Effect of experimental azotemia on renal clearance of furosemide in the dog. The clearance of furosemide (F), whose renal tubular transport shares the classical characteristics of the organic acid system, was determined in dogs with varying degrees of azotemia and compared with tetraethylammonium (TEA), an organic base. Two normal and eight azotemic dogs [blood urea nitrogen (BUN), 12-273] were studied. Azotemia was produced by bilateral uretero-venous anastomoses. The left renal vein and ureter were cannulated and renal blood flow (RBF) was measured by electromagnetic flowmeter. Simultaneous left renal clearances (C) of subpharmacological doses of TEA-14C and furosemide-14C were determined at seven 30-minute intervals. Initial loading doses were followed by continuous maintenance infusions. For TEA, clearance (1.5 ml/min-g +/- 0.2 S.E.M.) and extraction (E) (0.83 +/- 0.02) are independent of the degree of azotemia. Renal plasma flow (RPF), calculated as CTEA/ETEA, agreed closely with directly measured RPF (2.0 ml/g-min +/- 0.3). RPF was independent of azotemia. To allow for individual differences in the animals in RPF, the ratio CTEA/CF was used. CF (1.07-0.17 ml/min-g) and EF (0.54-0.06) decreased as a linear function of the increase in uremic serum: (see article). Furosemide and its principle metabolite were greater than or equal to 97% of the furosemide portion of the radioactivity. The metabolite did not increase with time in either plasma or urine. After acute administration of exogenous urea to two dogs (BUN 170 and 253) CTEA/CF was unrelated to BUN. Thus, the CF decreases proportionately with progressive azotemia and is not related to RBF, exogenous urea or metabolite. This suppression of renal tubular secretion of furosemide may partially account for reduced therapeutic efficacy of furosemide in azotemia.


Is the peripheral sympatho-adrenal nervous system necessary for renal hypertension? Two-kidney renal hypertension in the rat (left renal artery narrowing) was shown to be dependent on the vasoconstrictor action of renin-angiotensin throughout its time course as evidenced by the simultaneous: 1) rise in blood pressure; 2) elevation in plasma renin activity; and 3) vasodepressor sensitivity to the converting enzyme inhibitor SQ-20881. One-kidney renal hypertension (left renal artery narrowing plus contralateral nephrectomy), in contrast, was shown to be independent of the vasoconstrictor action of renin-angiotensin. The role played by the sympathetic nervous system in one-kidney renal hypertension was studied in animals in which the peripheral sympathetic nervous system was completely ablated by chronic guanethidine treatment and adrenal demedullation. The completeness of the sympathectomy was pharmacologically confirmed by 1) marked reduction of tyramine vasoconstriction; 2) lack of sensitivity to ganglionic blockade (pentolinium); and 3) complete reversal of blood pressure responsiveness to phentolamine. When such animals were subjected to unilateral nephrectomy and left renal artery constriction, they still developed a significant hypertension compared to their unclipped controls and the hypertension remained renin independent. One-kidney renal artery-clipped animals that were only neonatally guanethidine-treated or were only adrenal-demedullated, also developed low-renin renal hypertension. It can be concluded that one-kidney renal hypertension is not only low-renin hypertension but that it can develop in the complete absence of adrenal medullary and peripheral adrenergic function.


Influence of prostaglandins E, A and F on vasoconstrictor responses to norepinephrine, renal nerve stimulation and angiotensin in the feline kidney. The effects of intrarenal infusion of prostaglandins (PGs) of the E, A and F series on renal vascular resistance and on vasoconstrictor responses to renal nerve stimulation (RNS), norepinephrine (NE) and angiotensin (A) were determined in the in situ feline kidney under conditions of controlled blood flow. Infusion of PGE2 (3 and 0.3 mug/min) and PGE1 (3 mug/min) resulted in a marked decrease in renal perfusion pressure and a reduction in responses to all vasoconstrictor stimuli. PGE2 (0.03 mug/min) did not alter perfusion pressure. However, responses to RNS and A but not to NE were attenuated. PGA2 (3 and 0.3 mug/min) had no significant effect on perfusion pressure. PGA1 (3 mug/min) resulted in a transient decrease in renal vascular resistance which was not maintained during the infusion period. PGA2 (3 mug/min) reduced the response to RNS at 10 and 30 cps and reduced the response to A, whereas responses to NE were not affected. PGA2 (0.3 mug/min) had no effect on responses to either of the pressor stimuli. PGA1 infusion resulted in an enhanced response to RNS at the highest stimulus frequency and decreased the response elicited by A. PGF2alpha (3 mug/min) had no significant effect on renal vascular resistance or on responses to NE and nerve stimulation. However, the response to angiotensin was decreased and responses to RNS at 10 and 30 cps were decreased 30 minutes after the PGF2alpha infusion. The present data demonstrate that, of the natural renal PGs, PGE2 and PGA2 possess the capacity to modulate the effects of the sympathetic nervous system on the feline kidney. In addition, the effects of PGE and PGA on responses to adrenergic stimuli and on vascular resistance could be separated.


Effects of nicotine on rebound excitation of guinea-pig small intestine. Poststimulus rebound contractions and associated action potentials of the circular muscle layer occurred after termination of transmural electrical stimulation. Low concentrations of nicotine (1 x 10(-6) to 5 x 10(-6) g/ml) either abolished or greatly reduced the poststimulus response. The contractile force and time duration of the response were reduced, and the latency of the response was increased by low concentrations of nicotine. The depressant action of low concentrations of nicotine was reversed by an increase in concentration from 5 x 10(-6) to 1 x 10(-4) g/ml. The effects of low concentrations of nicotine were mimicked by 1,1-dimethyl-4-phenylpiperazinium iodide, and they were prevented by hexamethonium, pentolinium, gallamine and large concentrations of atropine. Gallamine increased myogenic electrical and mechanical activity and potentiated the poststimulus rebound response. Pretreatment with guanethidine produced a small reduction in the inhibitory action of nicotine. Propranolol and phentolamine suppressed the poststimulus response, but the specificity of the action was questionable. The effects of nicotine may be mediated by excitation of intrinsic inhibitory neurons.


Actions of methoxamine and tryptamine and their interactions with cyproheptadine and phenoxybenzamine on cat spinal cord segmental reflexes. The effects of norepinephrine, methoxamine and tryptamine were assessed on the monosynaptic and polysynaptic segmental reflexes in the unanesthetized, decerebrated acute spinal cat. Their selectivity of action was determined by studying the interactions of methoxamine and tryptamine with two antagonists, cyproheptadine and phenoxybenzamine. Potentials were evoked by stimulating either the L7 or S1 dorsal root and were recorded from the corresponding ipsilateral ventral root. Norepinephrine did not affect reflex activity, whereas methoxamine facilitated both the monosynaptic and polysynaptic potentials in a dose-related manner when infused over 20 minutes. Tryptamine facilitated both the monosynaptic and polysynaptic reflex potentials. This increase was dose related for the monosynaptic reflex but not for the polysynaptic reflex. Phenoxybenzamine blocked the facilitatory effects of methoxamine and did not antagonize the effects of tryptamine on the segmental reflex. The facilitatory effects of tryptamine were effectively blocked by cyproheptadine. Cyproheptadine failed to reduce the polysynaptic response to methoxamine, although it partially antagonized the monosynaptic facilitation. These findings demonstrate that methoxamine and tryptamine facilitate the segmental reflex by different modes of action and provide additional evidence for noradrenergic and tryptaminergic systems in the spinal cord.


On the structure of medicinal chemistry. The great advances in biochemistry and molecular biology, the development of physical organic chemistry, and the availability of large computers are creating opportunities for restructuring medicinal chemistry. The enormous volume of scientific results relevant to medicinal chemistry which appear with each new round of the journals forces us to make greater efforts to bring the information together in more meaningful patterns. The QSAR paradigm redirects our thinking about structuring medicinal chemistry.


Improved delivery through biological membranes. 1. Synthesis and properties of 1-methyl-1,6-dihydropyridine-2-carbaldoxime, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride. A dihydropyridine-pyridine type redox pro-drug system was developed for delivering quaternary pyridinium salts through biological membranes. As a first application, the dihydropyridine derivative of N-methylpyridinium-2-carbaldoxime chloride (2-PAM) was synthesized using a reduction-addition-elimination sequence. The dihydro-2-PAM obtained has all the required properties for an effective transport through lipoidal barriers and it reverts easily back to 2-PAM as a result of a chemical or enzymatic oxidation process.


Improved delivery through biological membranes. 2. Distribution, excretion, and metabolism of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, a pro-drug of N-methylpyridinium-2-carbaldoxime chloride. N-Methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug of 2-PAM, was found to be converted in vivo to 2-PAM, rapidly and quantitatively. The significantly changed properties of the pro-2-PAM resulted in a longer biological half-life and a favorable distribution of 2-PAM formed upon its oxidation. No new metabolite was found when pro-2-PAM was administered intravenously; however, a new metabolic product was formed when the pro-drug was given by oral route.


Improved delivery through biological membranes. 3. Delivery of N-methylpyridinium-2-carbaldoxime chloride through the blood-brain barrier in its dihydropyridine pro-drug form. Administration of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride, the pro-drug form of 2-PAM, resulted in an average of 13-fold increase in the amount of 2-PAM delivered into the brain of mice as compared to the administration of 2-PAM. The pro-drug which crossed the BBB resulted in a dramatic increase in the reactivation of AChE blocked by DFP. In vivo studies of the "aging" of the phosphorylated AChE in the brain of mice could also be studied using pro-2-PAM.


Synthesis and biological actions of 2-substituted quinolizidines. A series of 2-substituted quinolizidines was synthesized and tested for their effects on motor activity in mice. In the 2-aryl-2-hydroxyquinolizidines (5 and 6) a difference was noted in potency between the axial and equatorial aryl analogs. A significant difference in activity was also found between the epimeric 2-(4-fluorobenzoyl) quinolizidines (10c and 11c).


