Ligneous cellulitis associated with an IUD. Many reports have documented serious pelvic infection associated with an IUD. A case of ligneous pelvic cellulitis with cutaneous sinus tract formation, hydronephrosis, and ureteral obstruction in a patient with an IUD is presented. This is an uncommon manifestation of chronic pelvic infection and responded to antibiotics and steroid administration. The origin and treatment of ligneous cellulitis are discussed.


Primary ovarian pregnancy associated with the dalkon shield IUD. This is the third case report of an ovarian pregnancy associated witth the Dalkon shield intrauterine device (IUD). The recent theories of mechanism of action of the IUD are described. The incidence of ectopic pregnancy with the IUD is discussed. The authors stress the fact of being alert to the possibility of an ectopic ovarian pregnancy with the IUD in the absence of suggestive signs and symptoms of pregnancy.


Carcinoma of the cervix complicated by a soup spoon. A case is reported of a large serving spoon discovered in the abdomen after an abdominal hysterectomy. The surgical use of this item is explained.


Sigmoidovaginal fistulae due to diverticular disease. Two case reports and an update. Sigmoidovaginal fistulae are rare. They occur as a result of malignancy, irradiation, pelvic surgery, or diverticular disease, the latter being the principal cause. Numerous diagnostic techniques are available. Therapeutic modalities for these fistulae are discussed.


Ovarian arteriovenous fistula. An unusual cause of abdominal pain. Arteriovenous fistulae of the ovarian artery may develop after gynecologic surgery. A case that occurred 9 years after hysterectomy with bilateral oophorectomy is presented and discussed. It illustrates an unusual cause of left lower quadrant abdominal pain. Surgical removal of the ovarian arteriovenous fistula resulted in complete relief of the patient's symptoms. This uncommon entity must be considered when dealing with lower quadrant pain and a past history of hysterectomy.


Rokitansky-Kuster-Hauser syndrome and leiomyoma uteri. A large leiomyoma found in a patient with Rokitansky-Kuster-Hauser syndrome 8 years following McIndoe's procedure for the creation of an artificial vagina emphasizes the need for continued long-term gynecologic care of these patients who are theoretically at average risk for the development of myometrial or ovarian neoplasia. The fact that with the syndrome leiomyomata have been reported only three times previously and ovarian malignancy never suggests that these patients are often lost to long-term followup.


An unusual complication of fetal blood sampling during labor. A female infant was delivered at term after biophysical and biochemical monitoring during the intrapartum period. At birth excessive bleeding was noted from the scalp incision sites, leading to severe anemia. The infant was also found to have congenital syphilis. The clinical course was complicated by the development of disseminated intravascular coagulation leading to death despite intensive management. Identification and appropriate management of excessive pre- and postnatal bleeding from a sampling incision is emphasized.


Incomplete testicular feminization with multiple congenital abnormalities. A female infant presented with absent vagina and uterus, absent left kidney, absent right gonad, growth failure, mental retardation, seizure disorder, and facial, limb, and hand anomalies. The chromosome karyotype was 46, XY in her blood and cultured cells, including cells from the sites of both gonads. Her H-Y antigen was positive. Specific dihydrotestosterone binding was reduced in cells from a labial skin biopsy. The case might be due to a minute deletion of the short arm of the X chromosome, resulting in loss of a gene for androgen receptors and of adjacent chromosomal material responsible for the growth failure and the somatic and neurologic anomalies.


Familial male pseudohermaphroditism with incomplete virilization. A 21-year-old 46 XY individual with familial male pseudohermaphroditism was investigated. Phenotype consisted of pseudovaginal perineoscrotal hypospadias with bilateral inguinal gonads and a masculine habitus without gynecomastia. Plasma testosterone, cortisol, follicle stimulating hormone, urinary 17-ketosteroids, and 17-ketogenic steroids were within the normal male range. Plasma dihydrotestosterone was at the lower limit of the normal male range. Plasma luteinizing hormone was three times and plasma estradiol was about one and a half times the upper limit of normal for men. These results are consistent with a partial defect in the mechanism of action of testosterone. The differential diagnosis of various forms of male pseudohermaphroditism is discussed.


Bacterial endocarditis due to Listeria monocytogenes in a pregnant diabetic. A case of bacterial endocarditis due to Listeria monocytogenes in a pregnant, Class D diabetic patient is presented. The importance of obtaining proper cultures and instituting appropriate antibiotic therapy promptly is emphasized. A favorable outcome was achieved in spite of the combined risk to the fetus of maternal diabetes and listeria endocarditis.


Problems of resistant thrombolysis and early recurrent thrombosis in streptokinase therapy. Problems of resistant thrombolysis and early rethrombosis during and immediately after streptokinase therapy have been studied with sequential phlebography in 39 patients. Early rethrombosis and resistant thrombolysis were found to correlate with the behavior of plasminogen and fibrinogen to streptokinase. Anticoagulants given during streptokinase therapy do not seem to affect these problems in a dramatic way.


Choledochoduodenostomy as an adjunct to choledocholithotomy. Choledochoduodenostomy was performed in 100 patients for calculus related disease of the common bile duct. There were no significant early or late complications of the anastomotic procedure. The 3 per cent mortality was related to antecedent advanced liver disease in two instances and, in one instance, to intra-abdominal sepsis. The surgical bypass has the advantage of circumventing the retained stone problem or the sequelae of benign obstructive disease in the distal part of the choledochus. It permits postoperative roentgenographic and endoscopic evaluation of the anastomotic site. Cholangitis, blind segment disability and malfunction have not been seen with these indications and this technique. When the common bile duct is at least 1.4 centimeters wide, primary or secondary choledochoduodenostomy with a wide anastomosis has significant advantages over T-tube intubation in the therapeutic and prophylactic management of choledocholithiasis.


The significance of elevated peritoneal fluid phosphate level in intestinal infarction. Early diagnosis seems mandatory if the mortality of mesenteric vascular occlusion is to be altered. A model has been developed in which intestinal infarction has been produced by ligation of either the superior mesenteric vein or the superior mesenteric artery. Results of earlier work, using this model, have shown a significant rise in the serum inorganic phosphate level and an associated severe metabolic acidosis. This article has confirmed these results as being statistically significant. In this experiment, a significant rise in the inorganic phosphate level of the peritoneal fluid has been shown in the same model. We suggest that, in the patient with possible intestinal infarction, an elevated serum phosphate level, elevated peritoneal fluid phosphate level, base deficit and leukocytosis may be useful in making an earlier diagnosis of this disease. If an earlier diagnosis is accomplished, the morbidity and mortality of this lethal disease hopefully will be reduced.


The prognosis of carcinoma of the colon and rectum complicating ulcerative colitis. Thirty-three carcinomas of the colon and rectum occurring in patients with ulcerative colitis have been compared with matched controls from a population without colitis. There is no difference in length of survival between the patients in the two groups. More extensive tumor spread in the control group is due to the method of selection.


Thymectomy in patients more than forty years of age with myasthenia gravis. Until recently, thymectomy has been reserved for patients with myasthenia gravis in the younger age groups. The use of transcervical thymectomy, with its reduction in morbidity and mortality, has allowed us to study the effects of thymectomy in the older age group. The records of 525 patients who underwent thymectomy were reviewed and divided into two groups: those less than and those more than 40 years of age. The incidence of thymomas was greatest in the older than 40 year group. This age group without thymoma was also noted to have a high incidence of absent germinal centers. The postoperative remission rates as well as the electromyographic improvement rates were comparable for both age groups. The evidence presented indicates that thymectomy improves the clinical course of myasthenia gravis in all age groups studied. We recommend transcervical thymectomy for all patients with generalized myasthenia gravis, regardless of age.


Comparative evaluation of surgical scrub preparations. The efficacy of 0.75 per cent available povidone-iodine scrub solution, 4 per cent chlorhexidine gluconate detergent solution and 3 per cent hexachlorophene emulsion against resident and transient flora of the hand has been compared using two currently accepted study designs. Chlorhexidine gluconate produced the greatest initial reductions against resident flora, followed by povidone-iodine and hexachlorophene, respectively. In subsequent washings, all three treatments further reduced the flora, chlorhexidine giving the greatest reduction on any test day. On gloved hands, there was significant regrowth following the use of povidone-iodine; there was no such significant regrowth on gloved hands which had been washed with chlorhexidine gluconate or hexachlorophene. Against transient flora, chlorhexidine gluconate gave the lowest over-all counts, followed by povidone-iodine and hexachlorophene, respectively. The reductions in bacteria counts increased following the repetitive use of chlorhexidine; no such trend was noted with either povidone-iodine or hexachlorophene.


Acute experimental autologous fat embolism in dogs. An experimental technique has been devised to study the acute respiratory and hemodynamic results of autologous fat embolism in dogs. By using a commercially available autotransfusion device, fat can be aspirated and reinfused into the venous circulation. Acute rises in pulmonary artery pressure and calculated pulmonary dead space can be produced, and arterial oxygen saturation is impaired. These changes correlate well with the appearance of intravascular embolized fat. Apparent intravascular clot formation is demonstrated, the fat droplet acting as a stimulus or nidus for clot formation. These changes were avoided when the infusate was first passed through a micropore filter.


Dose reduction in mammography.

Dose reduction in mammography. The Min-R system is more than a satisfactory substitute for xerography. At equal distances, the images obtained are equivalent. Radiation exposure was 25 per cent of xerography, a significant reduction in exposure. By using a long cone and improving geometry, superior images were obtained in 4 per cent of 400 comparison patients. If mammography is to be used as an early detection device in patients with carcinoma of the breast, modalities with lower exposure requirements must be used. Min-R, a new film screen system, fulfills the requirement of reduced patient exposure without loss of diagnostic accuracy.


Intraoral field block anesthesia for extraoral lesions. Intraoral field block anesthesia for extraoral surgical procedures provides a technique which is both extremely safe and easy to administer. As with all local anesthetics, injected volumes should be monitored at all times. Hemostasis may be augmented, if necessary, with topical epinephrine solution. When vasoconstrictors are contraindicated, mepivacaine, Carbocaine, may be substituted for its inherent properties.


Geriatric psychiatry training for the general psychiatric resident. Although there is a real need in variety of settings for psychiatrists trained in working with older people, a large proportion of psychiatric residency programs do not offer the opportunity for clinical experience with this age group. The author stresses the need to include this subject in the curriculum of residency training programs. He describes the features of one program that offers comprehensive training in this area.


