Hydantoin drugs inhibit polymerization of pure microtubular protein. 5,5-Diphenylhydantoin or 5-(4-hydroxyphenyl)-5-phenylhydantoin, 3.6 X 10(-4) M, inhibited polymerization of purified pig brain tubulin 50% as measured by viscosometric assay and estimation of tubulin length by electron microscopy. 5,5-Diphenylhydantoin did not bind to the low molecular weight fraction of tubulin or to guanosinetriphosphate; it displaced colchicine weakly from its binding site. 5,5-Diphenylhydantoin did not depolymerize established microtubules, indicating that it differs from colchicine in site and mode of action.


Morphologic effect of hydantoin drugs on mitosis and microtubules of cultured human lymphocytes. A new class of mitotic inhibitors is described. Diphenylhydantoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), its metabolite, increase the mitotic index of cultured human lymphocytes without affecting the second resting phase (G2). Mitotic inhibition by these compounds is time dependent, and not a property of hydantoins in general. HPPH proved to be more potent than diphenylhydantoin. Electron micrographs of HPPH-treated human lymphocytes showed changes in 45% of the cells in metaphase: a decrease in microtubules or the appearance of 100 A microfilaments. These changes resemble those induced by colchicine.


The effect of hydralazine and other drugs on the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase. The objectives of this study were to investigate 1) the tissue distribution of procainamide acetylase activity in the rat and 2) the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase and 3) to determine the effect of drugs thought to be similarly acetylated on procainamide acetylation. The cytosol fraction (100,000 X g) of tissue homogenates served as the source of N-acetyltransferase. Of the tissues studied the liver possessed the greatest acetylase activity followed by the kidney, lung, intestine and spleen. The apparent procainamide Michalis constant (Km) for liver and kidney was 2.03 X 10(-4) and 2.09 X 10(-4) M in the presence of 4.2 X 10(-4) M acetyl CoA. The liver Km for procainamide with "infinite" acetylCoA concentration was 4.36 X 10(-3) M. The liver Km for acetyl CoA in the presence of "infinite" PA concentration was 2.44 X 10(-3) M. Hydralazine, para-aminobenzoic acid, isoniazid, and sulfapyridine competitively inhibited procainamide acetylation by liver and kidney N-acetyltransferase.


The quantitative disposition of procainamide and N-acetylprocainamide in the rat. The objectives of this study were to investigate: 1) the rat acetylator phenotype, 2) the systemic availability of oral procainamide (PA), 3) the kinetic disposition of PA and its N-acetyl metabolite (NAPA) and 4) the relationship between PA dose and steady-state blood PA and NAPA levels. The rat acetylator phenotype seems to be monomorphic in type. The systemic availability of PA was estimated to be 78%. The half-life (T 1/2) of PA elimination was 55 minutes and that of NAPA was 51 minutes. PA clearance was 64 ml/kg/min and NAPA clearance 22.4 ml/kg/min. The apparent distribution volume for PA was 4.92 liters/kg and for NAPA 1.64 liters/kg. Acetylation accounted for 38% of PA disposition, urinary excretion 34% and other metabolism 28%. Urinary excretion of NAPA accounted for 72% of administered drug. Steady-state blood PA levels showed a linear increase with dose whereas NAPA did not. The latter observation suggests saturation of PA acetylation at higher PA doses.


Blockade of tissue uptake of the antineoplastic agent, doxorubicin. Myocardial uptake of doxorubicin (Adriamycin) and its inhibition by digoxin and propranolol were studied in paced, isolated perfused cat hearts using tritiated doxorubicin. Contractility was studied using a Walton-Brody strain gauge arch and its first derivative. Coronary blood flow was measured by collecting the effluent from the heart. The myocardial content of doxorubicin was 0.069 +/- 0.101 nmol/mg after 30 minutes. Combined administration of doxorubicin and digoxin reduced the myocardial content of doxorubicin to 0.025 +/- 0.010 nmol/mg (P less than .02). The combination increased contractility compared with doxorubicin alone and increased coronary blood flow compared with digoxin alone. The reduction in the myocardial content of digoxin by doxorubicin was not significant. Propranolol also reduced the myocardial uptake of doxorubicin (P less than .05) without changing coronary blood flow and without further reducing contractility. Thus, both propranolol and digoxin merit evaluation in preventing doxorubicin cardiotoxicity.