Synthesis and biological activity of 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines. Various 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisquinolines were synthesized and evaluated as substrates and inhibitors of catechol O-methyltransferase (COMT). In addition, these compounds were tested for their ability to release norepinephrine-3H from mouse hearts in vivo. Methyl substituents in the 2 and/or 4 positions of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline had little effect on the interaction of these molecules with COMT. In general, the substrate kinetic (Km, Vmax) and inhibitory kinetic (Kis) properties toward COMT were similar for each of these compounds. In contrast, norepinephrine depleting activity showed more strict structural requirements. Methyl substituents in the 2 or 4 positions of the parent compound, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, eliminated the norepinephrine depleting activity. The interesting exception was 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was found to be more active than the parent molecule as a depleter of norepinephrine from mouse hearts.


Comparative analysis of the cytotoxicity of substituted (phenylglyoxal bis(4-methyl-3-thiosemicarbazone)) copper (II) chelates. Seven para-substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)]copper (II) chelates (12-18) have been designed, synthesized, and tested for their ability to inhibit the respiration of rat liver slices as a normal cell model and Ehrlich ascites cells as a tumor cell model. Relationships between chemical structure and respiratory inhibition are described on a quantitative basis using substituent contants (pi, Es, and sigmap) by computerized multiparameter regression analyses. The correlations indicate that changes in Es have the largest effect on liver slice toxicity of chelates while pi and sigmap account for most of the variation in toxicity to ascites cells. A comparative analysis strongly suggests that electron-donating substituents with greater water solubility should increase cytotoxicity to ascites cells at the expense of cytotoxicity to the rat liver cells. The predictions of the equations were checked by synthesizing and testing an additional derivative. The results strengthen the initial predictions.


Relationship between analgetic ED50 dose and time-course brain levels N-alkylnormeperidine homologues. The brain levels of meperidine and three N-alkyl homologues were determined at equal analgetic iv doses in mice. The relative levels of the four compounds in brain were found to be closely proportional to their ED50 doses even though the compounds exhibit a wide range in partition coefficient and metabolic N-dealkylation. While lipid solubility and metabolism are undoubtedly important factors in the overall time-course brain levels, it appears that during the period of analgetic measurement (5-60 min after injection) these factors do not profoundly affect the relative brain levels because peak uptake occurs within the first 5 min after administration of the homologues. As a consequence, the observed ED50 potencies appear to provide a fair approximation of the relative receptor affinities of the four homologues. N-Dealkylation was observed as a major metabolic transformation by mouse liver in vivo for all four compounds, and the extent of this N-dealkylation was found to directly correspond to the rates of N-dealkylation by mouse liver homogenate seen in an earlier study.


Synthesis and evaluation of brain catecholamine depletion by N-alkyl derivatives of 6-aminodopamine. Three analogs of 6-aminodopamine were synthesized and tested for their ability to deplete the central nervous system of norepinephrine and dopamine. The compounds were analogs in which the aliphatic nitrogen of the ethyl side chain was substituted with dimethyl, isopropyl, and methyl groups. The first two compounds showed only very weak depletion of norepinephrine stores, while having no effect on dopamine levels. The third compound was not tested due to its instability.


Synthesis and antiinflammatory properties of N-substituted 4,5-dioxopyrrolidine-3-carboxanilides. The synthesis and physical properties of a series of N-methyl- and N-phenyl-4,5-dioxopyrrolidine-3-carboxanilides are described. Unlike previously reported carboxanilides derived from 1,3(2H,4H)-dioxoisoquinoline and 2-oxobenzofuran, the currently described agents exist solely as the enol tautomers and, as a result, do not display comparable acidic properties. None of the newly reported compounds exhibited activity equal to that of aspirin in the carrageenin-induced rat foot edema assay.


Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes. The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.


Intracyclization rates of 6-hydroxydopamine and 6-aminodopamine analogs under physiological conditions. It is agreed that the neurotoxic action of 6-hydroxydopamine and 6-aminodopamine is related to their ease of oxidation. The initial oxidation products, the p-quinone and p-quinone imine, readily undergo 1,2-intracyclization. These reactions could represent an important loss of active neurotoxic agent available uptake. A variety of substituted 6-aminodopamine analogs was prepared and their formal potentials and cyclization rates were measured accurately. The effect of the balance of ease of oxidation vs. rate of cyclization on their neurotoxicity was examined. The results are in general accord with in vivo lifetimes for 6-hydroxydopamine and 6-aminodopamine in rat caudate nucleus.


7-Aza analogs of the analgetic agent azabicyclane. Synthesis and pharmacologic analysis. Three 3,7-diazabicyclo[3.3.1]nonane derivatives (4) with a structural similarity to the analgetic agent azabicyclane (1) were prepared. The amino alcohol 4a was found to prefer a conformation wherein the six-membered ring to which the hydroxyl group is syn is in the boat form. These three compounds had increased basicity in comparison with 1 due to various forces stabilizing their monocationic states. Compounds 4a-c did not show analgetic activity at the dose levels tested.


2,3-Dihydroxyphenethanolamine as an adrenergic agent. In an attempt to further define the role of the m-hydroxy group in adrenergic agents, 2,3-dihydroxyphenethanolamine hydrobromide and N-isopropyl-2,3-dihydroxyphenethanolamine hydrobromide were prepared. These agents are less active than norepinephrine in alpha- and beta-adrenergic in vitro tests. The synthesis and conclusions from the tests are discussed.


Specificity of an antibody directed against d-methamphetamine. Studies with rigid and nonrigid analogs. The specificity of an antibody directed against d-(S)-methamphetamine (MA) was determined by competitive binding assay with more than 50 compounds-metabolites, homologs, and analogs of amphetamine. The antibody appears to be specific both for the side chain and the aromatic ring of d-(S)-amphetamine (A). The basic requirements for a compound to be bound to the antibody are (a) an aromatic ring, (b) a basic nitrogen, and (c) a two-carbon chain between the aromatic ring and the nitrogen. A transoid conformation for the phenethylamine skeleton is preferred. The interaction of the antibody with compounds differing from MA or A in side-chain substitutions was directly proportional to the closeness of their structure to MA and/or A. The antibody exhibited greatly reduced affinity for ring-substituted analogs of A; the p-hydroxy metabolite of A did not bind to the antibody. A radioimmunoassay of A is described; it was utilized to study the disposition of A in dogs.


Catechol O-methyltransferase. 7. Affinity labeling with the oxidation products of 6-aminodopamine. 6-Aminodopamine (6-NH2DA) and various analogs of 6-NH2DA have been evaluated for their ability to inactivate purified catechol O-methyltransferase (COMT) in vitro. The inactivation of COMT by these agents could be prevented by including an antioxidant in the preincubation mixture or by excluding oxygen; however, catalase did not protect the enzyme from inactivation. Substrate protection studies and kinetic studies suggested that the loss of enzyme activity resulted from the alkylation of an amino acid residue at the active site of COMT by the quinoid types products which were generated upon air oxidation of 6-NH2DA. In addition, we have explored in more detail the reactivity toward COMT of specific intermediates in the oxidation pathways of 6-NH2DA by using various 6-NH2DA analogs. From the above studies we have concluded that 6-aminodopamine-p-quinone (6-NH2DAQ) is perhaps the most toxic species toward COMT. However, the aminochromes which are formed from 6-NH2DAQ are also effective in inactivating COMT. The results of these studies have provided a useful model system for observing the interaction of 6-NH2DA and its oxidation products with proteins; in addition, it has provided additional insight into the topography of the active site of COMT.


Potential oxidative pathways of brain catecholamines. The possibility that catecholamines can be oxidized via aberrant pathways in vivo is open to question, but in vitro oxidation via aerobic manipulations is established. Assuming oxidation does occur, we have examined quantitatively the fast chemical reactions of the initial oxidation products, the o-quinones. The nature and rates of these reactions were studies under the conditions simulating closely those which presumably exist in mammalian brain. The results are in close accord with existing literature and especially support oxidation pathways recently reported in [3H]-norepinephrine binding to particulate cell fractions.


8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies. The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.


Novel analogs of tricyclic psychopharmacological agents. The synthesis of several novel analogs of amitriptyline and chlorprothixene, in a number of which the position of the side-chain nitrogen atom rigidly fixed with respect to the tricyclic nucleus, is described. The compounds were evaluated for antidepressant-like activity in the Dopa and serotonin interaction tests and for potential antipsychotic activity in the methamphetamine interaction test. 5-(3-Dimethylaminocyclohex-1-enyl)-5H-dibenzo[a,d]cycloheptene (12) was about equipotent with imipramine in the Dopa and methamphetamine tests, and 3-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-spiro-6'-3'-methyl-3'-azabicyclo[3.1.0]hexane (23) also displayed marked activity in the same tests. Prototype compounds for other ring systems, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene tropane (16) and 5-(3-dimethylaminocycloheptylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (18), were less active.


A conformational study of beta-phenethanolamine receptor sites. 8. Pharmacological study of 3-isopropylamino-2-phenyl-trans-2-decalols. Two N-isopropylnorephedrines and their four possible decalol analogs were compared pharmacologically. Four of the six compounds at a concentration of 1 x 10(-4) M caused a potentiation of D(-)-norepinephrine (NE) contraction of the rat vas deferens and increased the maximal response of the preparation to NE. Pretreatment in vivo with reserpine (5 mg/kg ip) 24 hr before the experiment in vitro did not change these effects. At a concentration higher than 1 x 10(-3) M all of the decalin analogs antagonized the effects of NE. All of the analogs lowered the dog blood pressure briefly. The lowering of blood pressure was augmented by alpha-adrenergic blockade and was not changed by beta-adrenergic blockade, atropine, or a ganglionic blocking agent. Tachyphylaxis was not observed. The spontaneous contraction of isolated rabbit atria was depressed by the substances at concentrations of 1 x 10(-4)-1 x 10(-3) M. Catecholamine uptake in rat vas deferens was lowered by the substances and all of them produced a release of catecholamines from vas deferens. By virtue of the conformational rigidity of the decalols, possible inferences concerning the stereochemical aspects of the interaction of the ephedrine analogs with adrenergic neurone-receptor sites are discussed.