The functions of experimental participatory experiences in the learning-teaching process. The author analyzes the process by which experimental approaches and observations are transformed into usable knowledge. She examines her past work within this framework. Flexibility and open-ended beliefs permit the testing of new, unfamiliar data against known theoretical backgrounds and their subsequent organization and incorporation into further learning experiences. This material, in turn, can be formulated into new content that enhances one's learning and teaching potentials.


"Organic brain syndromes": an empirical study and critical review. The authors found that all but 3 of 80 randomly chosen patients in a Veterans Administration hospital who had been given a primary nonspecific neuropsychiatric diagnosis (organic brain syndrome, organic psychosis, chronic brain syndrome, etc.) could be assigned to specific diagnostic categories. Diagnosis was based on chart review and thorough neurological and clinical evaluation. Senile and alcoholic dementia and Korsakoff's syndrome were seen most often, and 15% of the patients were diagnosed as having functional disorders of the mental state. The authors review the organic brain syndrome diagnosis in light of this and other evidence. They believe that fractionation into more specific diagnoses is essential to further understanding of this group of diseases. Use of the general term can result in inappropriate or no treatment; further, it hampers essential psychological, pharmacological, and biomedical research on these disorders.


The physician's knowledge of psychotropic drugs: preliminary results. A questionnaire about three commonly prescribed psychotropic drugs was administered to physicians and trainees in two specialties and to medical students. Psychiatrists and psychiatric residents had very low levels of knowledge about the physiology, pharmacology, and side effects of diazepam; their scores did not exceed those of medical residents or students. Trainees in internal medicine scored poorly regarding the diagnosis of depressive syndromes and the physiology and pharmacology of imipramine and amitriptyline, whereas psychiatrists performed well. The results of this preliminary study can provide guidelines for improving the teaching of psychopharmacology in general and the psychopharmacological treatment of the medically ill in particular.


Crime and violence among mental patients reconsidered in view of the new legal relationship between the state and the mentally ill. The author compared the arrest rates of 301 former state mental hospital patients with those of the local county population and selected U.S. cities. He found that the patients had a markedly higher incidence of arrests for criminal behavior, including violent offenses, than either of the comparison groups. Patients who were female, aged 20-30, and nonwhite had higher arrest rates for violent offenses than the rest of the study group. These findings are at variance with those of earlier studies but are in general agreement with more recent studies. The author suggests the need for further research in order to more completely identify those factors which explain the high crime rate among the mentally ill.


Adaptive and pathogenic aspects of sex-role stereotypes: implications for parenting and psychotherapy. There has been considerable controversy concerning adaptive versus pathogenic effects of sex-role stereotypes on individual development. The author evaluates both the positive and negative consequences of sex-role stereotypes without regard for any particular sociocultural definition of masculinity or feminity. She hypothesizes that the degree to which sex-role stereotypes are adaptive and facilitative (as opposed to restrictive and pathogenic) is inversely related to the degree to which an individual has consolidated a comfortable and stable gender is identity. Implications for parenting and treatment are elaborated.


The process of criminal commitment for pretrial psychiatric examination: an evaluation. The authors examined the records for 1975 of 87 pretrial commitments to Worcester State Hospital under a 1971 revision of the Massachusetts law regarding such commitments. They also compiled statistics on all admissions to the hospital for 1966-1975. They found that only 2 of the 87 pretrial commitments resulted in a final court disposition of commitment and that pretrial commitments increased during 1972-1975 in contrast to a decrease in other kinds of admissions. On the basis of these findings the authors suggest that serious attention be paid to arguments that pretrial commitment serves to control and sequester deviants. Dr. Alan A. Stone comments on the authors' presentation.


Sodium amylobarbitone in the differential diagnosis of confusion. The authors describe the use of intravenous sodium amylobarbitone to differentiate between functional and organic confusion. Four psychiatric patients with functional confusion developed a clear sensorium on this drug. Since previous studies have demonstrated that organic confusion is increased by sodium amylobarbitone, the authors conclude that the drug can be an aid in the differential diagnosis of confusion. They discuss possible applications.


Urinary 3-methoxy-4-hydroxyphenylglycol and psychiatric diagnosis. The authors examined the quantities of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the urine of 11 schizophrenic female patients, 14 primary affective disorder (depressed type) female patients, and 10 healthy comparison women. The primary affective disorder patients had significantly less MHPG in their urine than did the comparison subjects. The schizophrenic patients when compared with the healthy subjects or the depressed patients did not excrete significantly different amounts of MHPG in urine. The variance in MHPG in schizophrenic patients was quite large; some had very low urinary MHPG. There was a significant positive correlation between agitation and urinary MHPG for schizophrenic but not depressed patients. The authors discuss theoretical and practical implications of these findings.


Neurogenic and hysterical seizures in children and adolescents: differential diagnostic and therapeutic considerations. For patients whose seizures are not controlled by medication alone, psychotherapeutic intervention can sometimes play a useful adjunctive role in both differential diagnosis and treatment. Diagnostic issues include the differentiation between neurogenic and hysterical seizures as well as the delineation of the possible role of psychogenic stress in triggering neurogenic seizures. Therapeutic considerations focus on the alleviation of precipitating stresses as well as the development of a sense of mastery in the patient.


Platelet monoamine oxidase in chronic schizophrenic patients. The authors investigated platelet monoamine (MAO) activity in 40 chronic schizophrenic patients, 55 normal control subjects, and 16 hospitalized control subjects. The mean platelet MAO activity for the chronic schizophrenic patients was significantly lower than the mean in either control group. There were no significant differences between the mean platelet MAO activities in 21 chronic paranoid schizophrenic patients compared with 18 chronic undifferentiated schizophrenic patients.


Light-mediated reduction of flavoproteins with flavins as catalysts. It has been found that small amounts of free flavins greatly accelerate the photochemical reduction of flavoproteins both to the radical and fully reduced oxidation states. This catalytic effect has been shown to be due to the rapid photochemical reduction of the free flavin to its fully reduced state, followed by its reaction with the flavoprotein to yield flavoprotein radical and by its reaction with flavoprotein radical to yield fully reduced flavoprotein. Evidence is presented that the same route may occur with flavoproteins in the absence of added flavins. In this case the photoreduction is mediated by the small equilibrium concentration of free flavin coenzyme present in a flavorprotein solution. Hence, it is suggested that flavoprotein reduction with EDTA as photosubstrate does not involve an excited state of the holoprotein, nor contact of EDTA with the enzyme, but exchange of electrons between enzyme flavin and free reduced flavin.


Biosynthesis of uroporphyrinogens. Interaction among 2-aminomethyltripyrranes and the enzymatic system. Many hypotheses on uroporphyrinogen biosynthesis advanced the possibility that 2-aminomethyltripyrranes formed by porphobilinogen deaminase are further substrates or uroporphyrinogen III co-synthase in the presence of porphobilinogen. These proposals were put to test by employing synthetic 2-aminomethyltripyrranes formally derived from porphobilinogen. None of them was found to be by itself a substrate of deaminase or of co-synthase in the presence of porphobilinogen. The tripyrranes chemically formed uroporphyrinogens by dimerization reactions, and the latter had to be deducted in control runs during the enzymatic studies. Two of the tripyrranes examined, the 2-aminomethyltripyrrane 7 and the 2-aminomethyltripyrrane 8, were found to be incorporated into enzymatically formed uroporphyrinogen III in the presence of porphobilinogen and of the deaminase-co-synthase system. While the former gave only a slight incorporation, the latter was incorporated in about 16%. No incorporation of 8 into uroporphyrinogen I was detected. On the basis of these results, and of the previous results obtained with 2-aminomethyldipyrrylmethanes, an outline of the most likely pathway of uroporphyrinogen III biosynthesis from porphobilinogen is given.


Lysine transfer RNA2 is the major target for L-ethionine in the rat. Ethionine, a hepatocarcinogen, ethylates macromolecules in vivo especially tRNA of rat liver. When rats were injected with L-[ethyl-3H]ethionine, the tRNA fraction of the liver was found to be labeled. One tRNA with the highest specific activity was purified and identified as lysine-tRNA2.


Kinetic and equilibrium studies on steroid interaction with human corticosteroid-binding globulin. Kinetic and equilibrium studies on the interaction of steroids with human corticosteroid-binding globulin (CBG, transcortin) were performed with pH, temperature, and steroid structure as variables. Dissociation rate constants were determined fluorometrically; the values for cortisol, corticosterone, deoxycorticosterone, and progesterone are 0.031, 0.047, 0.10, and 0.16 s-1, respectively, at 20 degrees C, pH 7.4. The pH dependence of the dissociation rate constant for the corticosterone complex below pH 10.5 at 20 degrees C is given by koff = 0.043 (1 + [H+]/10(-6.50)) s-1; above pH 11, koff = 0.030 (1 + 10(-12.15/[H+] s-1. A temperature-dependence study of koff for the cortisol and progesterone complexes gave values of 0.0028 s-1 and 0.012 s-1 at 4 degrees C, respectively, and 0.88 s-1 and 4.5 s-1 at 37 degrees C, with progesterone dissociating about four to five times faster over the entire temperature range. The affinity constants, determined by equilibrium dialysis, for the binding of cortisol, corticosterone, and progesterone at 4 degrees C were 7.9, 7.2, and 7.0 X 10(8) M-1; values of 0.40 and 0.26 X 10(8) M-1 were determined at 37 degrees C for cortisol and progesterone. The close similarity of the affinity constants of the three steroids combined with differing dissociation rates implies that the association rate changes with steroid structure, in contrast to our earlier findings with progesterone-binding globulin.


Effect of stacking interactions with poly(riboadenylic acid) on the triplet state properties of tryptophan. Optically detected magnetic resonance (ODMR) signals of tryptophan (Trp) have been measured in L-lysyl-L-tryptophyl-L-lysine (Lys-Trp-Lys) and in its complex with poly(riboadenylic acid) [poly(rA)]. Measurements were made with optical narrow band detection through the Trp O-O band. Plots of [D] and [E] vs. lambda are distinctly different for Lys-Trp-Lys and its complex with poly(rA). A reduction of [D], in particular, is consistent with stacking of Trp with adenine in the complex, since this effect is expected from charge-transfer contributions in the excited triplet state. Triplet energy transfer from poly(rA) to Lys-Trp-Lys is nearly complete at 77 K, with a Trp:adenine ratio of 0.1. The energy transfer efficiency is considerably reduced at 4.2 K and below, probably resulting from reduction of the triplet mobility in the polymer. Analysis of the phosphorescence decays shows that the triplet states of poly(rA), Lys-Trp-Lys, and their complex decay nonexponentially. Binding of polylysine to poly(rA) has no effect on the phosphorescence spectrum, but the decay kinetics are changed.