Effects of intravenous and intraventricular prostaglandin E1 on thermoregulatory responses in rabbits. The thermal responses produced by both systemic and central administration of prostaglandin E1 (PGE1) at the three different ambient temperatures (Ta) of 2, 22 and 32 degrees C were measured to assess the possible involvement of PGE1 in temperature regulation. The body temperatures, metabolic rate, respiratory evaporative heat loss and vasomotor activity in response to PGE1 were measured. Intravenous administration of PGE1 produced dose-dependent hypothermia at Ta's of both 2 and 22 degrees C. The PGE1 hypothermia was due to cutaneous vasodilation. However, at a Ta of 32 degrees C, intravenous PGE1 produced no changes in rectal temperature and ear blood flow. On the other hand, the direct injection of PGE1 into the third ventricle produced dose-dependent hyperthermia. At a Ta of 22 degrees C, PGE1 fever was due to decreased heat loss along with a small increase in heat production. In the cold, PGE1 fever was due to increased heat production while in the heat heat losses were decreased. The data suggest that elevating PGE1 levels in the periphery causes a hypothermia, while elevating PGE1 levels in the central nervous system causes a hyperthermia at Ta's of both 2 and 22 degrees C.


Drug design and development. A realistic appraisal. The discovery of new biologically-therapeutically active structures continues to depend on screening and on isolated observations of unexpected drug metabolites and drug activities. The selection of therapeutically improved and useful chemicals requires molecular modification. Refinements in intuitive and physiochemical methodology can provide shortcuts in random choices and permit extrapolations of some facets of activity with a variable degree of accuracy. The final decisions concerning the usefulness of a drug remain in the domain of experimental and clinical pharmacology.


Nitrogen analogues of 1,4-benzoquinones. Activities against the ascitic sarcoma 180 of mice. Compounds having the basic structure N-(R)-substituted ring-substituted 4-iminocyclohexadienone have been synthesized and tested as antitumor agents against the ascitic sarcoma 180 tumor in Swiss mice. Among these compounds, the dimethylindoanilines [R = 4-(CH3)2NC6H4] are most stable in water at pH 7.0 and at 25 degrees C, the oximes (R = oh) are less stable, and the N-halo compounds (R = Br and Cl) are least stable. The N-halo derivatives have the highest redox potentials under the conditions used, the greatest effect against ascitic sarcoma 180 in Swiss mice, and the greatest acute toxicity when injected ip in the Swiss mice. Discriminant analysis of the results indicates that substituents with positive values of F and negative values of pi increase the antitumor activities, whereas those with positive values of sigma and R should lower the toxicity. The redox potential, a molecular parameter, is the best single variable for discriminating between the groups based on antitumor activities.


Synthesis of 1-deaza-6-thioguanosine and 1-deaza-6-(methylthio)guanosine. A synthesis of 1-deaza-6-thioguanosine (8) and 1-deaza-6-(methylthio)guanosine (9) from 2-amino-6-chloro-1-deazapurine (4) is described. The reaction of the N2-acetyl derivative of 4 with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride in the presence of Linde 4A molecular sieve gave the blocked nucleoside 6. Deacetylation of 6 gave the chloro nucleoside 7 which was treated at high temperature with hydrogen sulfide and methyl mercaptan to give 8 and 9, respectively. The structure of 7 was confirmed by 1H NMR and by conversion to the cyclonucleoside 14. Compound 4 gave a 79% increase in life span in the L1210 mouse leukemia screen.


Synthesis and some pharmacological properties (4-beta-(2-thienyl)-L-alanine)oxytocin. The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the conformation of the 20-membered ring portion of oxytocin. The analogue was synthesized in stepwise manner by solution techniques utilizing ethylcarbamoyl protection for cysteine side chains. The presence of thienylalanine in position 4 evokes a drastic reduction in both affinity and intrinsic activity; the reduction in intrinsic activity was greater than that found for [Leu4]oxytocin or [Phe4]oxytocin. The analogue possesses 0.51 +/- 0.03 unit/mg of rat uterotonic potency and less than 0.05 unit/mg of rat pressor and rat antidiuretic potency and behaves as a competitive inhibitor of the response to oxytocin in the avian vasodepressor assay with a pA2 value of 7.44 +/- 0.19.