Stereochemical studies on medicinal agents. 19. X-ray crystal structures of two (+/-)-allylprodine diastereomers. The role of the allyl group in conferring high stereoselectivity and potency at analgetic receptors. X-Ray crystallographic studies have been performed on the two diasteromeric racemates of 3-allyl-1-methyl-4-propionoxypiperidine hydrochloride (allylprodine hydrochloride) in an effort to determine the role of conformation in their interaction with analgetic receptors sites. The chiral orientation of the phenyl group in the highly potent isomer, (+)-1, is qualitatively in conformity with the stereo structure-activity relationship found among other analgetic 4-phenylpiperdines. The fact that (+)-2, a relatively weak analgetic with no stereoselectivity, also possesses this feature indicates that this conformational arrangement per se does not ensure high potency. The data suggest that the very potency and stereoselectivity which the allylic double bond confers to (+)-1 are due primarily to the interaction of this bond with an accessory site on the receptor.


Correlation analysis of Baker's studies on enzyme inhibition. 1. Guanine deaminase, xanthine oxidase, dihydrofolate reductase, and complement. Five correlation equations are presented which relate inhibitory activity of 578 inhibitors of guanine deaminase, xanthine oxidase, dihydrofolate reductase, and complement to their chemical structures. The use of correlation analysis in enzyme studies for drug development is discussed. The importance of indicator variables in such studies is emphasized.


Ergoline congeners as potential inhibitors of prolactin release. 2. In our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared one indolealkylamine and several 2-aminotetralin derivatives. These congeners have been evaluated for inhibition of prolactin release in vivo. One congener, 5,8-dihydroxy-2-dimethylaminotetralin, and the drug M-7 significantly inhibited prolactin secretion.


Structure of anterior dorsal ventricular ridge in snakes. Anterior dorsal ventricular ridge (ADVR) is a major subcortical, telencephalic nucleus in snakes. Its structure was studied in Nissl, Golgi, and electron microscopic preparations in several species of snakes. Neurons in ADVR form a homogeneous population. They have large nuclei, scattered cisternae of rough endoplasmic reticulum in their cytoplasm, and bear dendrites from all portions of their somata. The dendrites have a moderate covering of pedunculated spines. Clusters of two to five cells with touching somata can be seen in Nissl, Golgi, and electron microscopic preparations. The area of apposition may contain a series of specialized junctions which resemble gap junctions. Three populations of axons can be identified in rapid Golgi preparations of snake ADVR. Type 1 axons course from the lateral forebrain bundle and bear small varicosities about 1 mu long. Type 2 axons arise from ADVR neurons and bear large varicosities about 5 mu long. The origin of the very thin type 3 axons is not known; they bear small varicosities about 1 mu long. The majority of axon terminals in ADVR are small (1 mu to 2 mu long), contain round synaptic vesicles, and form asymmetric active zones. This type of axon terminates on dendritic spines and shafts and on somata. A small percentage of terminals are large, 5 mu in length, contain round synaptic vesicles, and form asymmetric active zones. This type of axon terminates only on dendritic spines. A small percentage of terminals are small, contain pleomorphic synaptic vesicles, and form symmetric active zones. This type of axon terminates on dendritic shafts and on somata.


A brachial glycogen body in the spinal cord of the domestic chicken. When cervical segments 14 to 15 of the chicken spinal cord are cut transversely and studied by routine histological and histochemical methods, an onion-shaped region, filled with thread-like fibers, is seen to surround the ependymal cells of the central canal and to be bounded laterally by the neural elements of the spinal gray matter. This area is negative for succinic dehydrogenase, beta-hydroxybutyrate dehydrogenase and cholinesterase activity, but very strongly periodic acid-Schiff positive. Diastase controls show the positive material to be glycogen. Parasagittal sections through this cervical region and into the upper thoracic cord, show the glycogen-rich region to extend longitudinally throughout the region. Because of its location and histochemical characterization, which are similar to that of the ventral portion of the glycogen body, the term brachial glycogen body is proposed for this structure.


The development and replacement of teeth in viviparous caecilians. Tooth development and replacement in fetal and adult viviparous caecilians (Amphibia: Gymnophiona) are described and analyzed according to current theories of tooth succession. The fetal dentition differs from that of the adult in morphology, position, and function. Teeth are used by fetuses to scrape the oviducal epithelium, thus stimulating the secretion of a nutrient substance. Fetal dentitions vary in morphology and position in different species. The ontogeny of teeth of several species is described and the patterns of addition of loci and of replacement are analyzed. Loci are added both posteriorly along the jaw and between existing loci as the jaw grows prior to ossification; subsequently addition is restricted to the posterior part of the jaw. Tooth replacement is alternate. The several rows and patches of teeth are the result of retention of replacement series on the dentigerous elements. Tooth development and replacement in a series of juveniles and adults of different sizes in a single species are also considered. Post-fetal patterns of development and replacement are similar to those seen in larvae and adults of oviparous species. Variation in numbers of teeth and proportions of teeth at particular stages occurs ontogenetically and among individuals of the same size, though proportions occur in a similar pattern throughout the series. The general pattern of tooth replacement in fetuses and adults can be explained by either Edmund's Zahnreihen theory or by Osborn's Tooth Family theory, but replacement in fetal tooth patches and the fetal-adult dentitional transition are explained by neither.


The pectoral anatomy of selected Ostariophysi. I. The Characiniformes. The muscles and bones of the pectoral fin of Serrasalmus nattereri, the piranha, resemble those of generalized, lower teleosts with specializations related to a body shape adapted for high-speed carnivory; the pectoral fins being highly mobile with strong ligaments to the rays. The presence of two occipital nerves appears primitive, while the emergence of the subclavian artery within the branchial cavity, as in Gasteropelecus sternicla, appears specialized. The muscles and bones of the latter fish, a fresh-water flying fish, are specialized for self-propelled, aerial flight in the fusion of the right and left girdles greatly expanded for insertions of complex appendicular (flight) muscles, and in the consolidation of the rays and radials into one functional unit moving vertically in flight through contraction of vertical, massive ventral flight muscles. The bony pectoral anatomy of Electrophorus electricus, the electric eel, is specialized in having a mobile joint between the primary girdle and the cleithrum, the former being suspended vertically from the cleithrum by ligaments. The proximal radials and rays are very numerous and vertically aligned. The cleithrum is shaped to accommodate the extensive sternohyoid and pharyngocleithral muscles. The sheet-like appendicular muscles extend beyond the special joint and control its movement. The deeper muscles do not cross this joint. The arterial system is specialized in lacking a deep brachial artery.


Some interactions of light, riboflavin, and aflatoxin B1 in vivo and in vitro. In previous studies, artificial sunlight and riboflavin synergistically increased acute aflatoxin toxicity in rats. Three new experiments were designed to provide information on the interaction of riboflavin, aflatoxin, and light. In a study of carcinogenesis, rats received low levels of aflatoxin 5 days/wk for 3 wk; 30 min after each dosing, half of them were irradiated for 2 hr. In some, levels of glucose-6-phosphatase and acid phosphatase were determined 5 days after completion of treatment. Remaining rats were killed at 30 or 53 wk. All underwent complete necropsies and histopathologic examination. In the second experiment, rats were dosed with riboflavin and divided into four groups: no further treatment; aflatoxin (LD50); irradiation (1-2 hr); or aflatoxin plus irradiation. Blood riboflavin levels were determined at intervals following these treatments. In the third experiment, the chemical reactions of irradated aflatoxin and/or riboflavin were studied by uv spectroscopy and TLC. The 53-wk study showed clearly that light decreased the incidence of aflatoxin-induced cancer. The other results may provide an explanation. Aflatoxin caused blood riboflavin levels to decrease-an effect enhanced by irradiation, suggesting that photosensitized riboflavin and aflatoxin form a complex. This interpretation gains support from studies in vitro that showed that riboflavin quenched aflatoxin photodegradation, perhaps by complexing with aflatoxin. Thus, low, carcinogenic doses of aflatoxin may complex with endogenous, photosensitized riboflavin, inhibiting its degradation into carcinogenic metabolites.


Quantitative relationship of fecal asbestos to asbestos exposure. A method is descirbed for isolating chrysotile fibers from feces and counting them with an electron microscope. The detection limit was 150,000 fibers per gram feces; average recovery was 85.5%. When the method was used to check the asbestos in feces of people subjected to industrial exposure vs. controls, the means were significantly different (p less than 0.02). Duplicate fecal samples were found to check within an average of +/- 31.1% of their means.


Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. Finding at least 2-3 ppm and occasionally as much as 10-20 ppm of vinyl chloride monomer in a wide range of foodstuffs has prompted concern for a possible human health hazard. The recognition of vinyl chloride as a carcinogen to humans in April 1974, following the discovery of angiosarcoma as the cause of death in at least 25 workers who had been engaged in the manufacture of polyvinyl chloride, enhanced this concern with respect to the presence of vinyl chloride monomer in foods. To assess the hazard presented by the oral ingestion of vinyl chloride monomer, rats that had been surgically prepared with an indwelling jugular cannula were dosed by intragastric intubation with aqueous solutions containing up to 2.0 mg/ml vinyl chloride. Time-concentration curves were obtained from sequential samples of blood. The uptake of vinyl chloride by this route was found to be extremely rapid; peak concentrations were achieved less than 10 min after administration of the dose. Elimination from the blood compartment appeared to be biexponential. Studies with the same animal model in a single restraint cage that allowed a "head only" exposure to concentrations of vinyl chloride up to 7,000 ppm in the gas phase have shown a similar rapid uptake followed by a plateau blood concentration during several hours of exposure. On removal from the vinyl chloride atmosphere, blood levels fell rapidly to barely detectable concentrations after 2 hr. The precise kinetic coefficients that describe the distribution and elimination rates of vinyl chloride from the blood compartment were also determined from the blood concentration data after the administration of an intravenous dose of aqueous or vegetable oil solution.


