation of tRNA, A "VERIFICATION" PROCEDURE SEEMS ESSENTIAL. The proposed mechanism is quite general for catalysis and could be a reason why so many nonregulatory enzymes have subunits.


Crystallization and partial characterization of prenyltransferase from avian liver. Prenyltransferase (EC 2.5.1.1) has been obtained from chicken liver in a stable crystalline form. The enzyme has been shown to be homogeneous by polyacrylamide gel electrophoresis at pH 8.4, and by electrophoresis in sodium dodecyl sulfate containing gels. Electrofocusing of the crystalline enzyme results in a single sharp protein peak with a pI of 5.72. The protein is a dimer of molecular weight 86,000 whose subunits were not resolved by gel electrophoresis in sodium dodecyl sulfate. Michaelis constants of 0.5 muM for both isopentenyl pyrophosphate and geranyl pyrophosphate are 3-20-fold lower than those found for prenyltransferase from yeast or pig liver (Eberhardt, N., and Rilling, H. C. (1974), J. Biol. Chem. (in press); Dorsey, J. K., Dorsey, J. A., and Porter, J. W. (1966), J. Biol. Chem. 241, 5353; Holloway, P. W., and Popjak, G. (1967), Biochem. J. 104, 57). The enzyme primarily synthesizes farnesyl pyrophosphosphate from dimethylallyl or geranyl pyrophosphate although some geranylgeranyl pyrophosphate is formed under certain conditons. This is the first preparation of a stable crystalline enzyme of sterol and terpene biosynthesis.


Studies on the binding of acylaminoacyl-tRNA to rat liver 60S ribosomal subunits and its participation in the peptidyltransferase reaction. Peptidyltransferase with rat liver 60S subunits can be measured by the reaction between exogenous acylaminoacyl-tRNA and puromycin to form acylaminoacylpuromycin in the presence of 33% methanol, 0.3 M KCl, and 4 mM MgCl2. An assay system has been developed that allows examination of the binding of acetylphenylalanyl-tRNA to the ribosomal subunit "P" site, the transpeptidation of the 60S-bound substrate to puromycin, and the requirements for these individual steps. Binding of acetylphenylalanyl-tRNA to 60S subunits is stimulated several-fold by the addition of methanol, but the extent of binding in alcohol is the same in 60 as in 300 mM KCl containing solutions. Formation of acetylphenylalanyl-puromycin from 60S-acetylphenylalanyl-tRNA complex and puromycin stringently requires alcohol and the initial rate of the reaction is markedly greater at 300 mM KCl than at 60 mM KCl concentrations. Thus, alcohol and high concentrations of monovalent cation affect the reaction of an event subsequent to the binding of substrate to the "P" site. Preincubation of 60S subunits with poly(U), which stimulates the overall peptidyltransferase reaction, does not affect the amount of acetylphenylalanyl-tRNA that is bound to the particles; however, it markedly stimulates the initial rate of the transpeptidation reaction between 60S-acetylphenylalanyl-tRNA complex and puromycin. The codon specificity and the failure to affect binding with poly(U) suggest a role for the polynucleotide in the alignment or stabilization of the acylaminoacyl-tRNA on the "P" site rather than an effect on binding to either of the two particle sites or on the peptidyltransferase "active center." The effect of 40S subunits, which inhibit the overall peptidyltransferase reaction, on the binding of substrate could not be clearly interpreted since all three preparations, 60S subunits, 40S subunits, and combinations of 60S plus 40S particles, appear to bind acetylphenylalanyl-tRNA in the presence of methanol. However, the initial rate of peptide bond formation is several times greater with 60S-acetylphenylalanyl-tRNA complex than with 60S plus 40S particles containing bound acetylphenylalanyl-tRNA and the addition of 40S subunits to preformed 60S-acetylphenylalanyl-tRNA complex during the transpeptidation phase of the reaction in methanol does not affect the rate of peptide bond formation. Thus, 40S subunits seem to inhibit peptidyltransferase by forming less reactive particles in aqueous solutions. Contd.


Evidence for multiple forms and partial resolution of rabbit reticulocyte alpha- and beta-globin messenger RNA by gel isoelectric focusing. Isoelectric focusing in polyacrylamide gels has been used to fractionate and characterize RNAs from rabbit reticulocytes with major emphasis on globin mRNA. Reticulocyte 18S and 28S RNAs banded essentially as single components, well separated from each other and from the multiple forms of tRNA. By contrast, mRNA was resolved into a number of major and minor components. These bands were shown to contain intact globin mRNA by translation in a messenger-dependent cell-free protein synthesizing system. One major band was enriched slightly in alpha-globin mRNA and a second major band was enriched considerably in beta-globin mRNA. Reticulocyte supernatant mRNA, containing predominantly alpha-globin messenger, demonstrated only one major component which banded at the same position as the alpha-enriched band from total mRNA. Little of this material behaved as beta mRNA either by its focusing profile or by its translation products. Globin mRNA fractions with high and low 3' poly(A) contents also demonstrated differences in focusing distribution profiles. Although the basis for separating RNA by this technique has not been established, our results suggest that isoelectric focusing may offer a new approach to fractionation and characterization of specific mRNA species.