Replacement of the disulfide bond in oxytocin by an amide group. Synthesis and some biological properties of (cyclo-(1-L-aspartic acid,6-L-alpha,beta-diaminopropionic acid))oxytocin. As part of a continuing investigation of the steric and electronic functions of the disulfide group in neurohypophyseal hormones on their biological activity, the synthesis of "oxytocin lactam", [cyclo-(1-aspartic acid,6-alpha,beta-diaminopropionic acid)]oxytocin, has been undertaken. The protected nonapeptide was prepared in a stepwise manner by solution techniques; after removal of side-chain protecting groups, formation of the briding amide bonds was accomplished by oxidation-reduction condensation. The analogue possesses rat uterotonic, avian vasodepressor, and rat antidiuretic potencies of 16 +/- 2, 6.6 +/- 0.6, and 5.6 +/- 3.8 units/mg, respectively.


Synthesis and comparative skeletal muscle relaxant activity of some 2,4-imidazolidinediones and their corresponding 5-hydroxy-2,4-imidazolidinediones. A series of 5-hydroxy substitution products of 2,4-imidazolidinediones, including the 5-hydroxy metabolite of the skeletal muscle contraction antagonist, dantrolene sodium, has been synthesized and evaluated for skeletal muscle relaxant activity. Most of these analogues are active in vivo with iv administration and in vitro. While two analogues are also active by oral and ip administration, only 1-[[[5-(3,4-dichlorophenyl)-2-furanyl]methylene]amino]-5-hydroxy-2,4-imidazolidinedione is sufficiently active in inhibiting the Straub tail in mice. However, none of these analogues has a muscle relaxant efficacy index greater than 1, comparable to dantrolene.


3-Benzazocine amidinium nitronates. An unusual type of opiate antagonist. An interesting type of 3-benzazocine ring system which contains amidine functionality has been found to have significant narcotic antagonist activity. The isomeric 2-benzazocine, which incorporates similar structural features, except for the position of the ring nitrogen and adjacent phenyl substituent, is inactive. These 2- and 3-benzazocines can be synthesized in a single step from appropriately structured amidines and naphthalenes, and such syntheses may provide useful routes to new and interesting types of narcotic antagonists.


Anomalous chiroptical properties of warfarin and phenprocoumon. The configurationally similar enantiomers of warfarin and phenprocoumon are found to exhibit circular dichroism curves which are nearly mirror related in the range of 240-340 nm. This effect is interpreted as being due to spatial similarities of the preferred conformations of opposite configurations of the two drugs in solution. An inherently dissymmetric chromophore (theta approximately 1.2 x 10(5)) is observed at approximately 220 nm for warfarin, the cyclic hemiketal tautomeric forms, and the cyclic methyl ketals.


Phosphorus-nitrogen compounds. 21. Murine oncolytic and antifertility effect of adamantylaziridine compounds. P,P-Bis(1-aziridinyl)-N-adamantylphosphinic amide and N,N'-bis(ethylene)-P-(1-adamantyl)phosphonic diamide were synthesized as potential anticancer and male antifertility agents. Log P values (octanol-water) of the agents were determined and compared to calculated values. Both derivatives displayed intraperitoneal murine antileukemic activity and antifertility effects when given intraperitoneally and orally.


Structure-activity relationships in antitumor aniline mustards. Quantitative structure-activity relationships (QSAR) have been formulated for the hydrolysis of aniline mustards and their antitumor activity against Walker 256 tumor and L1210 and P388 leukemia. In general, the antitumor activity parallels hydrolysis under the conditions defined by Ross; toxicity (LD50) parallels antitumor efficacy. Chlorambucil is an exception. A most important finding is that ideal lipophilicity for effectiveness against Walker tumor appears to be much higher than for the leukemias which suggests that solid tumors may, in general, require more lipophilic drugs than leukemias.