Dimethylnitrosamine-demethylase: molecular size-dependence of repression by polynuclear hydrocarbons. Nonhydrocarbon repressors. Studies with 58 polynuclear aromatic hydrocarbons have shown that to repress demethylation of dimethylnitrosamine (DMN) in rat liver, the hydrocarbons must satisfy specific requirements of molecular geometry regarding size, shape, and coplanarity. Expressing the molecular size of these planar compounds by the two-dimensional area occupied, the size for maximal repressor activity ranges between about 85 and 150 A2. In addition to being within the correct molecular size range the hydrocarbons must have an elongated-rather than compact-molecular shape; circularly shaped and/or highly symmetrical hydrocarbons, such as coronene, triphenylene, ovalene, and tetrabenzonaphthalene, have very low activity or are inactive, in spite of being in the optimum size range. Coplanarity of the molecule is a critical requirement; thus, the potent carcinogen, 9,10-dimethyl-1,2-benzanthracene, is inactive as repressor of DMN-demethylase synthesis. Two exceptions, fluoranthene and benzol[ghi] fluoranthene, showed significant induction of DMN-demethylase. The molecular size distribution of hydrocarbons that repress the DMN-demethylase shows a mirror-image relationship with respect to the earlier reported molecular size requirement for indcution of azo dye N-demethylase. Compounds other than hydrocarbons also show the mirror-image relationship in the sense that pregnenolene-16alpha-carbonitrile, alpha- and beta-naphthoflavone, and Aroclor 1254 (known to be inducers of various mixed-function oxidases) are strong repressors of DMN-demethylase. Aminoacetonitrile, a strong inhibitor of carcinogenesis by DMN, is also a potent repressor of DMN-demethylase. The enzyme is inhibited by pretreatment of the animals with cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450. Pregnenolone-16alpha-carbonitrile and 3-methylcholanthrene, despite their similarity of action on DMN-demethylase, have different effects on azo reductase, which is repressed by the former and induced by the latter compound.


Effects of delta9-tetrahydrocannabinol and ethanol on body weight protein and nucleic acid synthesis in chick embryos. Delta9-Tetrahydrocannabinol (THC) and/or ethanol were administered into the yolk sac of chicken eggs at various times of incubation. Repetitive injections of 1 or 2 mg THC and/or 10 mul of alcohol were fiven. With a schedule of injections on days 2, 4, 7, and 9 with sacrifice on day 11, or on days 2, 4, 7, 9, and 11 with sacrifice on day 15, the body weight was reduced and the liver weight increased. The latter schedule also decreased the weight of the forebrain. Injections of labeled leucine and uridine were also given 1 hr before sacrifice to determine the rate of incorporation of these precursors into protein and RNA. Apparent changes were found in the specific activities of protein and RNA in different parts of the brain and liver. No overall metabolic trends emerged, however. No teratogenic effects were visible with the dosage schedules used.


Sequential histopathologic, hematologic, and blood chemistry changes induced in mice by a technical and a purified preparation of 2,4,5-trichlorophenoxyacetic acid. Maternal mice were given 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on days 6 through 14 of pregnancy in a tetratologic study at the National Center for Toxicological Research. Sick or moribund mice sacrificed after 4-8 doses of 120 mg/kg 2,4,5-T often showed severe myocardial lesions, hypocellularity of the bone marrow, and depletion of lymphocytes in the thymus, spleen, or lymph nodes. Healthy mice sacrificed on day 17, 11 days after treatment began, showed few or no severe lesions. To determine if lesions earlier in gestation contributed significantly to an increase in fetal abnormalities in the healthy 17-day survivors, dihybrid croos F2 pregnant and nonpregnant mice received by gavage 0, 60, or 120 mg/kg 2,4,5-T on days 6 through 14 of pregnancy. One group received a technical preparation containing 97.9 +/- 0.4% 2,4,5-T; another received a purified preparation containing 99 +/- 0.3% 2,4,5-T. Mice were sacrificed when they became moribund and at 6, 24, and 30 hr, as well as at 4, 6, 8, and 11 days after beginning treatment. Almost all mice given 60 mg/kg and many given 120 mg/kg 2,4,5-T appeared normal at sacrifice either early or late in pregnancy and showed little or no pathologic changes. Mice that became ill or moribund often showed severe lesions; few survived 11 days. Severe myocardial lesions were seen in 26 of 70 moribund mice fiven the technical 2,4,5-T and 24 of 33 given the purified preparation of 2,4,5-T. The moribund mice, particularly those given the purified compound, also showed a high incidence of lesions in other organs and marked hematological and blood chemistry changes. These findings indicate that the lesions are primarily due to 2,4,5-T rather than to impurities in the technical preparation; also impaired maternal health is not the primary cause of the increase in fetal abnormalities.


Chlordane: effects on several estuarine organisms. Dynamic marine toxicity tests were performed with technical grade chlordan and eastern oysters (Crassostrea virginica), pink shrimp (Penaeus duorarum), grass shrimp (Palaemonetes pugio), sheepshead minnows (Cyprinodon variegatus), and pinfish (Lagodon rhomboides). The 96-hr LC20S (and 95% confidence limits) based on measured concentrations of chlordane (in mug/liter) are: ping shrimp 0.4 (0.3-0.6); grass shrimp, 4.8 (4.0-6.0); sheepshead minnows, 24.5 (19.9-28.6); and pinfish, 6.4 (5.0-7.3). The 96-hr EC50 for eastern oysters was 6.2 (4.8-7.9). In a flow-through test, embryos and fry of sheepshead minnows were exposed to average measured concentrations of chlordane from 1.3 to 36.0 mug/liter for 28 days. Neither fertilization success nor embryo survival was affected by the concentrations of chlordane to which these life stages were exposed. However, sheepshead minnow fry did not survive for more than 10 days in chlordane concentrations greater than 7.1 mug/liter.


Subacute toxicity studies with prostaglandin E1 (PGE1) in laboratory animal species. Prostaglandins are a group of modified hydroxy fatty acids with a wide distribution in mammalian tissues. They possess a wide range of potent biological activities and promise to be useful clinically in areas as diverse as the treatment of asthma and termination of pregnancy, in spite of the voluminous scientific literature on prostaglandins, there is little information on the relative safety on these agents in animals. In the present study subacute effects of prostaglandin E1 (PGE1), a representative of the series, were studied in albino rats and Bealge dogs. The compound was dissolved in phosphate buffer and administered by continuous intravenous infusion for 3-6 hr daily, at dose levels up to 2.0 mug/kg/min for 14 consecutive days. Conventional physical, cardiovascular, hematologic, clinical chemical, and postmortem examinations were performed. Dogs exhibited occasional episodes of stupor and/or excitement and emesis. In rats no compound-related physical signs were observed. Cardiovascular parameters and hematology findings were unremarkable. A decrease in blood glucose was observed sporadically in both rats and dogs. Postmortem findings, gross and microscopic, were unremarkable. It is concluded that daily iv infusion of PGE1 up to 2.0 mug/kg/min for 14 consecutive days to rats and dogs causes no biologically meaningful detrimental effects.


Intracellular effects of chronic arsenic administration on renal proximal tubule cells. Arsenic is one of the more common toxic elements in the environment. The kidney accumulates this element and plays a major role in its metabolism and excretion. Mitochondria have been found in vitro to be highly sensitive to the toxicity of this element. Combined oxygen electrode and electron microscopic studies were conducted on kidneys of rats exposed to arsenate in the drinking water at concentrations of 40, 85, or 125 ppm for 6 weeks to evaluate in vivo mitochondrial toxicity. Decreased state 3 respiration and respiratory control ratios were observed in kidneys of rats given the 85 and 125 ppm dose levels. Ultrastructural alterations, which consisted of swollen mitochondria and increased numbers of dense autophagic lysosome-like bodies, were confined to proximal tubule cells of these same animals. This study places renal arsenate mitochondrial toxicity into an in vivo context and points to the value of using complementary techniques for assessing the subacute or chronic toxicity of environmental agents.


Comparative toxicological studies of indole, benzo[b] thiophene, and 1-methylindole derivatives. The comparative LD50 values have been determined in mice for 34 indole, benzo[b] thiophene, and 1-methylindole derivatives of related structures. No clear-cut correlations could be obtained with regard to physicochemical properties across all structures although some relationships are evident within subgroups.


Joint action of insecticides against houseflies. Mixtures of DDT, lindane, endrin, isobenzan, malathion, thiometon, and carbaryl were formulated on an equitoxicity basis. The joint action of 14 mixtures of insecticides was studied against the female housefly (Musca nebulo L.) by a topical application method. In general, the intragroup combinations of the chlorinatophosphate plus a chlorinated hydrocarbon insecticide exhibited no loss in either potency or synergism. An independent joint action was observed only in those mixtures containing DDT and either malathion or thiomethon. The toxicity of all the formulations containing carbaryl and a chlorinated hydrocarbon insecticide was found to be more than additive. The mixture of isobenzan plus carbaryl exhibited the highest degree of synergism of all the combinations tested, while those containing carbaryl and either malathion or thiometon showed a slight antagonism.


Respiratory retention of inhaled toluene and benzene in the dog. This study deals with the inhalation of toluene and benzene found in the vapor phase of cigarette smoke. Determined in this study were the uptake of each substance by the total respiratory tract and by the upper and lower portions under varying conditions of ventilatory rate, tidal volume, and concentration inhaled. Retention by the total tract of toluene fell within the range of 91-94% at all ventilatory rates seen, indicating no relationship between rate and retention. With benzene, total tract retention varied from 88 to 68% with an inverse relationship between retention and rate apparent. This relationship was seen in all types of experiments conducted with benzene. Upper tract retention revealed an uptake of about 89% for both one- and two-way experiments with toluene. In the benzene experiments retention varied from 80 to 61% and from 81 to 63% in the one- and two-way procedures, respectively. Mean lower tract retention was 90% with toluene at all ventilatory rates considered. Benzene retention varied from 74 to 61% as the rate increased from 6 to 18 inhalations/min.


Categorization of hospital emergency capabilities: a progress report. Categorization of hospital emergency service capabilities in a community, region (irrespective of state boundaries), or possibly a state, should contribute significantly toward an improved EMS systrm serving the area and, in turn, contribute to improved care of the seriously ill or injured. Community or regional categorization appears preferable in most situations to statewide categorization. Nationwide categorization seems particularly undesirable. The AMA Guidelines for categorization currently are the best available. While they certainly are not perfect, they deserve testing by surveys and studies in many communities, regions and states. Thereafter, they must be revised and updated utilizing input from those who have provided tests in the field. The merits of categorization of hospital emergency service capabilities transcend all petty objections in the best interest of the care of emergent patients. The profound hope is that the private sector will implement CHES and avoid the threat of government imposition. The time to do so is now.