Preparation and preliminary characterization of purified ovalbumin messenger RNA from the hen oviduct. Preparation of milligram amounts of purified ovalbumin mRNA was accomplished by a sequential combination of precise sizing techniques with the selective purification of the poly(A) containing RNA by either affinity chromatography or adsorption to nitrocellulose filters. Several new techniques were applied to the purification of ovalbumin mRNA including Sepharose 4B chromatography and agarose gel electrophoresis in the presence of 6 M urea at pH 3.5. All the procedures used were adapted on a preparative sacle to the fractionation of large quantities of RNA. The purity of the ovalbumin mRNA was assessed by several independent criteria. (1) Purified ovalbumin mRNA migrated as a single band during both agarose-urea and formamide-polyacrylamide gel electrophoresis at pH 3.5 and 7.4, respectively. A single absorbance peak containing all of the ovalbumin mRNA activity was also found using linear formamide-sucrose gradients. (2) Determination of both total mRNA activity and ovalbumin mRNA activity in the wheat germ cell-free translation assay revealed that 92% of the total peptides synthesized were specifically immunoprecipitable with an ovalbumin antiserum. (3) Analysis of the total peptides synthesizied in the wheat germ assay by sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated the presence of a single radioactive peak that corresponded exactly to a specifically immunoprecipitable ovalbumin standard. Thus, based on these observations ovalbumin mRNA appears to be greater than 95% pure. A preliminary estimation of the molecular weight of purified ovalbumin mRNA by formamide-containing sucrose gradients yielded a value of 520,000 or approximately 1600 nucleotides. This value was considerably less than the value of 900,000 obtained by gel electrophoresis under denaturing conditions. Analysis of the poly(A) content by a hybridization assay with (3H)poly(U) revealed the presence of a poly(A) region containing approximately 70 adenosine residues. Thus, the size of the ovalbumin mRNA is considerably greater than that required to code for a protein of 387 amino acids. The availability of large quantities of purified ovalbumin mRNA should now permit a more thorough analysis of its physical and chemical properties.


Purine nucleoside phosphorylase. Microheterogeneity and comparison of kinetic behavior of the enzyme from several tissues and species. The purine nucleoside phosphorylases (PNPases) from human and rat erythrocytes and bovine spleen have been subjected to isoelectric focusing. The crystalline bovine spleen PNPase emerged as a single peak of pI = 5.4 whereas the rat erythrocytic PNPase was distributed into two variants of pI = 5.6 and 5.7 and the crystalline human erythrocytic enzyme produced six variants ranging from pI = 5.85 to 6.25. Treatment of human erythrocytic PNPase with dithiobisnitrobenzoate changed the enzyme to a more acidic form (pI = 5.05). The kinetic behaviors of these electrophoretic variants were studied and compared with the unresolved bovine erythrocytic PNPase. All six variants of the human erythrocytic PNPase and the two variants of rat erythrocytic PNPase displayed substrate activation at high concentrations of inosine and deoxyinosine. Bovine erythrocytic PNPase did not show activation with any of the nucleosides whereas with the bovine spleen enzyme activation occurred only with the deoxynucleosides, deoxyinosine and deoxyguanosine. The Km values for inosine, deoxyinosine, guanosine, deoxyguanosine, guanine, and hypoxanthine, where determined, ranged from 1.3 x 10-5 to 3.0 x 10-5 M for all the enzymes except the rat erythrocytic PNPase variants which have higher Km values for inosine (5.9 x 10-5 M, 8.3 x 10-5 M) and deoxyinosine (13 x 10-5 M, 20 x 10-5 M).


Library cooperation: wave of the future or ripple? Little of the literature in library cooperation applies specifically to library service for the health sciences. Based on experience in and observations of the cooperation of health science libraries, this short lecture reviews aspects of general library cooperation, networks, and consortia. The effects on library operation of several cooperative activities are enumerated and cooperation management is discussed briefly.


National Library of Medicine: international cooperation for biomedical communications. The international programs of the National Library of Medicine may vary in mechanism, but all share the common objective of improved medical research, education, and practice. They are a natural extension of domestic responsibilities and represent a sharing of time, talent, and resources. The programs may be service-oriented, cooperative efforts based on the computerized information storage and retrieval system (MEDLARS), or establishment of regional medical library programs. Policy and operational aspects are presented.


Components for consideration by emerging consortia. The Consortium for Information Resources of the West Suburban Hospital Association in Boston is presented as one model for library cooperation. It is described in generalized terms that may be of interest to other consortia planners, rather than as a model for exact replication. Four components are discussed in detail: (1) composite resources, (2) multi-institutional environment, (3) leadership, and (4) activities.


Cost-performance analysis of cataloging and card production in a medical center library. The unit cost of cataloging current English language monographs was studies and compared with the cost of purchasing catalog cards from a commercial source. Two hypotheses were proposed: (1) in-library costs for cataloging and card production are higher than those for the purchased-card method; (2) throughput time is faster for the in-library method. In addition, the data can be used to develop an analytical cost-performance model for administrative purposes. The data presented support the hypotheses. The model developed provides a mechanism for arriving at a cost for different levels of service and can be used to measure the performance of other alternative methods of cataloging. Implications for the use of CATLINE are discussed and suggestions for further studies are described.


Mechanization of library procedures in the medium-sized medical library: XV. A study of the interaction of nonlibrarian searchers with the MEDLINE retrieval system. The MEDLINE searchhes of sixteen nonlibrarian searchers at the School of Medicine Library, Washington University, were examined to determine the amount of utilization of the interactive capabilities of the system. The searchers made an average of 5.7 search statement modifications of their original searc statements and it was concluded that they did indeed use the interactive capabilities of MEDLINE.


Building a medical history collection.

Building a medical history collection. The importance of a clearly defined policy for building a medical historical collection is stressed in relation to the type of library and to the financial possibilities for building the collection and for the proper housing, preservation, servicing, and bibliographic control of such a collection.


A further perspective on medical history collecting. Part of the proper academic function of the medical librarian is to pay attention to the sources of modern medical knowledge. Secondary works on the history of medicine should be acquired and at least one subject field emphasized for collection in depth historically.


Health science libraries in the United States: a five-year perspective. Two surveys of the universe of health science libraries in the United States have been completed by the Medical Library Association's Committee on Surveys and Statistics over a five-year period. This paper compares, for 1969 and 1973, summary data on the universe, and the distribution of libraries, resources, personnel, and salaries.