Molecular size heterogeneity of human leukocyte interferon. Molecular sieving of human leukocyte interferon revealed an apparent molecular weight of 26,000. However, after denaturation by guanidine hydrochloride in the presence of a reducing agent and reactivation by extensive dialysis, a molecular weight of only 21,000 was observed. The reactivated human leukocyte interferon (mol wt 21,000) gave a single peak of activity when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, confirming that a single molecular weight species was generated by the denaturation and reactivation procedure. A partial unfolding of the molecule was evident when the interferon preparation was heated to 50 degrees C in the absence or presence of an unfolding agent and then sieved on Sephadex G-100 Superfine. These results suggest that the interferon molecule undergoes a proteolytic cleavage probably by a protease present in extracellular fluid. Thus, a peptide fragment dissociates from the parent molecule when human leukocyte interferon is denatured in the presence of a reducing agent, resulting in a drop of 5,000 in molecular weight; interestingly, the resultant 21,000 molecular weight form still retains its antiviral activity.


Interaction of the peptide bond with solvent water: a vapor phase analysis. A dynamic technique, using radioactivity as a means of detection, makes it possible to measure the partial pressures of highly polar compounds in dilute aqueous solution. The results can be expressed in terms of the dimensionless distribution coefficient for transfer of a compound from dilute aqueous solution to the vapor phase. For acetic acid this coefficient is 1.1 X 10(-5), for acetamide 7.6 X 10(-8), for N-methylacetamide 4.1 X 10(-8), and for N,N-dimethylacetamide 5.4 X 10(-7). Thus acetamide is much more strongly solvated than the uncharged acetic acid molecule. The results suggest: (1) that the peptide bond represents an extreme among uncharged functional groups in the degree to which it is stabilized by solvent water; (2) that the very great hydrophilic character of the peptide bond may be associated mainly with hydrogen bonding of the solvent to the carbonyl oxygen atom (rather than the N-H group); and (3) that the observed equilibria of biosynthesis and hydrolysis of peptide bonds in aqueous solution are largely determined by differences between reactants and products in their free energies of solvation. It is anticipated that where "bound" water is found in proteins, it will often be found to be associated with peptide bonds, and will tend to be associated with the C-O group rather than with the N-H group.


Binding of carbon monoxide to isolated hemoglobin chains. Binding of carbon monoxide to the separated alpha and beta chains of hemoglobin, with and without bound p-mercuribenzoate, has been measured at temperatures from 5 to 340 K for times 2 mus to 1 ks using flash photolysis. All four proteins exhibit three different rebinding processes. The data are interpreted by a model in which the carbon monoxide, moving from the solvent to the binding site at the ferrous heme iron, encounters three barriers. The temperature dependences of the three processes yield activation enthalpies and entropies for the three barriers for all four proteins. Binding at temperatures below about 200 K is nonexponential, implying that the innermost barrier has a distribution of activation enthalpies. The distributions for the four proteins have been determined. At temperatures below 30 K, the CO binding rates approach finite low-temperature limits; binding thus proceeds by quantum-mechanical tunneling. Invoking a simple model, the widths of the innermost barriers are extracted from the measured tunneling rates. The experimental parameters are correlated with structural features of the hemoglobin chains and compared with previously published data on myoglobin and protoheme. A correlation is established between the height of the innermost barrier and the equilibrium CO pressure.


Complexity of nuclear and polysomal polyadenylated RNA in a pluripotent embryonal carcinoma cell line. The base-sequence complexities and relative abundance of polysomal and nuclear polyadenylated [poly(A+)] RNA sequences have been analyzed in a pluripotent embryonal carcinoma cell line. Polysomal RNA and nuclear poly(A+) RNA have a complexity representing respectively 0.5% and 2.5% of the single copy component of haploid mouse DNA (1.8 X 10(6) K base pairs). By hybridization with specific cDNAs, three abundance classes were found in polysomal poly(A+) RNA, representing respectively 31%, 33%, and 36% of the RNA, with base sequence complexities of 0.1 X 10(3), 0.9 X 10(3), and 14.5 X 10(3) kilobases. This corresponds to 7000-8000 different mRNA species of an average length of 2000 nucleotides, present on an average of 5 to 600 copies per cell. In nuclear RNA, a major class of abundance was found with a complexity of 100 X 10(3) kilobases, each sequence being present in 1 copy per nucleus. The majority of the polysomal poly(A+) RNA sequences are represented in the nuclear poly(A+) RNA but are present in a more restricted range of relative abundance implying posttranscriptional mechanisms of quantitative modulation: polysomal RNA sequences appear to be preferentially transcribed into nuclear cDNA suggesting a preferential location of these sequences close to poly(A) sequences. The presence of a specialized gene product, globin specific RNA, could not be detected either in the nuclear or polysomal compartments of embryonal carcinoma cells, even at levels that would have detected one sequence per 50 cells.


Photoreduction of flavoproteins and other biological compounds catalyzed by deazaflavins. Deazaflavins have been found to act as potent catalysts in the photoreduction of flavoproteins in the presence of EDTA and other "photosubstrates". In distinction to the catalysis brought about by normal flavins which involves dark reaction of the photoreduced flavin catalyst, the mechanism of the catalysis by deazaflavins has been shown to involve unstable, strongly reducing radicals which are generated by photolysis of a preformed covalent dimer. By this new method it is possible to reduce not only flavoproteins but a variety of other redox proteins, including heme proteins and iron-sulfur proteins. By virtue of its great catalytic efficiency, it is possible to employ concentrations of deazaflavin sufficiently low as not to interfere with the spectral evaluation of the reduced proteins obtained.


Design of new photoaffinity labels for ribosomal peptidyltransferase. The chemical syntheses of 6-azido-2'(3')-O-L-phenylalanylpurine ribonucleoside (4a), 2'(3')-O-(4-azido-L-phenylalanyl)adenosine (4b), and cytidylyl(3' leads to 5')-6-azido-2'(3')-O-L-phenylalanylpurine ribonucleoside (7) are described. 6-Azidopurine ribonucleoside 5'-triphosphate (10) was also synthesized starting from 6-methylmercaptopurine ribonucleoside. All of these compounds (4a, 4b, 7, and 10) are readily photolyzed by ultraviolet (UV) light. Compounds 4a, 4b, and 7 are active in the ribosomal peptidyltransferase-catalyzed release of the Ac-Phe residue from the Ac-Phe-tRNA-70S ribosome-poly(U) complex. It follows that the 6-azidopurine moiety of compounds 4a and 7, as well as the 4-azido-L-phenylalanine moiety of 4b, are recognized by the peptidyltransferase enzyme, and therefore these moieties are suggested for incorporation into tRNA as photoaffinity labeling reagents.


Congenital nonspherocytic hemolytic anemia with an unstable hexokinase variant. We report a family with a new hexokinase variant that gives rise to nonspherocytic hemolytic anemia in one apparently homozygous family member. The variant enzyme has a normal pH optimum, normal reaction kinetics, and normal electrophoretic properties, but has reduced activity and is apparently inactivated rapidly as the affected erythrocytes age.


Effects of short-term hypoxia on platelet counts of mice. Recent studies have shown that long-term hypoxia causes decreased platelet counts in mice and short-term hypoxia increased platelet counts. In an attempt to explain the mechanism that increases platelet counts of mice after exposure to short-term hypoxia, we measured platelet counts, total circulating platelet counts (TCPC), total circulating platelet masses (TCPM), percentages of 35S incorporation, and platelet sizes. Platelet counts, as well as TCPC and TCPM of mice, increased after 1-3 days of hypoxia, but these values were decreased after 6-7 days of hypoxia. Although platelet counts were increased in hypoxic mice, the percentage 35S incorporation into platelets and platelet sizes did not show a concurrent increase. After 6 days of hypoxia, average platelet diameters began to increase as platelet counts decreased. Splenic release did not account for the increase in platelet counts of mice after short-term hypoxia. It seems possible, therefore, that megakaryocytes "shed" platelets into the circulation in response to hypoxia. The platelets that enter the circulation in response to short-term hypoxia are smaller and incorporate less 35S than platelets that are produced in response to acute thrombocytopenia.


Marrow culture in diffusion chambers in rabbits. I. Effect of mature granulocytes on cell production. Factors influencing granulopoiesis have been evaluated using diffusion chambers implanted in the peritoneal cavity of rabbits. An increase in granulopoiesis in chambers implanted in hosts made neutropenic by nitrogen mustard occurs in mice made neutropenic by x-ray or drug. The intraperitoneal injection of leukocytes inhibited the growth of cells in chambers implanted in rabbits. Removal of mature granulocytes from marrow prior to chamber inoculation produced a marked in-increase in cell growth, especially of granulocytes. Mature granulocytes clearly inhibited cell replication and this inhibition involved both myeloid and erythroid elements, although the data suggest a greater effect on myelopoiesis. In contrast to the mouse, erythropoiesis in chambers in rabbits remained prominent for over 1 wk.


Antibody-dependent lymphocyte-mediated granulocyte cytotoxicity in man. Sera from two patients with granulocytopenia associated with collagen vascular disease caused the destruction of normal human granulocytes by autologous lymphocytes in vitro. Granulocyte cytotoxicity was measured by the release of 51Cr during incubation with test sera and lymphocytes in microtiter plates. Between 8% and 46% granulocytoxicity was produced in granulocytes from 8 normal donors by the sera from these two patients. Less than 6% granulocytotoxicity was seen with the sera from 14 normal subjects and 29 patient controls. Treatment of lymphocyte preparations with carbonyl iron and magnetic separation to remove phagocytic cells or treatment with complement-coated red cells followed by repeated gradient centrifugation to remove complement receptor-bearing lymphocytes did not reduce the granulocytotoxicity. There was a dose-response relationship between the concentration of positive sera and granulocytotoxicity. When these sera were fractionated by Sephadex G-200 gel filtration and by ion-exchange chromatography with DEAE-cellulose, the active component appeared in the IgG-containing fractions. Thus, IgG antibody-dependent, lymphocyte-mediated granulocyte cytotoxicity represents a means of detecting human granulocyte antibodies and is a possible mechanism of autoimmune neutropenia in these two patients.