Amputation as a salvage for patients with incapacitating infected fractures of the lower limbs. Most serious lower-limb injuries with severe bone and soft tissue damage heal when treated wisely by techniques available today. Unfortunately, a small percentage of patients face prolonged physical and economic disability as a result of extensive damage to bone and soft tissue, nonunion of fractures with infection, nerve and blood-vessel injury, and complications of surgical treatment. Every effort should be made to effect union by established methods but a small percentage of fractures do not heal satisfactorily. Failure of infected lower-limb fractures to unite after prolonged treatment or the prospect of prolonged treatment or the prospect of prolonged morbidity and disability occasionally justify amputation in one lower limb. When a lower-limb prosthesis can provide stability support, and mobility painlessly, and overcome the morbidity and disability of an infected ununited fracture, amputation may be the treatment of choice. In the present review of our experiences in the past 17 years with patients having severly injured and diseased lower limbs where little chance existed for rehabilitation to acceptable levels of function by various methods of treatment, open amputation through infected bone followed by secondary closure was chosen to salvage the unfortunate patient with littlw chance of achieving acceptable function after infected ununited fractures of the lower limbs.


Cerebral contusions: re-evaluation of the mechanism of their development. At the present writing, the biomechanics of "coup-contrecoup" contusions may be summarized as follows: 1) "Coup" contusions are caused by the slapping effect of discrete areas of inbeding bone during impact. "Contrecoup" contusions are caused by the movements of the brain against irregular and rough bony enviornment. 2) When the head is relatively fixed, a blunt discrete impact causes a "coup" lesion with no "contrecoup" effect. 3) When the head is free to move, a blunt impact will cause a contrecoup lesion or lesions and no "coup" effect. 4) "Fracture contusion" is caused by the slapping effect of the fracture site on the outbending cerebral surface. In such cases, occassionally the dura may be torn. 5) Deeper contusions in the substance of the brain are due to inertial stresses from relative movements and pressure gradients. 6) Contusions of the cerebral tonsils are due to their relative movements at the posterior fossa-foramen magnum junction.


Traumatic pseudoaneurysms: a review of 32 cases. The management of 23 patients with traumatic pseudoaneurysms is presented. A pulsatile mass associated with pain was the usual presentation. Hypertension and hypovolemic shock from rupture are uncommon presentations but potential hazards of this lesion. Twenty-one pseudoaaeurysms were treated surgically. Resection with end-to-end anastomosis (eight patients), with graft replacement (one patient), with lateral repair (seven patients) was done. Hypothermia with circulatory arrest and external Dacron shunt were used to prevent visceral ischemia during high aortic occlusion. There were no mortalities or significant postoperative complications.


Fat embolism associated with an atrial septal defect. A case of a patient with pulmonary fat embolism following fractures of femurs and pelvis, with a fatal outcome after 3 days, is presented. Post mortem examination revealed a congenital osteum secundum heart defect, and widespread capillary occlusions from systemic fat microembolization.


Acute interstitial nephritis.

Acute interstitial nephritis. Acute allergic interstitial nephritis is manifested clinically by rash, fever, eosinophilia, hematuria, oliguria and azotemia. Histologically a monocytic inflammatory process in the renal interstitium is seen. The clinical course of a patient after excessive sodium cephalothin administration suggested allergic interstitial nephritis and implicates this drug as an etiologic agent.


Nephrotic syndrome secondary to chronic pyelonephritis and ureterovesical reflux. Vesicoureteral reflux and chronic pyelonephritis are usually associated with proteinuria of less than 1 gm. per 24 hours. When there is massive proteinuria an associated glomerulopathy is usually present. We describe a patient who had nephrotic syndrome with radiological evidence of ureterovesical reflux and histological evidence of chronic pyelonephritis without associated glomerulonephritis.


Salmonella lithiasis.

Salmonella lithiasis. A case of Salmonella lithiasis in a 60-year-old woman is presented and the relevant literature is discussed. Nephrectomy instead of lyelolithotomy was undertaken to eliminate the carrier state, and cholecystectomy and exploration of the common bile duct were required.


Echinococcal cyst involving the prostate and seminal vesicles: a case report. Echinococcal cyst presenting with urinary symptomatology is uncommon. A case describing the symptoms, diagnostic procedures and treatment with good outcome is presented. The need for further followup is emphasized in that additional cysts can appear later in other sites.


Surgical management of renal lesions using in situ hypothermia and ischemia. Many renal lesions that were once treated by nephrectomy now lend themselves to surgical correction. The value of in situ hypothermia and ischemia produced by occlusion of the renal artery is detailed. This technique has proved to be a simple, safe and effective surgical approach to the management of most difficult renal lesions.


Dissolution of residual renal calculi with hemiacidrin. Hemiacidrin irrigation of the renal collection system via nephrostomy for the dissolution of residual postoperative calculi is described in 14 cases. The irrigation successfully dissolved 13 to 16 caliceal calculi. It did not dissolve any parenchymal calcifications. No known stones of pure calcium oxalate or apatite have been dissolved. Residual stones can safely be dissolved with hemiacidrin irrigation via nephrostomy if clear open drainage and scrupulously sterile urine are maintained.


Experience with indwelling ureteral stent catheters. A new indwelling ureteral stent to provide long-term ureteral drainage is described. This radiopaque stent is manufactured of non-reactive, non-collapsible tubing and is designed to resist downward expulsion and upward migration. Internal stent diversion offers advantages in managing patients whose ureters are obstructed by malignancy. 1) Endoscopic placement of the ureteral stent is associated with less morbidity and mortality than supravesical diversion. 2) Unilateral obstruction can be corrected at the time of diagnosis, thus ensuring that later supravesical diversion will not be necessary. 3) If time proves that the urinary diversion is no longer desirable in terms of quality of life, the stent can be removed.


Urinary diversion: adjunctive tube gastrostomy. A series of 98 patients who had undergone construction of ileal conduits is discusses. Of the 76 patients who had gastrostomy drainage 2 had complications related to the procedure. Complications occurred in 6 of the 22 patients who had nasogastric drainage. The advantages and disadvantages of postoperative gastric decompression by tube gastrostomy and the nasogastric tube are discussed. We conclude that the gastrostomy tube has a definite place in pediatric and adult urological cases in which postoperative ileus may be expected.


Ureteroileourethrostomy: 16-year followup. Ureteroileourethrostomy has been abandoned at our institution for replacement of the bladder because: 1) it compromised the cancer operation and 2) upper urinary deterioration forced conversion to ureteroileocutaneous diversion in 2 of 3 patients. The ureteroileourethrostomy may have future application if all of the prostate is removed when cystectomy is necessary for bladder cancer. The urinary retention can be satisfactorily managed with clean, intermittent self-catheterization. The hyperchloremic metabolic acidosis can be satisfactorily managed by reducing residual urine and potassium citrate administration. The upper urinary tract changes can be partially or wholely prevented with antirefluxing ureteroileal anastomoses.


Venacavography, corticosteroids and surgery in the management of idiopathic retroperitoneal fibrosis. Four patients with idiopathic retroperitoneal fibrosis were found to have characteristic obstruction and anterior displacement of the lumbar vena cava. Varying degrees of venous collateral circulation were present, depending on the degree of vena caval compression. All 4 patients underwent ureterolysis to relieve the hydronephrosis and to confirm diagnosis by biopsy. Two patients were treated with corticosteroids postoperatively. Followup venacavography demonstrated improved filling and decrease in the collateral circulation in these 2 patients. Of the remaining 2 untreated patients 1 was lost to followup and the other revealed no change. Diagnosis of idiopathic retroperitoneal fibrosis can be made if characteristic changes are present on inferior venacavography and may provide an objective measure for following the basic disease process during medical treatment.


An attempt to understand and to treat voiding dysfunctions during rehabilitation of the bladder in spinal cord injury patients. An attempt to understand and treat dysfunctions during bladder rehabilitation in 150 spinal cord injury patients is presented. The 25 problem patients were further analyzed to identify and manage the dysfunctional bladder and bladder neck, dyssenergic pelvic floor, vesicoureteral reflux, areflexic detrusor muscle and also to discontinue prolonged intermittent catheterization. The initial excellent results with a modified approach to sphincterotomy and the bladder neck operation in 15 patients are presented. Early recognition of patients in whom intermittent catheterization may not be successful will allow one to intervene and establish an early catheter-free status. A new concept of the existence of receptors in the posterior urethra has been postulated.


Primary adenovillous carcinoma of the bladder. Two cases of primary adenovillous carcinoma of the bladder are presented: one in a normally placed bladder and the other in an exstrophied bladder. The close association of these 2 neoplasms with coexistent cystitis glandularis would seem to support the possible precancerous nature of the latter entity. The remarkable similarity of these neoplasms to villous adenocarcinomas of the rectum is also described, a finding which may reflect the close embryologic origin of the rectum and bladder neck. A brief review of the classification of vesical adenocarcinomas is also given.


Cytogenetic analysis: a potential index for recurrence of early carcinoma of the bladder. In 15 cancer patients cystoscopic resection or biopsy coupled with cytogenetic analysis at intervals of 3 to 69 months showed persistence of chromosomal patterns with markers (abnormal chromosomes) in 4 of 7 non-invasive and in 6 of 8 submucosal invasive carcinomas. Recurrence was limited to but constant in those carcinomas containing markers. Marker chromosomes have potential value as a prognostic aid. Further, the triad of tetraploidy, markers and submucusal invasive moderately well differentiated carcinoma appears to carry such a lethal prognosis as to militate for early radical resection.


Treatment of autonomic dysreflexia with phenoxybenzamine. Our 9 patients with severe autonomic dysreflexia treated with phenoxybenzamine, an alpha-sympatholytic agent, had a dramatic relief of symptoms. Bladder and urethral pressure studies before and after treatment with this agent suggest that the inappropriate rise in urethral resistance in these patients is a result of an appropriate but extraordinary response to bladder filling.


Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. Charcteristics of urethral transitional cell carcinoma in patients who have undergone cystectomy for bladder cancer have been reviewed. The retained urethra was the site of urothelial malignancy in 7 per cent of 348 patients who underwent cystectomy alone. Urethras removed during prophylactic cystourethrectomy in 110 patients showed unsuspected carcinoma in situ and marked atypic in 12.5 per cent. Patients with urethral cancer were at greater risk for meatal and upper tract tumors, a reflection of multicentric tumor neogenesis, and at greater risk for perineal tumors and inguinal metastases, a reflection of direct invasion. Cytology is advocated for examining the retained urethra. However, urethrectomy to include a fossa navicularis and glandular meatus at the time of cystectomy seems justified as a definitive means of guarding against the often asymptomatic and potentially lethal urethral occurrences of transitional cell carcinoma. Furthermore, incontinuity removal of the bladder and urethra more nearly satisfies the requirements for cancer surgery by avoiding transection of a tumor containing viscus.