Congenital oesophageal strictures due to cartilaginous rings. Two cases of distal oesophageal stricture secondary to tracheo-bronchial remnants containing cartilage are presented. The clinical histories and radiographic appearances of these lesions are discussed as is the postulated embryogenesis. A characteristic finding, when present, is the linear collection of barium projecting horizontally from the area of stricture, representing respiratory epithelial ducts.


Gall-bladder emptying measured by a radioisotopic method. A method of oral radioisotope cholecystography is described using 131I sodium ipodate. Gall-bladder emptying was measured by this method and radiographically: (a) in a model, (b) in 34 patients having oral cholecystography. There was a good correlation between the two methods of measuring volume changes, both in vitro and in vivo. The isotope cholecystogram has the advantage of a lower radiation hazard, and is the only satisfactory method of studying the onset, rate and duration of gall-bladder emptying. These may be easily measurable markers of disorders of the upper small bowel.


The "chest-abdomen sign" in familial dysautonomia. Both lung pathology and bowel distension are seen simultaneously on radiographs in familial dysautonomia. These are constant findings even in the absence of acute disease. One may thus speak of a "chest-abdomen sign" in this entity. Cases with this sign are presented in illustration and the differential diagnosis is discussed.


A comparison of x-ray spectra and outputs from molybdenum and tungsten targets. The relative merits of tungsten and molybdenum targets for mammography have been the subject of much discussion. Therefore the spectra and outputs (at constant potential) from molybdenum and tungsten targets, interchangeable in the same tube, have been measured with a Ge(Li) detector and ion chamber respectively. All conditions apart from the target material were unaltered. The spectra have been corrected for the distortions produced by the detector. The effects of filtration on spectra and exposure rates have been calculated and are in agreement with measured values. The spectra and outputs from molybdenum and tungsten targets filtered by aluminium and molybdenum have been investigated and the results are discussed with reference to mammography and the radiography of specimens.


Intravenous salbutamol in management of status asthmaticus. After the administration of intravenous salbutamol (100-300 mug) to 11 patients admitted to hospital with a severe exacerbation of asthma there was a mean increase in peak expiratory flow of 44% accompanied by a rise in pulse rate of 24 beats/min. Blood gas tensions showed a trend to improvement and there were no serious side effects. It is concluded that intravenous salbutamol is an effective and apparently safe bronchodilator in the management of acutely ill patients with severe asthma.


Effect of surgery on tumour-directed leucocyte responses. Leucocytes from 22 out of 26 patients with mammary carcinoma were significantly cytotoxic in vitro for cells cultured from mammary tumours though only two out of 17 of these preparations were cytotoxic for cells cultured from tumours arising at other sites. In the immediate postoperative period reactivity of patients' leucocytes with mammary tumour cells was undetectable but returned within one week of surgery. Leucocyte cytotoxicity may therefore offer a model in which the mechanism of postoperative depression of immunological competence may be investigated.


Study of dust mites in three Birmingham hospitals. Samples of dust were collected from wards in a general hospital, a geriatric hospital, and a skin hospital. Mites were found on the floors of all three hospitals; Surprisingly, the skin hospital showed fewer mites than the general hospital. The differences were attributed to the variation in ward activity, the number of visitors on the wards, and the differing cleaning regimens. Plastic-covered mattresses were almost completely free from mites, but foci were found on soft furnishings and on the jackets and overcoats of hospital workers. The total numbers of mites were small compared to those found in house dust, and hospital mites probably do not consitute a serious problem for asthmatic patients.


Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Eleven patients with asthma and aspirin hypersensitivity have been challenged with eight non-steroidal anti-inflammatory drugs. Each drug was given by mouth in at least three different doses and the patients' symptoms and peak expiratory flow (PEF) rates were observed over a three-hour period. Indomethacin 5 mg caused bronchoconstriction in all patients. Therapeutic doses of mefenamic or flufenamic acid caused bronchoconstriction in most patients. Phenylbutazone 200-400 mg induced a moderate fall in PEF. There were no reactions to therapeutic doses of salicylamide, paracetamol, benzydamine, and chloroquine. Microsomal prostaglandin synthetase, activity was inhibited by aspirin, indomethacin, mefenamic acid, flufenamic acid, and phenylbutazone. The other four drugs had no inhibitory effect. We suggest that precipitation of attacks in asthmatic patients hypersensitive to certain anti-inflammatory drugs is related to drug's ability to inhibit prostaglandin biosynthesis.


Cutaneous necrosis due to cetrimide application. Reports of necrosis caused by quaternary ammonium compounds, such as cetrimide, are rare. The case is reported of a 77-year-old woman who was admitted to hospital for four months with cutaneous necrosis of the left foot and leg owing to the topical application of cetrimide powder.


Oesophagoscopy, biopsy, and acid perfusion test in diagnosis of "reflux oesophagitis". The results of fibreoptic endoscopy have been assessed retrospectively in 71 patients referred for consideration of the oesophagus as the possible or probable cause of their symptoms. Gross endoscopic abnormality was uncommon but friability of the mucosa was seen in about half of the patients with typical symptoms of "reflux-pain" and a quarter of those without. The combination of radiological reflux and endoscopic abnormality--that is, true reflux oesophagitis--was seen in only a third of the patients with typical symptoms though much less commonly in those with atypical symptoms. Histological abnormality was common but did not relate well to symptom pattern. The results of the acid perfusion test were significantly related to symptom pattern though overlap was observed between the two symptomatic groups. Six of these patients had had or were awaiting surgery to correct reflux and they all had uniformly positive findings. This study confirms the value of the acid perfusion test in clarifying the diagnosis of reflux pain, espcially if the symptoms are difficult to assess. Endoscopy and biopsy added little further information of diagnostic value and could probably be reserved for the small minority of patients who have special problems such as blood loss or dysphagia or where clarification of a radiological lesion is required.