Effects of potassium dichromate on nucleic acid and protein syntheses and on precursor uptake in BHK fibroblasts. Treatments for 1 to 4 hr with 10-4 m potassium dichromate, a soluble hexavalent chromium salt with a strong oxidizing power, markedly reduce DNA and RNA accumulation rates in hamster fibroblasts grown in vitro (BHK line), as shown by quantitative spectrophotometric determinations. Such inhibitory action is not immediately evident on the basis of the incorporation rates of labeled nucleosides into DNA and RNA, as dichromate affects also the relative concentrations of labeled precursors in the intracellular pool. Dichromate first stimulates and then inhibits nucleoside (mostly thymidine) uptake, whereas amino acid uptake is immediately inhibited. Actual rates of macromolecular syntheses have been calculated by taking into account the induced changes of soluble precursor concentrations; sucn normalized rates point out that dichromate induces a sudden blockage of DNA replication, whereas RNA and protein syntheses are secondarily inhibited. The observed cytotoxic effects of dichromate are tentatively referred to the oxidation of cell components by hexavalent chromium and thereby to the interaction of reduced trivalent chromium with specific biological ligands on cell membrane and on DNA.


Transplacental lung tumorigenesis in the athymic mouse. Female BALB/c nu/+ mice, pregnant by nu/+ males (nu: gene for hairlessness-athymia) were given injections of urethan, a transplacental tumorigen, on Day 17 or 19 of gestation. After an average of 16 weeks under clean conventional conditions, the incidence of primary lung tumors was similar in nude and normal offspring treated with carcinogen on either gestational day, with a higher incidence after treatment of Day 19. Thus, the absence of thymus did not affect the occurrence of transplacentally induced primary lung tumors or alter the well-known perinatal increase in sensitivity. Histologically, the nu/nu tumors differed from normal in the appearance of many atypical basophilic cells and in a tendency to invade both the parenchyma and the pleural surface. These results suggested progression of the lung adenomas to a more atypical, invasive form, a progression that may have occurred prematurely in the absence of thymus-dependent immune response.


Carcinoma of the prostate in irradiated parabiotic rats. Twelve hundred fifty-two pairs of male NEDH rats were parabiosed, one partner received a single dose of 1000 R X-radiation, and the other rat was shielded with lead. Eleven hundred twenty pairs survived over 200 days and constitute the basis of this report. Twenty-five of the irradiated partners developed malignant tumors of the prostate, 19 of which were adenocarcinomas. One adenocarcinoma appeared in the shielded partners and one in a control group of 586 parabiosed and single rats. The long-term effect of a single dose of 1000 R whole-body X-radiation is weakly carcinogenic for the rat prostate.


Reevaluation of the number of cells involved in the neutron induction of mammary neoplasms. The shape of the curve relating carcinogen dose to the number of animals developing neoplasms is reexamined; a family of curves relating expected tumor incidence to carcinogen dose, if tumors arose from one cell or two or more interacting cells, is calculated; and how closely these curves correspond to reported radiation dose inrelation to mammary tumor incidence is tested. The results are in conflict with the conclusion of Rossi and Kellerer that the induction of mammary tumors in Sprague-Dawley rats is dependent on the action of neutron radiation on more than one cell. Indeed, there appears to be no reason to reject the simplest hypothesis that one transformed cell is sufficient to produce a mammary tumor.


Evidence for metabolic alpha hydroxylation of N-nitrosopyrrolidine. Metabolic alpha hydroxylation of cyclic nitrosamines is important in the activation of these compounds to their ultimate carcinogenic forms. Direct evidence for this process is presented. Both alpha-hydroxynitrosopyrrolidine and 3-formyl-1-propanediazohydroxide, which are unstable intermediates resulting from alpha hydroxylation of nitrosopyrrolidine, were generated inaqueous solution from the stable precursors alpha-acetoxynitrosopyrrolidine and 4-(N-carbethoxy-N-nitrosamino)butanal. The major product resulting from the decomposition of slpha-hydroxynitrosopyrrolidine and 3-formyl-1-propanediazohydroxide was 2-hydroxytetrahydrofuran, the cyclic hemiacetal of 4-hydroxy-butyraldehyde. The same product was isolated as its dinitrophenylhydrazone derivative after incubation of rat liver microsomes with nitrosopyrrolidine and after treatment of rats with nitrosopyrrolidine.


A basis for fluoropyrimidine-induced antagonism to methotrexate in Ehrlich ascites tumor cells in vitro. The inhibitory effect of methotrexate on [3H]deoxyuridine incorporation into DNA is reduced as the basal rate of this reaction is inhibited by pretreatment of Ehrlich ascites tumor cells with fluoropyrimidines. This observation is a basis for fluoropyrimidine-methotrexate antagonism in anticancer regimens and supports the concept that the sensitivity of thymidylate synthesis in tumor cells to methotrexate is related, in part, to the basal rate of thymidylate synthesis from deoxyuridylate.


Correlation of antitumor chemoimmunotherapy with serum inhibition of tumor cell destruction. The administration of cyclophosphamide and Corynebacterium parvum in combination results in tumor growth inhibition greater than that resulting from the use of either agent alone. The precise mechanism(s) by which this chemoimmunotherapy combination results in a synergistic inhibiting effect is not known. The possibility was entertained that the tumor effect might be related to a greater decrease in serum-mediated interference with cellular cytotoxicity, i.e., "blocking" activity, by both agents in combination rather than by either alone. The present findings fail to support such an explanation. C. parvum by itself failed to decrease serum inhibition and in conjunction with cyclophosphamide resulted in an effect that was no greater than that produced by cyclophosphamide alone.


Cardiac performance in patients with anorexia nervosa. The heart function in 15 female patients with anorexia nervosa was examined by means of systolic time intervals. In 3 patients, pulmonary wedge pressure and cardiac output were measured. The findings indicate impaired myocardial contractility in patients with anorexia nervosa.


Hemodynamic findings before and after surgery for atrial septal defect of the secundum type in middle-aged patients. 84 patients without concomitant pulmonary or cardiac disease, underwent surgery for atrial septal defect of the secundum type (ASD II) at the age of 40 years or more. Hemodynamics were studied preoperatively at rest, and postoperatively at rest and during exercise during a follow-up investigation which took place 74 months (range 22-174) after surgery. Preoperatively, the pulmonary artery mean pressure (PAMP) exceeded 20 mm Hg in 24 patients (30%). In the patients aged 50 years or more PAMP was significantly higher than in the younger patients, whereas the shunt ratio did not show any increase with age. After surgery, the pressures in right atrium, right ventricle and PA showed significant changes towards normalization. During exercise, a considerable increase of the PA pressures appeared, and this increase correlated significantly with the PA pressures obtained preoperatively at rest.


Persistent atrial standstill with limb girdle muscular dystrophy. A case of persistent atrial standstill associated with muscular dystrophy of the limb girdle type is reported for the first time in the literature, In spite, of advanced myopathy, the patient delivered an apparently normal child. Hemodynamic studies including a normal coronary cinearteriography were performed in the post-partum period. The patient also had clinical and radiological evidence of peptic ulcer which may be the expression of an excessive vagal tone. A congenitial anomaly of the conduction system might explain the association of left anterior hemiblock with persistent atrial standstill, but could not be demonstrated.


Automated phonocardiographic screening for heart disease in children. Mass screening for heart disease in children can be accomplished by automatic analysis of phonocardiograms (PCG) obtained from five routine auscultation points. An ECG signal serves as reference. PCG signals exceeding 20% of the amplitude of the first heart sound S1 in the diastolic interval and 40% of S1 in the systolic interval are considered as abnormal. Signals in the systolic interval with an amplitude between 20 and 40% of S1 are classified as normal if their duration is less than two-thirds of the interval from the first to second heart sound. Thus, the method takes into account innocent murmurs and classifies them as normal. The splitting of the second sound is detected by monitoring its duration at a level of 20% of S1. This method was tested on 2,583 children aged from 3 to 14 years and on 345 children with proven heart disease. The results obtained showed a sensitivity of 96.5% and a specificity of 92.4%.


Ventricular premature beats. Reliability in various measurement methods at rest and during exercise. The yield and reproducibility of various methods of ventricular premature beat (VPB) detection are examined in otherwise healthy middle-aged men first found to have VPB in a 2-min lead I ECG rhythm strip. With a combination of an isometric and treadmill exercise test, VPB were repeatedly detected in 83%. Test-retest reliability in classifying the subjects by frequency of VPB was 67%. The reliability of detecting complex VPB was 47% for multiform VPB, 35% for pairs of VPB, 17% for runs and 36% for VPB showing the R-on-T phenomenon. These data suggest that simple and complex VPB detected by the described methods among normal men are poorly reproducible in the individual. Taking the VPB reproducibility for the group as a whole, the proportion of subjects having different frequency or kinds of ectopic beats is reasonably stable for the different test occasions.


Regional oxygen saturation of small arteries and veins in the canine myocardium. Oxygen saturation of small arteries and veins (20-500 micron) was determined microspectrophotometrically in the hearts of 12 pentobarbital-anesthetized open-chest dogs. Hearts were removed, quick frozen in liquid propane, and O2 saturation was determined in blood vessels on a regional basis between and within ventricular walls. No significant differences existed in arterial O2 saturation between right, left, and septal walls or regionally within any wall by depth or in base-to-apex comparisons. Although there was variation in arterial saturation, it was independent of vessel size. Arteries were followed by serial section into the left ventricular wall for distances up to 7.5 mm without significant saturation change. The average venous saturations of the right, septal, and left ventricular walls were not significantly different. No regional differences in venous saturation were found within any ventricular wall in comparisons between base and apex. In the left ventricle, subepicardial venous saturation (29.8%) was significantly higher than subendocardial saturation (16.4%). In veins traced from the surface, saturation decreased with depth. Greater variability of saturation was found in small compared to large veins. The greater O2 extraction in the subendocardium may indicate a higher O2 consumption than in the subepicardium.