Urethral meatal carcinoma following cystourethrectomy for bladder carcinoma. The multicentric potential of urothelial malignancy is well recognized, and the occurrence of urethral neoplasm after cystectomy is attributed to this characteristic of urothelial tumors. Eight instances of tumors in the glandular urethral remnant after subtotal urethrectomy illustrate the necessity of excising the fossa navicularis and urethral meatus when performing urethrectomy.


Radical retroperitoneal lymph node dissection: how effective in removal of all retroperitoneal nodes? Several large series have supported the success of retroperitoneal lymphadenectomy as a primary therapeutic modality in the management of non-seminomatous germ cell testicular neoplasms. In 1963 Tavel and associates reported on the inadequacy of this procedure in the complete extirpation of all the retroperitoneal lymph nodes. Our investigation was undertaken to test their conclusions, the sole difference in technique being that the infrarenal lumbar vessels were ligated and divided during the lymph node dissection. Results in 12 cadavers revealed that all retroperitoneal nodal tissue could be excised with the modified technique. These findings were further verified by the absence of any residual retroperitoneal lymph nodes in 3 patients who died of metastatic embryonal cell carcinoma. The extirpative efficacy of this procedure having been established, any major deleterious effects of lumbar ligation, primarily spinal cord ischemia, must be considered. Based on our experience and that of others it may be concluded that this complication represents a minimal risk that should not discourage use of this effective therapeutic procedure.


Clomiphene citrate in the management of male infertility. There were 35 hypofertile men who underwent assay of serum follicle stimulating and luteinizing hormones, and testosterone, and were placed in a trial program using clomiphene citrate in a 25-day cycle, with 5-day rest periods. Therapy has been maintained for up to 9 months with a projected termination of 12 months. No relationship could be established between serum follicle stimulating hormone and spermatozoal number in this population. The spermatozoal count improved in 31 men while they were on therapy and 8 pregnancies have occurred. Clomiphene citrate seems to be effective in improving the quanttity of spermatozoa and the spermatozoal motility in these hypofertile men.


Sperm antibodies after vasectomy with fulguration. Whether antisperm antibodies develop after vasectomy probably depends on several variables, 1 of which may be the surgical technique. The levels of serum antisperm antibodies were compared in men vasectomized by 1 techniques: vasoligation and fulguration. No difference in the incidence of spermagglutinating antibody was found in the 2 groups. However, immobilizing antibodies were observed in 43 per cent of the men undergoing vasoligation but in only 29 per cent of the men vasectomized by fulguration.


Prostatic carcinoma: incidence and location of unsuspected lymphatic metastases. Prospective pathologic staging by pelvic lymphadenectomy in 60 patients with clinically localized carcinoma of the prostate disclosed a high incidence (35 per cent) of clinically silent and unsuspected lymph node metastases. When present, metastatic disease was frequently bilateral (57 per cent) and most commonly involved the obturator-hypogastric lymph nodes (87 per cent). Micrometastases alone were found in 5 patients and the potential significance of this finding on survival is discussed. Although the presence or absence of metastases could not be accurately predicted by histologic analysis of biopsy or prostatectomy specimens, the finding of undifferentiated tumor, marked anaplasia and penetration through the capsule correlated positively with nodal metastases. Pelvic lymphadenectomy is a safe and important diagnostic tool in the accurate staging of these patients. Its widespread use is advocated in patients with clinical stage B1, B2 and C tumors prior to definitive therapy. Based on the prospective data generated in this study lymphatic metastasis appears to be an early event in the spread of prostatic cancer.


Changes in alveolar capillary configuration at different levels of lung inflation in the rat. An ultrastructural and morphometric study. Changes in alveolar capillary configuration during positive pressure lung inflation were investigated by transmission and scanning electron microscopy as well as by morphometric methods. As the airway pressure was raised, an increasing number of alveoli expanded. However, in fully inflated or overinflated lungs, a few collapsed areas persisted. In such areas, the air-blood tissue barrier was folded into the capillary space, dividing it into intercommunicating chambers. In expanded alveoli, the capillaries appeared as a continuous space delimited at each side by a tissue leaflet. This space was crossed by tissue bridges consisting of the thick portion of air-blood barrier. In overinflated lungs, the capillary space was compressed between the alveoli and thus collapsed. Our findings suggest that the thin porne. The variations of the capillary configuration seem to be determined either by "passive" deformations or by compression of the alveolocapillary membrane, or as a result of contraction of interstitial cells which are located in the thick portion of the air-blood barrier and are attached to the basement membranes of two adjacent alveoli. The relationship between alveolar dynamics and capillary configuration is considered to be a basic factor in ventilation/perfusion auto-regulation.


The scanning electron microscopy of elastase-induced emphysema. A comparison with emphysema in man. Emphysema was produced in hamsters by a single intratracheal injection of 25 units of porcine pancreatic elastase. The lungs were examined by scanning electron microscopy at intervals from 24 hours to 1 year after the injection, and the appearance was compared to examples of human emphysema. Within 24 hours of injection, the alveolar ducts were dilated and air spaces were of more variable size than normal. Fibrin strands, erythrocytes and phagocytic cells were present in air spaces. By a week the hemorrhage and exudate had resolved, but adnormal air spaces continued to enlarge over the period of study. The abnormal airspaces formed by progressive dilation of alveolar ducts with shortening and occasionally effacement of interalveolar septa. Interalveolar pores were occasionally enlarged but only focally increased in number. The appearance of single examples of human congenital lobar emphysema and panlobular emphysema resembled the animal model. Abnormal air spaces were formed by dilated alveolar ducts with retraction of interalveolar septa. In contrast, in some cases of centrolobular emphysema marked fenestration of alveolar septa occurred and large air spaces were often traversed by threadlike strands of tissue remnants of some preexisting alveolar walls. The results suggest that there are at least two morphogenetic processes leading to emphysema. One is the coalescence of fenestrations leading to destruction of alveolar walls, and the other is a gradual remodeling of lung structure by mechanisms still to be defined.


Autologous immune complex nephropathy. I. Sequential study of immune complex deposition, ultrastructural changes, proteinuria, and alterations in glomerular sialoprotein. Experimental evidence suggests that barriers to glomerular filtration of macromolecules exist at the glomerular basement membrane itself and at the level of the epithelial cell and epithelial slit pores. The distribution of negatively charged glomerular sialoprotein (GSP) at the latter site and the reduction in histochemical staining for GSP reported in several clinical and experimental glomerular diseases suggest a role for this material in the regulation of glomerular permeability. Alternatively, reductions in GSP associated with proteinuria may reflect only epithelial cell swelling consequent to the proteinuria. The sequence of subepithelial immune complex deposition, epithelial cell swelling and foot process fusion, alterations in histochemical staining for GSP, and development of proteinuria was studied in 12 Lewis rats biopsied weekly during development of autologous immune complex (Heymann) nephropathy. Deposition of IgG was detectable 3 weeks after antigen injection by immunofluorescence. Electron-dense deposits were first seen by electron microscopy coincident with the appearance of complement at week 4. Proteinuria began at 6 to 8 weeks, 3 to 5 weeks after detectable immune complex deposition. Proteinuric animals had marked subepithelial immune complex deposition and extensive epithelial cell swelling and foot process fusion. Despite these changes, there was no detectable reduction in staining for GSP until week 14, 6 to 8 weeks after onset of proteinuria. Reductions in GSP apparently do not play a role in altering glomerular permeability early in autologous immune complex (Heymann) nephropathy, and proteinuria and epithelial cell swelling can be present in this model without detectable changes in GSP. These findings suggest that early alterations in GSP reported in some other proteinuric disorders may be of pathogenetic significance rather than simply a reflection of changes in epithelial cell morphology secondary to proteinuria. In this experimental model of membranous nephropathy, immunofluorescence was more sensitive than electron microscopy in the early detection of immune deposits.


Peroxidase activity of alveolar macrophages. Peroxidase activity was studied in alveolar macrophages and compared to the peroxidase activity in polymorphonuclear leukocytes using cytochemical techniques. A dense reaction product for peroxidase was observed in the primary lysosomes of polymorphonuclear leukocytes, but no significant peroxidase or peroxidative enzymes could be detected in rabbit alveolar macrophages. Furthermore, following vigorous phagocytosis of zymosan particles by alveolar macrophages in vitro, no peroxidase could be detected in association with the phagocytic vacuole. Exogenous horseradish peroxidase was ingested readily by alveolar macrophages so that abundant reaction product was demonstrated in pinocytotic vesicles and phagocytic vacuoles. The uptake of exogenous peroxidase by pinocytosis appeared to be more vigorous in alveolar macrophages than in polymorphonuclear leukocytes. These studies demonstrate that alveolar macrophages do not contain significant quantities of peroxidase and suggest that, it contrast to polymorphonuclear leukocytes, peroxidative metabolism does not contribute in a major way to microbial killing by alveolar macrophages.