Pathophysiology of subendocardial ischaemia. Most forms of heart disease cause myocardial damage which often is confined to the deep (subendocardial) layer of left ventricular muscle. Much clinical and experimental evidence suggests that subendocardial muscle is prone to ischaemic damage, and a physiological mechanism for this vulnerability is described. Furthermore, experiments suggest that pressures recorded at cardiac catheterization can help to assess if there is subendocardial ischaemia in a variety of lesions in man.


The general practitioner and changes in obstetric practice. Compared with the 1960s fewer general practitioners today are obtaining a postgraduate diploma in obstetrics, and the future more stringent criteria for practitioners wishing to undertake this will probably restrict the numbers of family doctors wishing to practise in this field. More deliveries are being performed in institutions--either in consultant or general-practitioner units. Morever, within a decade probably few G.P.s will attend during normal labour or delivery, which can and should be conducted by midwives. In future, therefore, G.P.s should have a new role in obstetrics, being responsible for some antenatal supervision and postnatal care, including postnatal examinations, taking a cervical smear, and advice on birth control.


Effects of amphetamine isomers and neuroleptics on self-stimulation from the nucleus accumbens and dorsal noradrenergic bundle. In an attempt to examine the possible role of noradrenergic (NA) and dopaminergic (DA) systems in intracranial self-stimulation (ICS), the rate-increasing effects of D- and L-amphetamine on ICS were determined in rats with nucleus accumbens electrodes (DA placement) or dorsal NA bundle electrodes (NA placement). The D-isomer produced a significantly greater increase in ICS than did the L-isomer in animals with dorsal NA bundle electrodes. In contrast, the amphetamine isomers were equipotent in facilitating ICS in animals with nucleus accumbens electrodes. These data, together with previous observations, suggest that there exists a correlation between equipotential effects of D- and L-amphetamine and DA electrode placements on the one hand, and prepotent effects of D-amphetamine and NA electrode placements on the other. Pimozide and haloperidol, which in low doses are thought to specifically block DA receptors, decreased ICS obtained from both DA and NA electrode placements. It is suggested that neuroleptic drugs may produce a general disruption of operant behavior and that the decrease in ICS produced by these agents does not therefore necessarily implicate dopaminergic mechanisms in the neurochemistry of reward.


A consideration of ketamine dreams.

A consideration of ketamine dreams. This study was designed to see whether covering of the eyes during and after ketamine anaesthesia would reduce the incidence of dreams. One hundred and fifty patients, randomly divided into three groups, underwent therapeutic abortion with ketamine as the sole anaesthesia. One hundred patients had their eyes completely covered, 50 in the operating room only and 50 in the operating room and in the recovery room. The third 50 were controls, with their eyes uncovered. All patients were questioned post-operatively about dreams, nausea and vomiting, headache, dizziness and experiences, and also how frequently they dreamed at home. Although covering the eyes in the recovery room only reduced the incidence of dreams marginally, it became obvious that the patients who dreamed after ketamine (in all 3 groups) were those who normally dreamed at home. There were 82 patients who were recorded as not being home-dreamers, and only two of these dreamed after ketamine. In contrast, of the 68 home-dreamers, 50 dreamed after ketamine, and 17 of these had unpleasant dreams. In the home-dreamers, covering the eyes reduced the incidence of dreams from 86 per cent in Group 1 to 72 per cent in Group 2 and 64 per cent in Group 3. It is suggested that goggles may be advantageous when dealing with home-dreamers, and a question about the patient's tendency to dream should be included in the preoperative questioning. Alterations in premedication and the use of a quiet dark room during recovery may even further reduce unpleasant dreams in this group.


Anaesthetic technicians in the province of Quebec. I have described the recent history of the development of anaesthetic technicians in the Province of Quebec. Anaesthetic technicians will have the same training program as inhalation therapists. This program is organized through the CEGEP (College D' Enseignement General et Professionnel) system in Quebec. The Association of Anesthetists of the Province of Quebec (AAPQ) has sponsored inhalation therapy and now sponsors fully the program for training anaesthetic and technicians. The Government has approved the program. It is now in operation and the first anaesthetic technicians in Quebec have in fact graduated in 1973.


A simplified scoring system for the post-operative recovery room. A new and very simple scoring system for recording post-anaesthetic recovery is described. When numerical values are assigned to factors indicating recovery progress or lack of it is obvious. The records may have medico-legal value. It can be incorporated into the Recovery Room Record.


Blood substitutes.

Blood substitutes. Substitutes for whole blood include blood fractions such as plasma, serum albumin and other fluids of various kinds which are not derived from blood but are used as plasma volume expanders; these, include the usual crystaloid intravenous solutions. Since in comparison to blood far more of these later solutions are given intravenously, a thorough knowledge of plasma volume expanders is essential. The first use of such expanders in human patients was by Hogan in 1915. He used colloidal gelatin and noted an improvement in blood pressure in shock. In 1945, Gronwall and Ingelman advocated the use of dextran in shock. The reguirements for an acceptable plasma substitute are: a satisfactory colloidal osmotic pressure, constand composition at reasonable cost, a viscosity suitable for intravenous administration, stability in prolonged storage at variable temperatures, and sterilization by autoclaving. Such substances must be either fully excreted or metabolized, and must cause no early or late tissue damage. They must be non-antigenic and pyrogen free. They must cause no change in the blood such as haemolysis, R.B.C. agglutination, increased sedimentation rate and no impairment of haemostasis. The presently available plasma expanders include blood derivatives (plasma, albumin), modified protein (gelatin, oxypolygelatin), polymerized carbohydrates (dextran) and plastics (polyvinyl pyrrolidone-PVP). All these substances expand plasma volume, decrease haematocrit and plasma proteins, increase sedimentation rate and blood pressure. Dextran, PVP and geletin do not alter hepatic function. Dextran and gelatin have no deleterious effects on renal function. Features of the clinically used plasma expanders are: 1. Fresh Frozen Plasma Fresh frozen plasma contains all clotting factors except platelets. The risk of the transmission of hepatitis is present as it is with whole blood. 2. Plasma Protein Fractions Plasma protein fractions are free of hepatitis virus, but may cause arteriolar dilatation and hypotension. 3. Serum Albumin Serum albumin is a concentrated blood protein fraction. It is salt poor, stable and does not transmit the virus of hepatitis. Since it has a high oncotic pressure it is necessary to give significant quantities of clear fluids with it. It is expensive, scarce, and dilutes the clotting factors. It is, however, a first choice for emergency treatment of shock; 4. Dextran The dextrans may be of medium or low molecular weight. They are inexpensive and readily available, and do not transmit the virus of hepatitis. In large amounts they cause a coagulation defect and may be antigenic. Continued.