Hemodynamic components of a cardiogenic hypertensive chemoreflex in dogs. The mechanical and hemodynamic components of a cardiogenic hypertensive chemoreflex were studied in 50 dogs. Within 6 seconds after a single injection of serotonin (100 microgram/ml) into the left atrium, mean pressure (mm Hg) rose in the aorta from 103 to 197 and in the pulmonary artery from 21 to 34. Left ventricular dp/dt virtually doubled. There was an increase (75%) in peripheral vascular resistance that returned to control within 10 seconds. There was no significant change in pulmonary vascular resistance. Aortic and pulmonary arterial hypertension were associated with a profound depression (82%) in atrial force. Atropine transformed this negative inotropic effect on the atria into a positive inotropic action that averaged 65%. In contrast, ventricular force was  always sharply increased, more in the right (95%) than in the left ventricle (50%). Bilateral stellectomy did not eliminate the reflex but it completely abolished the initial increase of cardiac contractility; a delayed increase in contractility persisted and was due exclusively to release of catecholamines from the adrenal glands. This cardiogenic hypertensive chemoreflex uses the vagus for its afferent neural traffic and both the sympathetic and the vagus nerves for its efferent route. The brief and intense systemic vasoconstriction concomitant with an increase in cardiac contractility might represent a kind of "aortic cough." Some possible clinical implications are discussed.


Fluid dynamics of coronary artery stenosis. A large-scale model of the coronary circulation, instrumented to permit detailed pressure and velocity measurements, has been used to study flow through isolated stenotic elements in large coronary arteries. Pulsatile aortic and instantaneous peripheral resistance were stimulated with servovalves. A variety of axisymmetric and asymmetric stenoses were studied and flow separation was found to occur for all but very mild stenoses. Pressure recovery downstream of the stenosis throat was limited and, in some cases, no recovery was observed. Pressure drop was primarily dependent upon the minimum area of the stenosis and relatively independent of stenosis geometry. Flow was quasi-steady at normal heart rates, and simple steady flow theory proved adequate to describe the pressure drop through the stenosis. The theory yielded results that agreed well with published data for dogs and appears promising for predicting effects of hemodynamic variables on a given stenotic lesion. Thus, principal findings of the study are that a relatively severe stenosis behaves essentially like an orifice and that a simple quasi-steady theory appears adequate to predict effects of a stenosis on coronary flow.


Plasma vasopressin concentrations and effects of vasopressin antiserum on blood pressure in rats with malignant two-kidney Goldblatt hypertension. Male Sprague-Dawley rats with unilateral renal artery stenosis and a contralateral untouched kidney develop a malignant hypertension (MH) which is characterized by high blood pressures, sodium and water depletion, and subsequent activation of the renin-angiotensin system. In the present studies we found plasma arginine vasopressin (AVP) concentrations-3-fold higher than those in rats with benign renal hypertension, and 4- to 5-fold higher than those in normotensive control rats. Analysis of individual values showed considerable scatter; about 50% of the values fell in the range of benign hypertensive or control rats. When a specific AVP antiserum was injected, iv, into eight conscious unrestrained MH rats, BP transiently fell toward control values in four; in one, BP fell by only 10 mm Hg, and three other MH rats showed no response. In the same rats, injection of a specific angiotensin II antiserum always induced a transient fall in BP. On the basis of these and previously reported observations, we conclude that, subsequent to sodium and water loss and activation of the renin-angiotensin system, vasopressin release is stimulated in a significant number of MH rats and that, in these rats, vasopressin may cause significant systemic vasoconstriction. Thereby vasopressin may contribute to the development of malignant renal hypertension in rats.


Failure of chronic sodium chloride loading to protect against norepinephrine-induced acute renal failure in dogs. We previously  have shown that chronic sodium chloride (NaCl) loading protects against HgCl2-induced acute renal failure (ARF) in dogs. To determine whether NaCl loading protects against an ischemic model of ARF, unilateral oliguric renal failure was produced by the infusion of norepinephrine (NE) into the renal artery of both saline-expanded (SE) and water-drinking (WD) dogs (n = 7). The renal renin content (30 U/g kidney) of SE dogs was suppressed (P less than 0.001) compared to that of WD dogs (132 +/- 18). Forty-eight hours after infusion of NE (1.5 microgram/kg per min X 100 min), inulin clearances from the infused kidney of SE (6 ml/min +/- 2) and WD dogs (7 +/- 2) did not differ; in both groups, respective clearances from the noninfused kidney (43 ml/min +/- 3) and (36 +/- 5) also did not differ from each other. The present fall in renal blood flow to the infused kidney 48 hours after NE in SE (44%) and WD dogs (38%) did not differ. Because of failure to demonstrate protection, a lower dose of NE (0.75 microgram/kg per min X 40 min) was infused into SE and WD animals (n = 6). Forty-eight hours after low dose NE, inulin clearances of the infused kidney of SE (17 ml/min +/- 5) and WD dogs (17 +/- 4) did not differ. Respective clearances in the noninfused kidney of SE (46 ml/min +/- 6) and WD dogs (35 +/- 4) did not differ. Therefore, despite suppression of renal renin content, NaCl loading failed to protect against this ischemic model of ARF. In conclusion, unlike HgCl2-induced ARF, it is unlikely that the renin angiotensin system contributes to the pathogenesis of this ischemic model of ARF.


The mechanism of K+-induced vasodilation of the coronary vascular bed of the dog. We tested a number of hypotheses concerning the mechanism of K+-induced vasodilation of the coronary vascular bed. Blood flow in the circumflex artery was measured in pentobarbital-anesthetized, open-chest dogs. Intracircumflex artery bolus injections of 40 mumol of isomotic KCl produced decreases in coronary vascular resistance ranging from 34% to 48%, depending on the initial resistance of the vascular bed. K+ administration had no effect on heart rate and produced a 4 mm Hg decrease in mean arterial pressure. K+ injection caused a 0.2 vol% increase in coronary sinus O2 content in a preparation in which left common coronary flow was held constant. The magnitude of K+-induced vasodilation was not significantly affected by the administration of propranolol, atropine, phentolamine, or lidocaine. K+-induced vasodilation was attenuated (50%) by ouabain plus lidocaine. Acetylcholine-induced vasodilation was not significantly diminished by ouabain plus lidocaine. We conclude that the mechanism of K+-induced vasodilation does not involve an increase in the metabolic activity of the heart or an interaction between K+ and tissue neural elements. Our data do support the hypothesis that K+-induced vasodilation is at least partly the result of an activation of the electrogenic Na+-K+ transport system of coronary smooth muscle.


Enhanced renal prostaglandin production in the dog. The effect of sodium arachidonate in nonfiltering kidney. Sodium arachidonate, 10(-5) g/kg per minute, was infused into the renal artery of a nonfiltering canine kidney in situ in order to determine the effects of enhanced prostaglandin synthesis on renal blood flow and its distribution in circumstances where prostaglandins produced in the medulla could not gain access to the cortex via tubular fluid. The contralateral normal kidney was also infused with sodium arachidonate and served as control. Radioactive microspheres were used to calculate the hemodynamic effects. In the nonfiltering kidney, the total renal blood flow increased after sodium arachidonate from a mean of 105 ml/min per 100 g to 146 ml/min per 100 g (P less than 0.01). This increase was completely abolished by prior treatment with indomethacin, 8 mg/kg, intravenously. The normal kidney responded qualitatively the same as the nonfiltering side. In both kidneys, blood flow increased significantly to all cortical zones except the outermost (zone 1), but the fractional distribution of renal blood flow was significantly increased only in the innermost cortex (zone 4). Since the kidneys were nonfiltering, the increase of renal blood flow during infusion of arachidonic acid cannot be explained by prostaglandins being transported from renal medulla to the cortex through renal tubules. Most likely prostaglandins are produced locally in the cortex and have only local effects.


Failure of renin suppression by angiotensin II in hypertension. Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.


Detection of experimental pulmonary emboli in dogs by sequential positron imaging after inhalation of 15O-carbon dioxide. After inhalation, C15O2 (T1/2 = 2 minutes) rapidly diffuses into pulmonary blood and is cleared from the lungs within 10 seconds. The purpose of this study was to determine whether impaired clearance of inhaled C15O2 from oligemic zones, distal to areas of obstructed pulmonary blood flow, could be detected by serial pulmonary imaging with a positron camera. Experimental obstruction of branches of the pulmonary artery was induced in 19 anesthetized dogs by inflation of balloon-tipped catheters (8-12 mm in diameter), injection of radiopaque silicone spheres (0.5-4.0 mm), and embolization with barium-impregnated autologous blood clots (1-5 mm) via the right external jugular vein. After a single bolus injection of 2 mCi of C15O2 into the endotracheal tube, serial lung images of 15O activity were obtained over 60-180 seconds. Obstruction of pulmonary arterial branches resulted in visualization of discrete zones of impaired 15O clearance which varied in area with catheter diameter. Location and size of these zones were confirmed by repeat imaging after direct injection of 15O-labeled blood through the distal catheter lumen. In dogs receiving autologous clots (n = 8), similar zones of impaired 15O clearance were consistently imaged, and single emboli as small as 2 mm in diameter produced regions of retained 15O activity. Zones of retained 15O activity corresponded to the location of radiopaque emboli on chest radiographs. This study introduces a new technique of radionuclide imaging for detection of pulmonary emboli that is noninvasive, safe, sensitive, and repeatable at short intervals.


Gas exchange after pulmonary thromboemoblization in dogs. Gas exchange following experimental pulmonary thromboembolization was studied with an inert gas elimination technique in 17 dogs. Pulmonary arterial, systemic arterial, and expired gas concentrations of six gases infused intravenously were measured before embolization and 5, 10, 15, 30, 60, and 120 minutes after embolization. Distributions of ventilation-perfusion (VA/Q) ratios were derived from the measured concentrations. In all dogs, embolization caused an increase in blood flow and ventilation to VA/Q ratios less than 1. There were no lung units with VA/Q ratios between 10 and 100 before embolization, but, in two-thirds of the dogs, such regions developed after embolization. Ventilation to unperfused lung showed a transient increase of 2-6%. Radioisotope studies of lobes removed post-mortem indicated that thromboemboli rarely caused complete abolition of lobar blood flow. Pulmonary embolization did not cause arteriovenous shunts to appear. The hypoxemia caused by embolization could be accounted for by the changes in VA/Q distributions. Over the 2-hour period after embolization, lung function improved as the distributions partially returned toward the preembolization patterns.