Alterations of the glomerular epithelium in acute aminonucleoside nephrosis. Evidence for formation of occluding junctions and epithelial cell detachment. The visceral glomerular epithelium of rats made nephrotic by daily injections of puromycin aminonucleoside was examined from the time of onset of proteinuria (day 6) to the time when many animals die (day 15) in order to establish the chronology of the pathologic alterations which occur during the course of the disease. In addition, the structure of the residual epithelial slits was examined using special fixatives and freeze-fracture. Changes seen early in the disease (7 to 9 days) are: (1) a reduction in the number of foot processes and filtration slits; (2) occurrence of occluding junctions in many of the residual slits coupled with displacement of the slit diaphragms; (3) thinning of the dense central portion of the basement membrane (lamina densa) with a corresponding widening of the space (lamina rara externa) between it and the epithelium; (4) heightened epithelial pinocytosis with increased numbers of protein absorption droplets or lysosomes. In freeze-fracture preparations the occluding junctions were seen to be limited in extent and made up of only a few strands, indicating they are incomplete and represent occluding maculae or fasciae rather than zonulae. Later on in the disease (10 to 15 days) no further changes in the number or arrangement of slits is evident, but other alterations occur: (1) denuded regions of basement membrane are seen where there is initially partial and eventually complete detachment of the epithelium from the basement membrane; (2) increasing numbers of large vacuoles or phagosomes and decreasing numbers of fully condensed lysosomes are present; and (3) basement membrane-like material is seen in the spaces between the partially detached epithelium and basement membrane. The new findings in this study are: (1) the clarification of early (reversible) versus late (probably irreversible) changes in the glomerular epithelium in a acute aminonucleoside nephrosis; (2) delineation of the structure of the residual epithelial slits; (3) the description of progressive loosening of the attachment between the epithelium and the basement membrane leading to focal or complete epithelial cell detachment; (4) the presentation of evidence indicating that exhaustion of the lysosomal system of the glomerular epithelium (in protein absorption and concentration) occurs late in the disease. The available evidence is summarized and indicates that the glomerular basement membrane, the main glomerular filter, is defective in aminonucleoside nephrosis and allows increased protein leakage. However, it seems likely that the main site of action of aminonucleoside is on the epithelium leading to the production of defective basement membrane.


Effect of hashish compounds on mouse peritoneal macrophages. Light microscopy reveals an induction of extensive vacuolation in the macrophage after exposure to either delta 1-tetrahydrocannabinol or cannabidiol. Numerous small vacuoles appear in the cell periphery as early as 15 minutes after exposure (at 37degrees C.) to either of the compounds in 20 per cent newborn calf serum-Dulbecco's modified Eagle medium. The small lucent vacuoles coaleasce and yield enormous vacuoles which dominate the the cytoplasm. At approximately 3 hours, many of the vacuoles seem to burst with a concomitant expulsion of cell interior. The effect of hashish compounds on macrophages is essentially irreversible; exposure for 15 minutes to 10(-5) m of delta 1-THC or cannabidiol and a thorough wash in 20 per cent serum-medium, suffices to trigger the sequence of vacuolation and total cell death in the culture. Two major processes involving early reorganization of cellular membranes have been observed using electron microscopy. One relates to the formation of numerous autophagic vacuoles full of organelles, the other relates to the appearance of cytoplasmic inclusions representing extensive destruction of intracellular constituents. Both types of cytoplasmic change have been observed in alveolar macrophages of hashish smokers. Thus, the conditions in the in vitro studies are similar to conditions in people exposed to hashish smoke.


Combined cardiotoxicity of adriamycin and x-radiation. Our previous studies have shown that x-radiation produces cardiac lesions. Likewise, adriamycin,  a useful antineoplastic agent, is known to be cardiotoxic. Maximal "safe" doses have been established for each of these forms of therapy. Since combined therapy with adriamycin and radiation is being used for malignancies involving the mediastinum, it is important to know whether the combination of both agents is more cardiotoxic than either agent alone. In this study young New Zealand White rabbits were divided into five groups and given: (1) a single dose of x-radiation of 1600 rads in the cardiac area; (2) 167 mg. per sq. m. of adriamycin; (3) both raddiation and adriamycin at the same doses; (4) 255 mg. per sq. m. of adriamycin; (5) no treatment. Animals in the third (combined) group developed radiation and adriamycin lesions, the frequency and severity of which were greater than those in the single therapy groups at the same (low) doses. These observations suggest a synergistic effect of  the two agents. If so, patients receiving combined treatment are at risk of developing severe carditis from doses of adriamycin and cardiac x-radiation today regarded as safe. Although neither one is specific, the light and electron microscopic lesions caused by x-radiation (myocardial capillary damage, pericarditis) were easily distinguished from those caused by adriamycin (myocyte damage). Both agents led to diffuse myocardial fibrosis. These morphologic characteristics may have clinical applications.


An optical and ultrastructural study of the localization of carcinoembryonic antigen (CEA) in normal and cancerous human rectocolonic mucosa. An immunoenzymologic method using peroxidase-labeled antibodies has been applied for the localization of carcinoembryonic antigen (CEA) on frozen sections, on Araldite-embedded sections, and on isolated cell preparations of normal rectocolonic mucosa and of rectal and colonic cancers (adenocarcinomas and one villous tumor). CEA appears as a component intimately associated with the external coating of the striated border of the normal columnar cell and with the external coating of the apical pole of the cancerous cell. CEA is also found as an intracellular component of the normal epithelial cell of the rectocolonic mucosa, mainly the goblet cell. In tumors, it appears as an intracellular component of the mucussecreting cell. Its presence in the cell coat and interior of the cell correlates with the degree of differentiation of the cells, whether cancerous or not. Progressive accumulation of CEA in the normal colonic epithelial cell has been observed in cells undergoing maturation. Its release by the mature goblet cell has also been observed. These results confirm that CEA is a normal glycoprotein constituent of the epithelial cell of the human adult rectocolonic mucosa, synthesized and discharged by this cell. The difference in CEA content, already reported, between the cancerous and the normal rectocolonic mucosa appears quantitative and not qualitative.


Improving the results of ligation of patent ductus arteriosus in small preterm infants. Thirty-two consecutive preterm infants with birth weights under 1,500 grams and with respiratory distress syndrome (RDS) complicated by a patent ductus arteriosus (PDA) underwent ligation of PDA. The indications for operation were massive left-to-right shunting associated with heart failure (cardiomegaly and pulmonary edema) unresponsive to medical treatment. The clinical manifestations of heart failure were related to the severity of RDS. Infants with mild-to-moderate RDS (21) often recovered and later developed typical findings of PDA (bounding pulses, hyperactive precordium, and murmur). They are now operated upon as soon as respiratory support is required. Infants with severe RDS (11) develop cardiomegaly earlier, and retrograde aortography may show massive left-to-right shunting before the presence of a murmur. Ligation is indicated when blood-gas values deteriorate despite medical treatment. Nineteen (59 per cent) of these extremely preterm infants survived to be discharged and 16 (50 per cent) are developing normally. Three have neurologic impariment. None of the survivors has clinical respiratory disease, and their radiologic findings of bronchopulmonary dysplasia are improving.


Evaluation of aortic valve replacement with a porcine xenograft without long-term anticoagulation. From June, 1971, through November, 1974, 75 patients underwent aortic valve replacement with a Hancock "Stabilized Glutaraldehyde Process" porcine xenograft. Patients who underwent multiple valve replacements are not included in the study. Thirty-nine per cent of the patients had procedures for associated lesions or for removal of a Starr-Edwards prosthesis. The operative mortality rate was 6.7 per cent. Six patients died in the late postoperative period. Only one death was thought to be secondary to a valve-related problem. Actuarial analysis predicts 84 per cent survival at 3 years. Three patients initially received long-term antithromboembolic therapy. There have been three suspected or documented thromboembolic episodes (0.24 per cent per patient-month). Ten per cent of the patients surviving the operation developed murmurs of aortic insufficiency. There have been no documented valve failures. Ninety-eight per cent of the survivors have experienced an improvement in their New York Heart Association (N.Y.H.A.) classification.


Patent ductus arteriosus in premature infants. Indications for surgery. In order to establish more objective criteria for surgical intervention, the literature and our clinical experience with operative closure of patent ductus arteriosus in 11 premature infants was reviewed. A wide range of age at the time of operation underscored the spectrum of clinical presentation and the difficulty of interpreting the course of therapy. The presence of a typical continuous murmur established the diagnosis of patent ductus arteriosus in patients with respiratory distress syndrome. Cardiac catheterization confirmed the diagnosis and provided quantitation of the left-to-right shunt flow through the ductus arteriosus in 6 patients but did not influence the decision to operate. Progress of the clinical course as determined by the heart size on chest roentgenogram and the presence of hypercarbia (Paco2greater than60 mm. Hg) after respiratory assistance and medical decongestive measures were the two most helpful signs indicating the need for surgical intervention.


Functional reductions in left ventricular volume. Minimum chamber size consonant with effective hemodynamic performance. A heart model in dogs was developed to evaluate quantitatively the extent to which left ventricular chamber size could be reduced and yet retain residual mechanical function to perform adequately as a pump. In 9 animals placed on right heart bypass perfusion to control systemic flows; left ventricular performance was estimated from high-fidelity left ventricular pressure and aortic flowmeter recordings and from lateral plane left ventricular angiograms. Studies were made during unrestricted left ventricular filling at varying cardiac outputs and with inflation of a balloon in the left ventricular cavity at a physiological cardiac output. As compared with control data (cardiac output 1.4 L. per minute), balloon inflation to 18.7 ml. caused an increase in total left ventricular end-diastolic volume (from 35.4 to 44.3 ml., p less than 0.001) and left atrial pressure (from 7.8 to 21.2 mm. Hg; p less than 0.001); it also caused a reduction in left ventricular stroke work (from 12.5 to 8.1 Gm.-M., P LESS THAN 0.005) ANd max. dp/dt (from 2,487 to 1,320 mm. Hg per second, p less than 0.05). Importantly, left ventricular stroke volume was unchanged. When compared with preload augmentation (with the balloon deflated), the magnitude of depression of cardiac performance caused by balloon inflation was more fully appreciated (left ventricular stroke work, max. dp/dt, and ejection fraction reduced 69, 61, and 45 per cent, respectively). Even so, with appropriate compensations, principally by the Frank-Starling mechanism, up to 42 per cent of the left ventricular cavity volume could be functionally eliminated with retention of adequate mechanical performance. Such data may have implications regarding the extent of resections possible in patients undergoing surgery for left ventricular aneurysm.


Cephalothin prophylaxis assay during cardiopulmonary bypass. Efficient use of prophylactic antibiotics in surgery demands their presence in adequate serum concentration at the time of maximal potential contamination. This cover should extend from the moment of incision until at least the time of removal of large tubes and intravenous connulas. Critical cardiac contamination may occur during the bypass procedure while the operation within the cardiac chambers is being done. This is a special danger in valve replacement with prostheses. The antibiotic regimen of the Cardiothoracic Unit was studied in 12 consecutive patients and was generally found to provide adequate antibiotic coverage throughout the surgical procedure, including the bypass procedure. In all patients, a reinforcing cephalothin dose on completion of bypass ensured adequate circulating cephalothin levels for the completion of surgery. Clearance of the cephalothin from the blood of patients was found to decrease markedly during cardiopulmonary bypass.