Prediction of arterial carbon dioxide tension during controlled ventilation with a modified Mapleson D system. Based on measurements of arterial CO2 tension in 132 adult patients, a curve was constructed relating fresh gas inflow and arterial CO2 tension for a modified Mapleson D system. In patients on controlled ventilation using a ventilating volume greater than the predicted respiratory minute volume, it was found that the arterial Pco2 can be predicted from the fresh gas inflow with an accuracy sufficient to be clinically useful.


Early changes in lung water after haemorrhagic shock in pigs and dogs. This study has demonstrated a 34 per cent rise in lung water after shock and retransfusion of blood. This extra lung water was associated with increased pulmonary artery pressure, increased plumonary vascular resistance and reduced myocardial performance. These findings occurred despite the failure of arterial pressure to return to normal after retransfusion blood. Although this increased lung water is less than anything which can be detected clinically it may represent the beginnings of the shock lung syndrome as oedema progresses over period of weeks. A reasonable approach to the problem should include attempts to reduce the elevated plumonary vascular resistance. NaHCO3 should be infused before or during administration of the first bottle of blood in an attempt to improve myocardial function and reduce pulmonary vascular resistance. Fluids should not be infused simply to return arterial pressures in the pulmonary vascular bed. Pulmonary artery and wedge pressure monitoring with Swan Ganz catheters may improve the management of shock patients.


Use of aspirin in haemorrhagic shock.

Use of aspirin in haemorrhagic shock. Haemorrhagic shock was induced in two similar groups of dogs for two hours. One group received aspirin before shock and the other group served as a control. When blood was retransfused the PVR which was markedly elevated during shock returned to pre-shock value in the aspirin group but was elevated 100 per cent in the control group, despite correction of a cidosis. Aspirin reduces collagen-induced platelet aggregation and thereby inhibits the formation of platelet micro-emboli without affecting the coagulationfactors. This effect of aspirin is thought to be responsible for the lowering of the elevated PVR to pre-shock values in the aspirin group following retransfusion. Because of the metabolic acidosis associated with the shock state, concurrent administration of sodium bicarbonate is recommended when transfusing shocked patients with blood. A clinical trial of aspirin in early treatment of shocked patients as well as for prophylaxis in high risk situations is justified.


Chloroprocaine-bupivacaine sequence for obstetric extradural analgesia. Two case reports, one a vaginal delivery, the other a Caesarean Section, have been presented to demonstrate the rationale of employing a chloroprocaine-bupivacaine sequence for extradural analgesia in obstetrics. Use of chloroprocaine for initiation and bupivacaine for maintenance of the block offers at least three advantages: (1) onset of pain relief is prompt while duration is prolonged; (2) more than one "test" dose of chloroprocaine may be employed with safety in rapid succession; (3) two drugs with different metabolic patterns are used, each in reduced amount.


Anaesthesia for posterior cervical osteotomy. We have studied 22 consecutive cases of posterior cervical osteotomy done at the Toronto East General Hospital between October 1967 and November 1973. The anaesthetic management is discussed in some detail and consists of psychological preparation of the patient, and neuroleptanalgesia with infiltration with local anaesthetic by the surgeon. The reasons for this choice of technique have been discussed in some detail. There were no deaths during operation, but one patient suffered collapse on the table, which was thought to be due to air embolism. One patient died three weeks post-operatively of pulmonary embolism. Experience in anaesthetizing patients who require operation after previous posterior cervical osteotomy is mentioned briefly and techniques are recommended for successful management of such cases.


Direct arterial pressure monitoring from the dorsalis pedis artery. The arteria dorsalis pedis, when clearly palpable, is a suitable artery for direct arterial blood pressure monitoring. The systolic pressure and the pulse pressure are likely higher in the dorsalis pedis artery when compared to the radial artery but there is no clinically significant difference in mean pressures. In plethysmographic studies it was found that in 16 per cent of the patients examined the pulse in the second toe disappeared after occlusion of the dorsalis pedis artery indicating that it carried the main blood supply to the toes. Although no complications have resulted from cannulation of the dorsalis pedis artery in our practise, some caution is in order and preliminary testing may be advisable even if the posterior tibial artery is distinctly palpable.


Prevalence and significance of hepatitis B surface antigen in a general hospital. Over a 6-month period 2025 patients admitted to New Mount Sinai Hospital, Toronto were screened for hepatitis B surface antigen (HBsAg) by counter-immunoelectrophoresis (CIEP) and radioimmunoassay (RIA). CIEP detected 12 HBsAg-positive patients and RIA 16. RIA is therefore the more sensitive test for HBsAg. Of the 16 patients 2 had liver disease previously diagnosed, 3 had malignant disease and 11 were asymptomatic carriers. Of the 11 carriers all were born in countries where the carrier rate is known to be high. Routine screening of hospital patients on admission is of no value in detecting unsuspected liver disease but is of value in detecting asymptomatic carriers, which is of importance for the patient and his family. Routine screening tests for HBsAg in Canadian hospitals that treat many patients born in countries with a known high HBsAg prevalence is recommended. Routine screening is also recommended in all hospitals in Mediterranean and Asian countries.