Prolonged atrial conduction. A major predisposing factor for the development of atrial flutter. Electrophysiological studies were performed during sinus rhythm on 21 patients who had demonstrated the spontaneous occurrence of sustained atrial flutter. The purpose was to determine if atrial conduction disease is a prediposing factor for the development of atrial flutter. Patients with atrial enlargement were excluded from the series. The control group consisted of 11 age-matched patients with normal electrocardiograms and electrophysiology studies. The flutter group showed prolongation of the mean right intra-atrial conduction time at 50 msec (control of 37 msec, P less than 0.05), the mean interatrial conduction time at 92 msec (control of 44 msec, P less than 0.001) and the mean P wave duration at 132 msec (control of 112 msec, P less than 0.01). The flutter group also demonstrated a higher incidence of sinus node dysfunction and ventricular conduction disease compared to the control group. These data indicate that patients who develop atrial flutter have atrial conduction disease. Atrial conduction disease appears to be 1) a major prediposing factor for the development of atrial flutter and 2) a part of the fibro-degenerative conduction disease spectrum.


Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome. The intrinsic heart rate (IHR) was determined in 17 patients with symptomatic sinus bradycardia by administering atropine 0.04 mg/kg and propranolol 0.2 mg/kg, i.v. In this way, sick sinus (SSS) patients with intrinsic sinus node (SN) dysfunction could be distinguished from those patients with disturbed autonomic regulation of SN function. Sick sinus syndrome patients with normal corrected sinus node recovery time (SNRTC), adjusted for the magnitude and direction of autonomic chronotrophy, consistently had normal IHRs and therefore abnormalities of autonomic regulation. Sick sinus syndrome patients with abnormal adjusted SNRTC consistently had abnormal IHRs and therefore abnormalities of intrinsic SN function. We conclude that more than one pathophysiologic mechanism can produce the clinical manifestations of sick sinus syndrome and that abnormal prolongation of SNRTC is dependent upon the underlying mechanism of sinus node dysfunction.


The cellular electrophysiologic effects of digitalis on human atrial fibers. We used microelectrode techniques to study the indirect and direct actions of ouabain on human atrial fibers (HAF) obtained from patients with congenital heart disease undergoing open heart surgery. At 15 min of superfusion ouabain, 2 X 10(-7) M, induced an increase in maximum diastolic potential (MDP), action potential (AP) amplitude and upstroke velocity of phase 0 depolarization (Vmax) and a decrease in AP duration. Spontaneously beating HAF showed a decrease in automaticity. Acetylcholine (3 X 10(-6) M) induced identical effects on AP characteristics and automaticity. Prior treatment with atropine (1 X 10 (-6) M) blocked these effects of ouabain and acetylcholine. Superfusion with ouabain (2 X 10 (-7) M) for 30 to 90 min resulted in decreased MDP, AP amplitude and Vmax, and a further decrease in AP duration. Phase 4 depolarization and spontaneous rate increased and delayed afterdepolarization and tachyarrythmia occurred. The ACh-like effects of digitalis decrease automaticity and increase MDP of HAF; the direct effects decrease MDP, increase automaticity, and induce tachyarrythmias.


Detection of myocardial scar tissue by M-mode echocardiography. Wall thicknesses were measured and echo densities were evaluated from the left ventricular echograms of 182 patients. The echogram was considered to reflect scar tissue when 1) either the interventricular septum, the posterior left ventricular wall or the anterior left ventricular wall was less than 7 mm thick in mid-diastole and was more echo-producing than its opposing wall or another area of the same wall in a sector scan, or 2) an area of myocardium was 30% less thick than an adjacent area within a sector scan. Myocardial scarring was diagnosed by echocardiography in 52 of the 182 patients. The echocardiographic presence or absence of scarring was confirmed in 95% (173 of 182) of cases, 34 cases by microscopic examination and 139 by surgical appearance. This study shows that M-mode echocardiography is both a sensitive and specfic method for detecting myocardial scar tissue.


Alterations in ventricular mass and performance induced by exercise training in man evaluated by echocardiography. Few data are available regarding the effects of exercise training upon cardiac structure and performance in man. We evaluated the echograms of 24 normals before (PRE) and after (POST) 11 weeks of endurance exercise training. Conditioning consisted of a walk-jog-run protocol at 70% maximal heart rate for one hour four days per week. Training reduced heart rate and increased maximal duration and estimated oxygen consumption of treadmill exercise. Compared to PRE, the echogram in the POST training period revealed an increased left ventricular (LV) end-diastolic dimension (EdD), a decreased end-systolic dimension (EsD) and thus an increased stroke volume (EdD3-EsD3) and shortening fraction (EdD-EsD)/EdD). Cardiac output (CO) and peripheral vascular resistance (BP/CO X 80) were identical PRE and POST conditioning. Importantly, an increase in mean fiber shortening velocity was observed POST training as were increases in LV wall thickness, ECG voltage of S in V1 + R in V5, and LV mass. Thus endurance training was accompanied by increases in both LV dimension and mass as well as LV shortening fraction and contraction velocity as observed by echocardiogram.


Two-dimensional echocardiographic recognition of ruptured chordae tendineae. Real-time, phased-array, two-dimensional echocardiographic studies identified ruptured chordae tendineae in five patients: four patients had a flail mitral valve and one had flail mitral and tricuspid valves. The characteristic abnormality was a rapid systolic motion of the involved leaflet beyond the line of valve closure into the atrium. The maximal abnormal systolic motion was greatest at the tip of the leaflet with a loss of the normal coaptation point. By contrast, the two-dimensional echocardiographic feature of mitral valve prolapse is an abnormal systolic motion that is maximal in the body of the leaflet with intact leaflet coaptation. Thus, two-dimensional echocardiography can identify flail mitral and tricuspid valves and is useful in distinguishing ruptured chorade from valvular prolapse.


Prevalence and characteristics of disproportionate ventricular septal thickening in patients with coronary artery disease. Echocardiographic or necropsy studies were performed in 151 patients with coronary artery disease. Prevalence of disproportionate septal thickening (septal to free wall ratio greater than or equal to 1.3) was 11%. An abnormally increased septal-free wall ratio in these patients had two principal etiologies. First, it was a manifestation of genetically transmitted hypertrophic cardiomyopathy, as evidenced by disproportionate septal thickening in first degree relatives. Second, it was due to disproportionate septal thickening which did not appear to be a manifestation of genetically transmitted hypertrophic cardiomyopathy. This latter conclusion was suggested by negative echocardiographic studies in some families of patients with both coronary artery disease and disproportionate septal thickening. In addition, numerous disorganized cardiac muscle cells, characteristically present in patients with genetically transmitted hypertrophic cardiomyopathy, were absent from the septum of all patients with disproportionate septal thickening studied at necropsy. Although the mechanism responsible for this secondary type of disproportionate septal thickening is unknown, our results indicate that the presence of disproportionate septal thickening in a patient with coronary artery disease does not, per se, indicate the coexistence of genetically transmitted hypertrophic cardiomyopathy.


Aortic stenosis in children. Experience with echocardiographic prediction of severity. Fifty-six children with aortic stenosis were investigated both by echocardiography and cardiac catheterization. The ratio of end-systolic wall thickness (Ws) to internal diameter (LVES) across the minor axis of the LV as determined by echocardiography and multiplied by a factor of 245 predicts left ventricular pressure (r = 0.83). Subtracting the arm systolic blood pressure from the predicted intraventricular systolic pressure (PISP) gives a predicted systolic pressure gradient (r = 0.91). The technique is found to be useful for both initial and sequential noninvasive assessment of aortic stenosis with normal LV function irrespective of the level of obstruction. It is shown to apply equally well to wide range of LV pressures, is independent of volume load, and is useful in predicting small gradients. Some common problems encountered with the measurements are examined in detail.


The reliability and practicality of single crystal echocardiography in the evaluation of single ventricle. Angiographic and pathological correlates. A prospective clinical and echocardiographic diagnosis of single ventricle was made in 42 patients. Each was evaluated for the number of atrioventricular (A/V) valves, presence of an outflow chamber (OC), A/V valve-semilunar continuity, and orientation of the great arteries. Angiographic correlations were subsequently obtained in 40 and autopsies in 12. The overall diagnosis of single ventricle was substantiated in 39. Two other patients diagnosed as single ventricle by angiography were thought to have large ventricular septal defects on echocardiography. Tricuspid valve was interpreted as septum in one. The angiographic diagnosis of single ventricle was incorrect in another, correctly diagnosed by echocardiography and confirmed at pathology. The differential diagnosis also included A-V canal, L-transposition of the great arteries, double outlet right ventricle, and tricuspid atresia. This last condition has to be differentiated on clinical evidence. The echocardiograms were of particular value in determining the number of A/V valves. Two great arteries were demonstrated in 74% of patients and their relationship was correctly determined in 79% of these. Both imaging techniques agreed closely as to A/V valve-semilunar continuity and presence of an OC, but both showed some inaccuracies compared to pathological specimens. The echocardiogram helps both in planning catheterization and in evaluating the overall diagnosis.


Echocardiographic measurements in normal subjects. Growth-related changes that occur between infancy and early adulthood. Echocardiographic measurements of the left ventricular dimensions and wall thicknesses at end diastole and end systole, aortic root and left atrial dimensions, mitral valve E-F slope, left ventricular ejection fraction, percent fractional shortening of the left ventricular internal dimension, estimated left ventricular mass and percentage systolic thickening of the ventricular septum and left ventricular free wall were obtained in 105 normal subjects ranging from one day to 23 years of age. Each parameter was found to follow a linear regression upon one of three functions of the body surface area. The internal dimensions of left ventricle, the left atrium, and the aortic root, and the mitral valve E-F slope varied in a linear relation to the cube root of the body surface area. Thickness of the ventricular septum and left ventricular free wall varied in a linear relation to the square root of the body surface area. Estimated left ventricular mass varied linearly with the direct measurement of body surface area. Ejection fraction, percent fractional shortening of the left ventricle and percent systolic thickening of the ventricular septum and left ventricular free wall were independent of body surface area despite a marked increase in the size of the left ventricle during normal growth and development.