Chronic hemolysis following mitral valve replacement. A comparative study of the Björk-Shiley, composite-seat Starr-Edwards, and frame-mounted aortic homograft valves. Hemolysis was assessed in 86 patients after mitral valve replacement. Twenty-four patients had mitral valve replacement with a Björk-Shiley valve, 32 patients with a Starr-Edwards composite-seat valve, and 30 patients with an irradiated frame-mounted aortic homograft valve. Hemolysis was determined by red cell survival and autologous 51Cr-tagged red cells, LDH, serum haptoglobin, hemosiderinuria, reticulocyte count, red cell fragment count, and hemoglobin estimation. The degree of hemolysis was classified as mild, moderate, or severe. Thirty-five per cent (nine of 24) of the Björk-Shiley group showed mild hemolysis, whereas 85 per cent (28 of 32) of the Starr-Edwards group had evidence of hemolysis-of these, a third were mild and the rest moderate. The homograft series did not show any comparable evidence of hemolysis. Statistical analysis of the parameters of the study comparing homograft with Björk-Shiley valves showed no significant difference except in red cell survival, which showed a highly significant difference (p less than 0.001). Comparing homograft with Starr-Edwards valves, all parameters showed highly significant differences (p less than 0.001).


Results of mitral valve replacement with the Beall prosthesis in 209 patients. In this 3 year study of 209 patients who underwent mitral valve replacement with the newer Beall prostheses (Models 104 and 105) the operative mortality rate was 5.2 per cent. None of these deaths was related to the valve. This prosthesis features a larger frustrum area and a "turtle-neck" sewing ring which permits its rapid insertion with a continuous suture technique. Of the 20 (9.5 per cent) late deaths, two were due to thrombosis of the valve. Among the 178 survivors, 17 developed thromboembolic complications; however, 10 of these patients recovered. Late clinical results have been quite satisfactory in over 90 per cent of the survivors. In the 15 patients who underwent hemodynamic studies postoperatively, the cardiac index and pulmonary artery pressure showed significant improvement; however, they still had transvalvular gradients at rest. The improvement in the design of this prosthesis has been an important factor in lowering the operative risk and improving the late results of mitral valve replacement.


Isolated replacement of the mitral valve with the Starr-Edwards prosthesis. Isolated mitral valve replacement with the Starr-Edwards prosthesis has been performed on 657 patients at the Mayo Clinic during the 11 year period ending January, 1972. The most recent subset of that series comprised patients who received the Model 6120 prosthesis. In this group, the operative mortality rate was 9 per cent and the actuarial late death rate at 5 years was 20 per cent. This survival rate is a significant improvement over the natural history of severe mitral valve disease. Factors associated with operative deaths are large left artrial size, advanced functional class, and previous heart surgery. Variables associated with higher incidence of late deaths are large left atrial size, patient age at operation, and multivalve disease. Risk of thromboembolism is increased with large left atrial size, presence of left atrial thrombus, and inadequate anticoagulant therapy.


Aortico-left ventricular tunnel. Clinical profile, diagnostic features, and surgical consideration. Case histories of 2 patients with aortico-left ventricular tunnel are reported. A review of the literature on this subject shows a unique clinical profile. The electrocardiographic (ECG) and roentgenographic features as well as the hemodynamic and angiographic data of 18 previously reported patients are reviewed. The anatomy and pathophysiology of the defect are discussed and surgical management is described. It is recommended that surgical correction be carried out as soon as the diagnosis is established.


The non-hermetically sealed pacemaker myth, or, Navy-Ribicoff 22,000-FDA-Weinberger o. Although the Secretary of Health, Education and Welfare recently stated that hermetic sealing of all implanted cardiac pacemakers, as recommended by the Navy in 1969, is inadvisable, several small manufacturers are already marketing hermetically sealed devices (CPI, Pacesetter), all of the over 600 nuclear pacers implanted to date have been hermetically sealed, and belatedly the major manufacturers are developing hermetically sealed units. Total hermetic sealing of all implantable electronic devices has been technically feasible for years, and it is essential that device legislation include mandatory encapsulation standards.


Cannulation of the ascending aorta for cardiopulmonary bypass. Experience with 9,000 cases. The Cleveland Clinic team has now accumulated experience with cannulation of the ascending aorta for arterial return in more than 9,000 patients. Since adoption of this technique, only one lethal dissection has occurred and other related complications have been minimal. Technique, surgical pitfalls, contraindications, and complications of ascending aortic cannulation are discussed in this communication.


Cocking of a poppet-disc prosthesis in the aortic position. A cause of intermittent aortic regurgitation. Intermittent aortic regurgitation due to cocking is described for the first time after replacement of the aortic valve with a poppet-disc prosthesis. A combination of disc grooving and strut thrombus produced the cocking with resultant aortic regurgitation.


The prognostic value of measuring the gross linear radial growth of pulmonary metastases and primary pulmonary cancers. The gross rates of growth of pulmonary cancers and pulmonary metastases may be reduced to clinically useful nomograms and graphs. The constructs are feasible because most neoplasms growing in the lung are observed only during a limited segment of their life history, often being observed too few times to permit the identification of the growth curve of best fit. Consequently, the parameter that can be calculated most quickly, namely linear growth rate in mm./day, may be most useful. The linear radial growth rates are plotted against observed survival. The nomograms permit easy approximation of the volume doubling time and the exponential radial growth rate in mm./mm./day. The mean of the log normal frequency distributions of doubling times for common primary and metastatic cancers found growing in the lung is plotted on one nomogram to put the information in perspective. The more widespread reporting and tabulation of such data should lead to a highly useful kinetic staging and treatment evaluation system.


Changes in extravascular lung water during venovenous perfusion. The accumulation of extravascular lung water was related to changes in plasma colloid osmotic pressure and pulmonary hydrostatic pressures in 12 normal dogs and 13 dogs that had venovenous perfusion for 2 hours at 45 to 70 ml. per kilogram per minute. The venovenous perfusion system included a membrane oxygenator and a roller pump. Net intravascular filtration pressure was calculated from plasma colloid osmotic pressure and pulmonary hydrostic pressures. Rapid accumulation of extravascular lung water occurred in control and bypass animals when net intravascular filtration pressure exceeded zero. At lower filtration pressures, venovenous perfusion did not affect accumulation of extravascular lung water.


Collis-Belsey reconstruction of the esophagogastric junction. Indications, physiology, and technical considerations. Twenty-four patients underwent combined Collis-Belsey reconstruction of the esophagogastric junction. The primary indication for operation in 19 patients was gastroesophageal reflux. Three patients had achalasia, one diffuse spasm, and one an incarcerated combined sliding and paraesophageal hernia.  Postoperatively, symptoms were relieved in all 19 patiients undergoing repair for gastroesophgeal reflux with or without peptic strictures of the esophagus, and barium swallows showed no gastroesophageal reflux. Preoperative average mean and peak pressures in the distal esophageal high pressure zone (HPZ) were 1.38 and 2.72 mm. Hg, respectively; two thirds had no measurable HPZ. Postoperative mean and peak pressures were 6 and 12.36 mm. Hg, respectively; average HPZ length was 2.81 cm. Of 19 patients with massive reflux preoperatively, postoperative acid reflux testing demonstrated no reflux in 14 and minimal to moderate reflux in five. Collis-Belsey reconstruction ot the esophagogastric junction effectively relieves symptoms and controls the complications of gastroesophageal reflux.


Neonatal pneumopericardium.

Neonatal pneumopericardium. Three cases of neonatal pneumopericardium are presented. Detailed ventilatory measurements and chest roentgenographic changes are described for each of the three patients. The literature of neonatal pneumopericardium is reviewed, and based on that review and our own cases, we offer guidelines for managing these patients.


Generalized sharp and slow wave and electrodecremental seizure pattern in subacute sclerosing panencephalitis. Although subacute sclerosing panencephalitis (SSPE) often presents with a characteristic EEG pattern, a 13-year-old boy with a confirmed diagnosis of SSPE had several EEG features that are unusual for this condition, namely, generalized sharp and slow wave (slow spike and wave) discharges during the waking record, an electrodecremental pattern associated with clinical seizures, and activation of the typical periodic complexes of SSPE only during sleep.


Further study on the two-column plasma catecholamine assay. The two-column procedure for plasma catecholamine determination was adopted as a routine diagnostic test. It was found that the recovery of catecholamine added to properly preserved plasma was 65%. The most efficient recovery occurred when the water content of alumina used was above 23%. Both interassay and intra-assay precision were +/- 10% (coefficient of variation). The catecholamine was stable, in properly preserved plasma, for at least 18 days at -20 degrees C.


Clinically suspect pulmonary embolism after vein stripping. Clinically suspect but nonfatal pulmonary embolism followed vein surgery in 16 of 4,080 patients operated on over a 10-year period from 1962 to 1971, an incidence of 0.39%. The presence of superficial thrombophlebitis, previous or recent thromboembolic disease, or chronic deep venous insufficiency was a statistically significant factor in patients who had embolism. Prophylactic postoperative anticoagulant treatment in those with a thrombotic background appears justified.


Detecting intrapulmonary right-to-left shunt with contrast echocardiography. Observations in a patient with diffuse pulmonary arteriovenous fistulas. Contrast echocardiography has been useful in detecting intracardiac right-to-left shunts. In a patient with hereditary hemorrhagic telangiectasia and diffuse pulmonary arteriovenous fistulas, we have demonstrated the feasibility of detecting intrapulmonary right-to left shunting using this technique. After venous injection of indocyanine green dye, the characteristic contrast flow pattern consisted of a markedly delayed appearance of echoes in the left ventricle.


Spastic eversion of the upper eyelids.

Spastic eversion of the upper eyelids. A 2-year-old black Nigerian infant presented with eversion of the upper eyelids which followed an episode of presumed measles conjunctivitis. Eversion recurred despite patching and taping, but was terminated by facial akinesia and placement of lid sutures. Orbicularis spasm undoubtedly plays a role in the pathophysiology of this disorder, acting together with other etiologic factors.