Hepatitis B antigen in Montréal blood donors: childhood institutionalization as an epidemiologic factor. In 1971 the Canadian Red Cross blood tranfusion service instituted routine screening for HBAg of all blood donors, using nationwide a standardized counterimmunoelectrophoretic technique. The prevalence of carriers in the Province of Québec is unusually high (0.51%), being 3 to 12 times higher than in the other nine provinces. Among the carriers found in the Montréal area 289 volunteered to be seen by our group for an extensive interview and a series of laboratory tests. There were 243 men and 46 women; their ages ranged from 18 to 55, 90% being less than 40. Twenty-nine were of foreign origin and 260 were born in Canada. The epidemiologic data revealed that the reservoir of HBAg carriers among the blood donors of the Montréal area was found predominantly in the autochthonous population of French origin. Moreover, it appeared that 149 (52%) had lived in institution when they were infants or children: 127 were orphans and had been placed in institutions as newborns or babies, and 22 others had lived in institutions for at least 1 year between the ages of 5 and 10. This was by far the most important single epidemiologic factor that could contribute to the explanation of the abnormally high prevalence of HBAg carriers in the population studied.


Hepatitis B antigenemia among blood donors: the changing scene. For the period May 1973 to August 1974 inclusive, the mean prevalence of hepatitis B antigenemia (HBsAg) in all Canadian provinces (per 100,000 population) was, for "first-time" donors, 242 and, for "repeat" donors, 77. A modification of counterimmunoelectrophoresis was used in all 16 regional transfusion centres. The findings confirm the previously noted high prevalence for the Province of Québec and the continuing relatively high prevalence for Canada. The prevalence of HBsAg among donors could be lessened by institution of the following measures: development of a more effective technique for the screening of hepatitis carriers, study of nonparenterally transmitted hepatitis, better reporting of post-transfusion hepatitis, and greater discrimination in prescribing blood and blood components.


On the delivery of intensive care.

On the delivery of intensive care. A 12-bed medical-surgical intensive care unit in a provincial, university-affiliated teaching hospital had 810 admissions during an 18-month period. Most patients were admitted under the care of a family physician. Quality care in the ICU was maintained by the efforts of dedicated unit managers, specialists and house staff. The overall mortality in the ICU of 8.1%, when added to the post-ICU mortality of 2.7% (giving a total hospital mortality of 10.8%), compares favourably with the best reported figures. Strong emphasis on selection of patients with potentially reversible disease, prompted in part by the limited facilities, may have played a role in yielding such favourable statistics. It is possible to retain participation of all members of the health care team during the brief phase of severe illness requiring intensive care.


The pharmacist as a provider of primary care. A survey was undertaken to document the primary health care role of the pharmacist in London, Ont. Of particular interest was the volume of primary contacts, the type of problem handled and the advice given by the pharmacist. The contribution of pharmacists in primary health care was found to be large, with neighbourhood pharmacies being the most active. Eighty percent of all problems were handled by recommending an over-the-counter drug. The pharmacist appears to be comfortable in this function, although a conflict may exist between his professional and merchant roles.


Career and training patterns of students entering Canadian medical schools in 1965. This paper follows the careers of the 1128 students who entered Canadian medical schools in 1965, most of whom graduated in 1969. The type of career pursued (whether general or specialty practice or some combination thereof), the type of specialty undertaken, the place of internship and residency training and the 1973 practice location of the graduates are examined. The wide variation in careers followed by the 12 schools' graduates provides the major focus of the paper.


Pathogenesis of the "sentinel headache" preceding berry aneurysm rupture. Pathologic examination in a case of fatal intracerebral hemorrhage from a berry aneurysm showed that the "sentinel" or warning headache in this patient was due to the leakage of blood into the subarachnoid space through a previous small tear in the wall of her saccular aneurysm. Oribital pain, transient, dysphasia, dizziness and, later, meningismus might have prompted the performing of a lumbar puncture to determine the presence of blood in the cerebrospinal fluid. This type of event is the likely pathogenetic mechanism for the premonitory headache that may precede a lethal rupture of a saccular aneurysm.


Reappraisal of hemiblock.

Reappraisal of hemiblock. The left bundle branch separates into the left anterior and the left posterior divisions. The impulse travels to the left ventricle via both divisions when they are intact. When one division is blocked, the diagnosis is hemiblock. Diagnostic criteria for left anterior hemiblock are marked left axis deviation, small Q wave in lead I and small R wave in lead III, little or no prolongation of the QRS interval, and no evidence of other causes of left axis deviation. Criteria for left posterior hemiblock are marked right axis deviation, small R wave in lead I and small Q wave in lead III, little or no prolongation of the QRS interval, and no evidence of other causes of right axis deviation. A pure form of hemiblock is not uncommon, especially during acute anterior myocardial infarction, but right bundle-branch block often coexists with hemiblock. Like left bundle-branch block, hemiblocks rarely occur in healthy persons. They are commonly associated with coronary or hypertensive disease or both and are less commonly associated with cardiomyopathies and calcified aortic disease.


Anemia in adolescence. 2. Hemoglobinopathies and other causes. Many complex forces are at work during adolescence which can contribute to the occurrence of anemia. Careful consideration of the entire patient should enable a physician to identify the unusual as well as the more common causes of anemia in this age group. Anemia in teenage girls is primarily due to menstrual iron loss. In boys, borderline diets and the demands of rapid growth predominate as causative factors. Hemoglobinopathies (thalassemia, sickle cell disease), G6PD deficiency, infectious mononucleosis, and illicit drug use account for small proportions of cases.