Cardiac structure growth pattern determined by echocardiography. Using M-mode echocardiography, we measured dimensions of the ventricular walls and cavities, great vessels, and left atrium and atrioventricular valve excursions on 93 infants and children without heart disease. The data were analyzed by relating each dimension in mm to body surface area in m2 and the 90% tolerance limits for the data were calculated. The tolerance lines of the data were wider than previously recorded. At birth and maturity they were similar to the range defined as normal by studies in neonates and adults. We suggest that the tolerance lines of these normal data may be used for quantitative echocardiography in childhood.


Echocardiographic and hemodynamic correlation in transposition of the great arteries. Echocardiography was performed in 36 patients with transposition of the great arteries (TGA). Twenty patients were studied before a Mustard operation, 14 patients after operation and two patients both before and after operation. Right ventricular end-diastolic dimension (RVED) was larger than normal in each patient and tended to increase postoperatively. In contrast, the left ventricular end-diastolic dimension (LVED) was significantly reduced postoperatively in all patients. A linear relationship was demonstrated between the ratio of LVED/RVED and the ratio of peak systolic pressures in the left and right ventricles in studies both before and after Mustard operation. Systolic anterior motion of the mitral valve was observed in 18% of peroperative patients and increased to 44% postoperatively. The incidence of fluttering of the mitral valve increased from 50% to 94% after the operation. Abnormal septal motion was found in 39% of cases. Abnormal movement of the mitral valve and of the interventricular septum seems to be related to a reversed pressure relationship in the ventricles. Shifting of the ventricular septum toward the left ventricle and consequent distortion of the left ventricular cavity and mitral valve apparatus may be responsible for the abnormal echocardiographic findings. Serial echocardiographic studies may be useful as a noninvasive tool in the assessment of left ventricular pressure or the status of the pulmonary vascular bed in TGA.


Combined double chambered right ventricle and discrete subaortic stenosis. Nine cases of combined double-chambered right ventricle (DCRV) and discrete subaortic stenosis (DSAS) are presented. A review of 1077 consecutively catheterized patients indicates an association of these two uncommon anomalies nine times greater than expected. One or both obstructive lesions may be hemodynamically significant and require surgery. Whenever DCRV or DSAS is suspected or identified, the cardiac catheterization should include studies of both the right and left ventricles.


The clinical estimation of acute myocardial infarct size with 99mTechnetium pyrophosphate scintigraphy. We evaluated scintigraphic techniques in estimating infarct size. In 26 patients with acute transmural myocardial infarction, 99mTechnetium pyrophosphate (TcPYP) infarct scintigraphy, gated cardiac blood pool scintigraphy and 201-Thallium (201-Tl) perfusion scintigraphy were performed. Invasive hemodynamic measurements were obtained and serial venous blood specimens taken for measurement of total and MB creatine phosphokinase (CPK). In farct size was estimated from the area of abnormal TcPYP uptake, the extent of reduced 201-Tl uptake, the percentage of abnormally contracting segments, and serial enzyme measurements. Left ventricular ejection fraction (LVEF) and stroke work index (LVSWI) were calculated. TcPYP infarct area was associated with the extent of reduced 201-Tl uptake (r = 0.66), the percentage of abnormally contracting segments (r = 0.64), and with both LVSWI (r = 0.73) and LVEF (r = 0.58). TcPYP infarct area did not correlate with cumulative total or MB-CPK release or the integrated total CPK-time curve, nor did the enzyme estimates of infarct size correlate with LVSWI or LVEF. Variable perfusion of infarcts of different sizes may explain the lack of correlation between TcPYP infarct area and enzyme estimates of infarct size. A combination of anatomic and functional indices derived from scintigraphic and hemodynamic measurements may provide the best assessment of infarct size.


The prognostic implications of acute myocardial infarct scintigraphy with 99mTc-pyrophosphate. The predictive value of the myocardial scintigraphy with 99mTc-pyrophosphate was studied in 100 patients admitted to the coronary care unit with suspected acute myocardial infarction. None of the 21 patients with normal scintigrams had acute myocardial infraction by other criteria. Fifty-five percent of patients with diffuse uptake (pattern B), 73% of patients with focal uptake (pattern C) and all patients with intense focal uptake (pattern D) and massive uptake (pattern E) had acute infarction. The complication rate in the hospital and after discharge (mean followup: 6.1 months) for patients with pattern E was 88% compared to 42% for D, 30% for C, 36% for B and 10% for patients with normal scintigrams (A). For patients with acute infarction with patterns C, D and E, the complication rate rose with increasing size of the myocardial uptake of 99mTc-pyrophosphate. In addition to its diagnostic potential, scintigraphy provides prognostic information which is useful for patient triage and for therapeutic decisions early in the evolution of the infarct.


Evaluation of left ventricular function (ejection fraction and segmental wall motion) by single pass radioisotope angiography. Changes in ejection fraction (EF) and segmental wall motion (SWM) have been shown to be sensitive indicators of left ventricular (LV) function. This information is only obtainable by contrast angiography or gated blood pool scans. Gated studies assume a fixed geometry for the LV for EF determinations, are lengthy and limited primarily to the LAO projection. We correlated contrast and Tc-99m pertechnetate angiograms by singl pass radioisotope angiography (immediately preceding the contrast study) in 12 patients. EF was calculated from the LV time/activity curve and values ranged from .21 to .72. Angiographic correlation yielded r = 0.97. Regional LV wall motion was evaluated by dividing a summated cardiac cycle into 16 frames and dynamically and sequentially displaying these frames. Regional wall motion evaluation of four LV quadrants correlated well with angiography (r = 0.97). For quantitation these images were divided into four anterior and four inferior segments and the areas of respective segments were compared and expressed as a shortening fraction. SWM compared favorably with angiographic determinations (r ranged from 0.70 to 0.99). Thus, single pass radioisotopic determinations of EF and SWM in the RAO projection correlated well with the angiographic values and provide essential quantitative information of LV function otherwise unobtainable at the bedside.


Early redistribution of thallium-201 after temporary ischemia. To define the time course of redistribution of thallium-201 (201Tl), ischemia was induced in seven pigs by temporary occlusion of the circumflex coronary artery. After 1 1/2 min of occlusion 201Tl and labeled microspheres were injected into the left atrium. Flow was re-established 4 min after occlusion. Prior to reflow, the relative activities of 201Tl and microspheres in the ischemic area were similar, but as early as 5 min after reflow the relative 201Tl activity was considerably higher than the relative microsphere activity and from 15 to 105 min after reflow, relative 201Tl activity (averabe 69% of that in normal myocardium) continued to be higher than relative microsphere activity (average 6% of normal). Myocardial arteriovenous differences for 201Tl were followed sequentially after 201Tl injection in normal dogs and in dogs with temporary coronary occlusions. The results suggested both loss of 201Tl from normal myocardium beginning 10 min after 201Tl injection and increased extraction of 201Tl from the blood pool immediately after release of a transient occlusion. Redistribution of 201Tl therefore begins very soon after relief of myocardial ischemia and even a short delay in initiating myocardial imaging may decrease the sensitivity of the technique for detecting transient ischemia.


Hypertensive crises in quadriplegic patients. Changes in cardiac output, blood volume, serum dopamine-beta-hydroxylase activity, and arterial prostaglandin PGE2. The syndrome of autonomic dysreflexia often occurs in quadriplegic subjects and is characterized by paroxysmal hypertension, headache, vasoconstriction below and flushing of the skin above the level of transection, and bradycardia. These attacks may cause hypertnesive encephalopathy, cerebral vascular accidents, and death. In five patients during crises, the mean arterial pressure changed from 95 to 154 mm Hg, heart rate 72 to 45 beats/min, cardiac output 4.76 to 4.70 L/min, and peripheral resistance 1650 to 2660 dynes.sec.cm-5. In eight subjects the control plasma, red cell, and total blood volumes were 19.1, 10.5, and 29.6 ml/cm body height, respectively, and when hypertensive, the plasma protein concentration increased by 9.9% and the hematocrit by 9.5%. Plasma volume was only reduced by an estimated 10-15%. At that time, arterial dopamine-beta-hydroxylase (DbetaH) activity increased 65% and prostaglandin E2 concentration by 68%. Thus, the augmented DbetaH activity presented primarily an elevated sympathetic tone and not hemoconcentration of that protein. The rise in prostaglandin may contribute to the severe headaches during hypertensive episodes.


Prediction of late survival in patients with mitral valve disease from clinical, hemodynamic, and quantitative angiographic variables. Late follow-up (average = 7.2 years) has been obtained in 249 patients with mitral valve disease who had quantitative angiographic assessment of left ventricular function at thetime of initial catheterization in the 1960s. Surgically treated patients with mitral valve disease had significantly improved survival as compared to medically treated patients with mitral disease. The subgroup with mixed mitral stenosis and regurgitation and the subgroup with moderate impairment of ejection fraction account for this improved survival in surgically treated patients, which occurred despite greater functional and hemodynamic impairment in the surgical cohorts. Using univariate life table survival analysis, ten variables were found to be predictive of survival in the medical cohort, and three in the surgical cohort. With multivariate Cox's regression analysis, end-diastolic volume and arteriovenous oxygen difference were significantly predictive of survival in the medical cohort; age was predictive of survival in the surgical cohort.


Blood volume prior to and following treatment of acute cardiogenic pulmonary edema. Following onset of acute cardiogenic pulmonary edema in 21 patients, increases in hematocrit, plasma protein concentration, and colloid osmotic pressure were associated with decreases in plasma volume. Accordingly, there was a loss of hypo-oncotic fluid into the extravascular spaces. Following treatment with oxygen, furosemide, and morphine sulfate and reversal of clinical and radiographic signs of pulmonary edema, declines in hematocrit, plasma protein concentration, and colloid osmotic pressure were associated with increases in plasma volume. Hypo-oncotic edema fluid was therefore reabsorbed into the vascular compartment. The concept that acute heeart failure with pulmonary edema is associated with an increase in intravascular volume is therefore not supported. To the contrary, there is a reduction of blood volume during acute pulmonary edema. During reversal of acute pulmonary edema with diuresis, there was re-expansion rather than contraction of blood volume.