Distribution of primary cancers of the liver in the Province of Québec. All records of primary liver cancer reported to the tumor registry of the Province of Québec from 1969 to 1972 were collected and were classified according to sex, age and place of residence. Men had higher incidence of primary liver cancer and the disease developed at an earlier age in men than it did in women. There was a noticeable difference in the number of cases in rural and urban areas, and a significant difference in the incidence in the 10 districts of the province. Cases in urban areas were clustered in a few industrialized cities. Our findings are in agreement with previous reports that show a relationship between primary cancer of the liver and the presence of chemicals in the environment.


Psoriatic arthritis in severe psoriasis. Of 100 patients admitted to hospital for treatment of psoriasis, 32 had clinical or radiologic evidence of psoriatic arthritis and 17 had both types of evidence. Eight had radiologic evidence of spinal or sarroiliac involvement without symptoms and seven had clinical evidence of peripheral arthritis without radiologic evidence. Patients with psoriatic sacroilitis and spondylitis were most likely to have typical radiograpic changes. It was concluded that psoriatic arthritis is common in patients with severe psoriasis and that is associated with more extensive skin disease than is found in patients without arthritis.


Clinical aspects of atypical mycobacterial infection. Atypical mycobacterial infections may give rise to various clinical difficulties. Case reports of six patients--three adult patients with pulmonary lesions, two children with cervical lymphadentis and one patient in whom the atypical mycobacterium appeared to be present as a commensal--illustrate these difficulties. Determination of the significance of the organism and differentiation of condition from tuberculosis and others requires consideration of the clinical picture, the results of skin testing, histologic features and cultural characteristics. Three patients, including the two children, were treated with a combination of surgery and chemotherapy, with satisfactory results. An elderly patient with chronic bronchitis and a pulmonary infection due to M. kansasii was treated successfully with antiuberculosis agents alone. Chemotherapy is being tried on a  fifth patient with cavitary disease due to M. intracellulare, but is seems likely that an operation will also be required.


Hepatic artery ligation in treatment of carcinoid syndrome. In a patient with malignant carcinoid syndrome with metastasis to the liver, cardiac lesions, pulmonary hypertension, pellagra-like skin lesions and depression developed. Her disability progressed despite medical therapy and two courses of chemotherapy. The primary tumour had been resected but the metastatic mass in the liver could not be resected because of its anatomic position. The dramatic improvement after hepatic artery ligation was correlated with urinary 5-hydroxyindole acetic acid excretion.


[Teaching of morphologic sciences in 13 Canadian medical schools (author's transl)]. A survey of teaching of morphologic sciences in Canadian medical schools has shown that few radical changes have taken place in most schools. The survey has also shown the following: (a) department chairmen have a major influence on teaching of morphologic sciences; (b) they are worried about the diminishing time alloted to them; (c) students, by their choice of electives, do not seem to share that worry; (d) lectures remain popular, as does disection in most schools; and (e) audiovisual methods, especially rediology, are becoming more popular but are not yet used on a very large scale.


Criteria of brain death: review and comparison. The concept of brain death has become important in law and medicine, replacing in some instances the concept of circulatory arrest as a definition of death. Yet, brain death has not been established as a clear clinical or pathologic entity, a point brought out here by comparison of criteria for identification. The need for more research is evident.


Symposium theme: a conceptual approach to integrated cancer therapy. The term "integrated cancer therapy" reflects treatment in which the decision making process is disease oriented rather than specialty or modality oriented. Two phases of integrated cancer therapy can be defined, the first being a determination of the treatment failure mechanisms for each of the variable clinical presentations of specific neoplasms. The second phase, integration of the available treatment modalities, is aimed at neutralizing the inherent weakness of any one method with the strength of other methods. A general strategic approach is presented.


Inhibitory effect of prolonged Corynebacterium parvum and cyclophosphamide administration on the growth of established tumors. The present study was carried out to investigate the effects of prolonged administration of C. parvum alone and in combination with cyclophosphamide for the treatment of established, measurable C3H tumors. The continued weekly administration of C. parvum by itself provided a limited but significant inhibitory effect on tumor growth and significantly prolonged survival. Intraperitoneal and intravenous administration was found to be more effective than the subcutaneous route. When C. parvum was administered asynchronously in combination with cyclophosphamide at weekly intervals a tumor growth inhibitory effect was achieved which was greater than that resulting from either agent along. Such an effect was consistently obtained and was seemingly independent of the sequence of drug administration. When cyclophosphamide preceded the initial C. parvum administration, arrest in the rate of tumor growth occurred, resulting in infinite tumor doubling time for the duration of observation (greater than 90 days). The combination of C. parvum and cyclophosphamide produced a more effective inhibition of tumor growth than did BCG and cyclophosphamide similarly employed. The importance of these findings relative to clinical application is considered. While the significance and genesis of the marked desmoplastic reaction characterizing tumors from animals treated with C. parvum and cyclophosphamide is at present speculative, consideration is given to the possibility that this could signify a host response against tumor growth.