The rate of atherosclerosis change during treatment of hyperlipoproteinemia. The rate of change of femoral atherosclerosis has been determined in 25 treated hyperlipoproteinemic patients. There were 13 Type II patients and 12 Type IV patients. Serial angiograms had been performed at an interval averaging 13 months. Film densities were analyzed by digigal image processing to yield a computer estimate of atherosclerosis (CEA). Serial measurements of CEA on each patient were used to determine atherosclerosis percent change per month in that patient. CEA percent change per month was significantly correlated ;ith triglyceride and cholesterol level. Lower lipid levels were associated with more rapid regression. When hyperlipoproteinemic types were considered separately, significant single correlates were confined to Type IV. Triglyceride level and CEA/age significantly predicted atherosclerosis change rate and accounted for 72% of the variability observed in Type IV patients.


Effect of dopamine on hemodynamics and myocardial metabolism in shock following acute myocardial infarction in man. Eight patients in shock associated with acute myocardial infarctions were treated with dopamine. We titrated the dopamine dose to increase mean arterial pressure to 65-70 mm Hg and urine output to greater than 40 ml/hr. Increase of heart rate to 120-125 beats/min and occurrence of potentially dangerous arrhythmias were limiting end-points. Dopamine administration averaged 17.2 microgram/kg/min. Heart rate increased from 95 to 118 beats/min (P less than 0.001), and mean arterial pressure rose from 60 to 65 mm Hg (P less than 0.05). Dopamine increased myocardial contractility as indicated by increase in cardiac index and systolic ejection rate, with only moderate decrease in systemic vascular resistance. Pulmonary wedge pressure and right atrial pressure decreased from 23 to 18 mm Hg (P less than 0.05) and from 10 to 8 mm Hg (P less than 0.001) respectively. Improvement in hemodynamic status by dopamine was associated with deterioration of myocardial metabolism. Myocardial oxygen extraction ratios and arterial-coronary sinus oxygen differences increased from 73 to 76% (P less than 0.05) and from 13.02 to 14.19 ml/100 ml (P less than 0.02) respectively. Myocardial lactate production increased from -8 to -15% (P = 0.05). We conclude that dopamine improved cardiac performance at the expense of myocardial oxygenation and that dopamine is potentially harmful to acutely ischemic myocardium.


Electrophysiologic and hemodynamic effects of verapamin. Correlation with plasma drug concentrations. Verapamil was administered intravenously to 30 open-chest dogs and the electrophysiologic and hemodynamic effects of the drug were correlated with the corresponding plasma concentrations. At concentrations below 152 ng/ml, verapamil prolonged the A-H interval, abolished ventriculoatrial conduction, but did not significantly change sinus rate, cardiac output, left ventricular dp/dt, of systemic vascular resistance. Concentrations above 200 ng/ml were associated with slowing of the sinus rat, high degree atrioventricular block during atrial pacing, 24% decrease in mean aortic pressure, and decreased cardiac output and left ventricular dp/dt. Sinus arrest, high degree atrioventicular block during sinus rhythm, decreased systemic vascular resistance and increased left ventricular end-diastolic pressure occurred when plasma verapamil concentrations exceeded 400 ng/ml. These results show that plasma verapamil concentrations reliably reflect the electrophysiologic and hemodynamic actions of the drug, and that "therapeutic" drug effects can be achieved at plasma concentrations at which myocardial depressant effects are unlikely.


Hemodynamic correlates of saralasin-induced arterial pressure changes. Angiotensin antagonists have proved useful in elucidating the clinical role of the renin-angiotensin system; and their diagnostic and therapeutic efficacy in hypertension has been the subject of many reports but the hemodynamic effects remain unknown. Therefore, saralasin was infused intravenously (1.3 mg/min for 30 min) in 26 sodium-depleted patients with hypertension. Systemic hemodynamic alterations were determined before, during, and after infusion. On the basis of mean arterial pressure (MAP) changes, patients were classified as responders, nonresponders, or pressorresponders (MAP changes greater than or equal to 10 mm Hg). MAP fall in responders was achieved through reduced cardiac output and/or total peripheral resistance, with minimal or absent reflexive heart rate increase. In nonresponders, despite no change in MAP, output fell in parallel with stroke index and left ventricular ejection rate, In pressorresponders, saralasin increased vascular resistance. Thus, in addition to variable effects on vascular receptors, saralasin produced inhibitory cardiac effects either through altered venous return or inhibition of contractility.


Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in man. Hemodynamic effects of dobutamine and dopamine (both 5, 10, 15 microgram/kg/min) and epinephrine (0.04 microgram/kg/min) were studied immediately following cessation of cardiopulmonary bypass in 34 patients with preoperative evidence of left ventricular dysfunction. Significant increases in mean cardiac index were seen with dobutamine (15, 25, and 26% respectively), and epinephrine (30%). The largest increases occurred with dopamine (44, 53, and 64 percent respectively). Responses varied from patient to patient, however. Seven patients developed marked output increases without concomitant increases in arterial pressure, whereas seven others showed "satisfying" increases in arterial pressure without appreciable output increases. Heart rate increases were small and few arrhythmias were noted. We conclude that dopamine, epinephrine, and dobutamine all are effective inotropic agents during the immediate post-bypass period, with variations discussed in detail. None possess the disturbing chronotropic and arrhythmogenic effects of isoproterenol (previously studied). Efficacy of administration of inotropic drugs seems best assessed by serial output measurements during this period.


De subitaneis mortibus. XXVIII. Apoplexy of the heart. Apoplexy of the heart can be responsible for sudden and for recurring instability of cardiac rhythm and conduction, and for the clinical counterparts of syncope and sudden death. Every pathophysiological mechanism which produces cerebral apoplexy has its counterpart in apoplexy of the heart. Among the mechanisms documented are thrombosis, embolism and rupture of those special vessels supplying the sinus node, atrioventicular (A-V) node and His bundle. Apoplexy of the heart can occur either with or without significant or recognizable ventricular myocardial infarction. Acute vascular accidents within the critical centers of cardiac impulse formation and conduction deserve more frequent consideration in the explanation of unusual cases of "epilepsy", of seizure disorders of the elderly, of neurologic manifestations (which may be secondary as well as primary) of systemic diseases such as lupus erythematosus or thrombotic thrombocytopenic purpura, and indeed of every case of otherwise unexplanined syncope or sudded death at any age.


Reduction of coronary blood flow during coronary artery spasm occurring spontaneously and after provocation by ergonovine maleate. A 50-year-old man suffering from recurrent chest pain accompanied by transient ST-segment elevation developed spasm of the left anterior descending coronary artery after receiving ergonovine maleate. During spontaneous chest pain, thermodilution coronary sinus blood flow fell from 96 ml/min to 46 ml/min, while the coronary sinsu arteriovenous oxygen difference widened from 9.82 volumes percent to 11.3 volumes percent. During spontaneous relief of pain, coincident with resolution of the ST-segment changes, coronary sinus blood flow gradually rose to 135 ml/min, while coronary sinus arteriovenous oxygen difference narrowed to 6.82 volumes percent. Similar aterations in coronoary sinus blood flow accompanied chest pain provoked by ergonovine maleate. A thallium-201 scan confirmed a perfusion defect in the distribution the left anterior descending coronary artery. Thus, coronary artery spasm can produce a marked deficity in coronary blood flow that is associated with increased myocardial oxygen extraction; release of spasm creates a hyperemic response.


A criss-cross heart with concordant atrioventriculo-arterial connections. Report of a case. A distinctive angiographic appearance is described in a case of "criss-cross" heart with concordant atrioventriculo-arterial connections. The atrial situs was normal, and the morphological right ventricle was superior to the left ventricle, and the ventricular septum was horizontal in position. Both ventricleswere connected by a small ventricular septal defect. The aorta was situated anteriorly and to the right of the pulmonary artery. Although the cardiac segment was the apparent [S,L,D] type, the heart had conconrdant atrioventriculo-arterial connections. The ventricular rotation of the solitus heart about the longitudinal and the anteroposterior axis affected the atrioventricular flows, the plane of the ventricular septum, the inflow and outflow tracts of the ventricles, the interrelationship of the great arteries, and the course of the left coronary artery. Using the recent definition of criss-cross heart, we classified the heart as solitus-concordant (l-rotated) -normal.


Automated enzymic measurement of total cholesterol in serum. We describe a completely automated enzymic system for measuring total cholesterol in serum. All reagents are contained in an analytical test pack and the test is performed on Du Pont's Automatic Clinical Analyzer (aca), which mixes the sample (20 microliter) and reagents and performs the necessary absorbance measurements and calculations. In the procedure, cholesterol oxidase oxidizes free cholesterol. The oxidation step produces cholest-4-en-3-one and hydrochloride peroxidesterase hydrolyzes cholesterol esters and cholesterol in direct proportion to the amount of cholesterol present. N,N-Diethylaniline hydrochloride and 4-aminoantipyrine react with the hydrogen peroxide to produce a quinoneimine dye (lambda max = 553 nm). Interacting reagents have been optimized simultaneously (coöptimization) utilizing response surface designs coupled with computer analysis of the data. Reagent efficiency is high and analytical performance reliable.


Faster radioimmunoassay of angiotensin I at 37 degrees C. We applied a 1-h radioimmunoassay incubation at 37 degrees C in determining generated angiotensin I in an assay for plasma renin activity. Under these nonequilibrium conditions, 26% of the 125I-labeled angiotensin I was bound at zero dose of unlabeled angiotensin, as compared to 57% at equilibrium after 18 h at 4 degrees C. Sensitivity and useful range for the standard curve remained unchanged. Blanks were not altered. There was a good (r = .971) correlation between renin values in 120 plasma samples from hypertensive patients as measured with both procedures. With isoelectric focusing, we detected no damage to the labeled angiotensin I during incubation for 1 h at 37 degrees C in the presence of diluted plasma, disodium ethylenediaminetetraacetate, hydroxyquinoline, and neomycin. Analytical recovery of unlabeled angiotensin I added to the assay mixture was 98 +/- 2.3% (mean +/- SD). We conclude that our incubation conditions allow rapid and accurate assay of plasma renin activity to be completed in one working day.


Direct analysis for cholesterol in gallstones by use of differential scanning calorimetry transition phase. A cholesterol transition phase at 37.5 degrees C has been shown by use of a Differential Scanning Calorimeter. The transition, reversible and reproducible, is useful for analytical purpose. We propose an analytical method for cholesterol in gallstones based on this transition. The method requires no intermediate reactions and cholesterol can be assayed directly in the powdered stone, with no other pretreatment or reagents. The analysis is highly specific, requires about 10 min, and is quite precise (CV about 1.5%) and accurate (about 2%).