Concepts for systemic treatment of micrometastases. If total tumor cell kill is a requirement for "cure," as it probably is for at least some tumors, treatment of micrometastases containing less than or equal to 10-6 viable tumor cells is a problem facing all cancer therapists. Metastatic tumor cell foci of less than or equal to 10-6 cells, particularly if widely disseminated, are, in the main, grossly undetectable and are, therefore, the proper targets for the chemotherapist and the immunotherapist. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable cells undergoing active cell replication) is inversely related to population size. Micrometastases should, therefore, be more sensitive to antimetabolite (cell-cycle-specific) anticancer drugs than the larger, grossly apparent, primary tumor from which they were derived. In fact, drug response of the primarytumor may not reliably predict the sensitivity of micrometastases to cell-cycle-specific drugs. In addition, optimal drug treatment scheduling for effective, but noncurative, drugs against clinically recognized tumors may not predict optimal scheduling of the same drugs against micrometastases. This is shown particularly in cell-cycle-specific drugs, since the generation time of tumor cells in small population foci (less than 10-7 cells) is often significantly shorter than in larger population foci (greater than 10-7 cells). Since first-order cell kill kinetics characterizes effective drug kill of tumor cells and the best currently known anticancer drugs have variable but generally limited tumor cell kill potential, drug treatment of likely micrometastases should be started as soon after the end of likely noncurative radiologic or surgical treatment as possible. Experimental data indicating that significantly smaller numbers of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence suggest that small populations of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than similar sized populations remaining in situ after surgery. Experimental data supporting the above concepts are presented and discussed.


Nodular mesothelial hyperplasia in hernia sacs: a benign reactive condition simulating a neoplastic process. Thirteen cases of hernia sacs exhibiting mesothelial hyperplasia of such a degree as to simulate a malignant process are presented. There were 2 infants, 7 children, and 4 adults. The hernias were inguinal in 12 patients and epigastric in the remaining. In 7 cases (52%) there was a history of trauma or some other source of injury to the sac, such as incarceration. Microscopically, solid nodules of atypical mesothelial cells were seen in the hernia sac, either free or attached to the wall. Mitoses, multinucleated cells, and "strap cells" were sometimes present. Clues to the mesothelial nature of the proliferation were the cytologic features and the presence of similar changes in the lining of the hernia sac.


A clinicopathologic study of 92 cases of granulosa cell tumor of the ovary with special reference to the factors influencing prognosis. Ninety-two cases of granulosa cell tumor of the ovary have been studied. The clinical and pathologic data from this group were similar to that obtained in previous series. Because of the long natural history of many granulosa cell tumors, crude death rates over a relatively short period give little indication of the true malignant potential of these neoplasms and hence corrected survival rates were calculated; these show that, if no patient died from any other disease, approximately half of the women with this neoplasm would die, as a result of the tumor, within 20 years. Factors indicating a relatively poor survival rate were: age over 40 at the time of diagnosis, a presentation with abdominal symptoms, a palpable mass, a solid large tumor, bilateral tumors, extraovarian spread, and numerous mitotic figures in the tumor. It is suggested that all granulosa cell tumors should be considered as malignant and that the factors pointing to a poor prognosis are those indicating that a particular tumor has been diagnosed at a late stage in its natural history, either because it has been present for a long time or because it is highly malignant. There are no definite criteria for defining the prognosis in a case in which the tumor has been removed at any early stage in its natural life history.


Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). I. Observations concerning the multicentricity of mammary cancer. Microscopic foci of multicentric cancer were detected in 121 of 904 breasts surgically removed for a clinically overt, invasive cancer. This incidence of 13.4% is regarded as a conservative estimate since examples of such lesions occurring in the same quadrant as the dominant mass, except in those instances in which the latter was present within the tail of the breast or beneath the nipple, were excluded from the analysis. Further, this data was obtained from only one randomly selected block of the quadrants, and in 41% of the cases only one or two were available for study. Multiple multicentric cancers were found in the same breast in two and three quadrants in 11.6% and 5.8% of the cases respectively. In 9.3% of the cases the multicentric cancers were designated as noninvasive (lobular in situ and/or intraductal) and in 4.1% invasive. An attempt to correlate the occurrence of multicentric cancers with a large number of pathologic and some clinical features disclosed a statistically significant association between multicentricity and grossly nonencapsulated dominant cancers with maximum diameters greater than 5 cm, the presence of a moderate or marked intraductal component and noninvasive cancer in its vicinity, and tumor involvement of the nipple. In addition, it was noted that there was a greater likelihood that the primary tumor was of the lobular invasive type and that the overlying skin was involved when the multicentric cancer was invasive rather than noninvasive. Lymphatic tumor emboli were observed in quadrants in 18 or 2.0% of the cases. Although the number of examples is small, nevertheless positive associations were noted with the occurrence of primary tumors that were in the left breast or beneath the nipple and were not grossly circumscribed, but exhibited a nuclear grade of 1, intralymphatic and blood vessel invasion, calcium, and involvement of the overlying skin as well as nipple. In addition, patients with such intralymphatic extension were more likely to have clinically detectable lymph nodes of which four or more contained metastases. The relationship of these findings to the rationale of such procedures as segmental resection in the surgical treatment of breast cancer is discussed.


A family with atypical colonic polyposis and gastric cancer: a three-decade followup. A three-decade followup of a family in whom multiple colonic polyps were found in 5 out of 11 members of one generation is presented. In 3 of these members, cancer was present in the colorectum. The clinical picture as well as the pathologic findings differ from those seen in familial polyposis. In the previous generation two cases of gastric cancer were found, as well as one case of colonic cancer. The high incidence of colonic polyps and cancer suggests a hereditary disease, but the mode of transmission cannot be definitely determined without following this family for a longer period.


Lymphatic drainage of the breast on and through the pectoral muscles: importance in breast cancer. As proponents of lesser procedures have called into question the necessity of removing the pectoral muscles in surgery for cancer of the breast, there has been a need to establish accurately the relationship of the lymphatics to the pectoral muscles and their fascia. This problem has been approached using the technique of high resolution autoradiography. After histologic review of pectoral muscles from rabbits into whom a tritiated high-molecular-weight dextran was injected subareolarly, a high degree of labeling was found deep within the septa of the pectoral muscle bundles as well as along the investing fascia. It was concluded that lymphatic draining mammary lymph pass deep within the pectoral muscles in this species.