Structure and tumor-promoting activity of analogues of anthralin (1,8-dihydroxy-9-anthrone). Seventeen analogues of the tumor-promoting agent anthralin were tested for the same biological property by repeated skin application on mouse skin using female ICR/Ha Swiss mice, after a single application of a subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Seven of the compounds tested are new compounds. They are 1,8-diacetoxy-9-anthrone, 1,8-dimyristoyloxy-9-anthrone, 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1,8,10-trihydroxy-9-anthrone, 1,8-dihydroxy-9,10-dihydroanthracene, and myristoyljuglone. All compounds were used in pure form for the bioassays. Of the 17 test compounds four showed notable tumor-promoting activity. They are 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1-hydroxy-9-anthrone, and juglone. In order to determine whether there is any relationship between tumor-promoting activity and metal chelation in this series, the chelating abilities of anthralin and of its inactive analogue 1,8-dihydroxyanthraquinone were examined using the bivalent metal ions Cu(II), Zn(II), Mn(II), Mg(II), and Ca(II). No relationship between chelation and tumor-promoting ability was found.


Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines. To investigate the possible importance of small levels of sulfonamide anion in the antileukemia (L1210) 4'-(9-acridinylamino)methanesulfonanilides, an anionic derivative was prepared, in which -COOH replaced -NHSO2CH3, and shown to have experimental antitumor activity. Analogue synthesis and evaluation show that acceptable placement of the carboxylate function on the 9-anilino ring is restricted to the 1'-position. While the 1'-COOH and 1'-(CH2)2COOH analogues proved active, the intermediate acetate variant (1'-CH2COOH) was inactive. There were marked differences in the effects of added acridine ring substituents, on biologic activity, depending on the function attached to the 9-anilino ring (1'-NHSO2CH3 or 1'-COOH). Consideration of the vector components of possible drug-binding forces, acting on a DNA-intercalated agent, suggests that there may be low-energy barriers to two-dimensional reorientation of a planar, intercalated chromophore in relation to the neighboring purine-pyrimidine base pairs. It is proposed that site forces from an added substituent could lead to modified DNA-binding orientations. Observed acridine-ring substituent effects on biologic activity would then depend on the 9-anilino ring function (1'-NHSO2CH3, 1'-COOH) employed.


Analogues of ornithine as inhibitors of ornithine decarboxylase. New deductions concerning the topography of the enzyme's active site. Fourteen structural analogues of ornithine were synthesized and evaluated as inhibitors of preparations of the enzyme L-ornithine carboxylase (ODC) (E.C. 4.1.1.17) obtained from rat liver, rat hepatoma cells in culture, or bull prostate. The synthesis of these compounds was achieved either via a Bucherer type reaction or via alkylation of carbanions derived from ethyl acetamidocyanoacetate, methyl isocyanoacetate, benzyl alpha-isocyanopropionate, methylbenzaldimine alanate, and the azlactone derivative of ornithuric acid. (+)-alpha-Methylornithine, which was assigned the L configuration on the basis of rotational criteria, was found to be the most potent reversible inhibitor of ODC among the synthesized compounds. From the degree of inhibition of ODC activity in the presence of the various ornithine analogues, it has been possible to delineate some of the structural features of the substrate L-ornithine which are required for binding to the mammalian ODC active site.


Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol. The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial bioisostere of norepinephrine, with direct agonist activity at the alpha-adrenergic receptor. The ED50 for 2 in contracting the guinea pig isolated aortic strip was determined to be 8.0 x 10(-6) M. Compound 4 was shown to be a partial bioisostere of isoproterenol, with direct activity as a beta-adrenergic agonist. The ED50 values for positive chronotropic and inotropic effects of 4 on the isolated guinea pig atrial preparation were determined to be 6.2 x 10(-6) and 3.8 x 10(-6) M, respectively. The ED50 for 4 on the isolated guinea pig tracheal preparation was determined to be 1.6 x 10(-6) M. These results indicate that 4 shows greater selectively for the beta-2 adrenergic receptor than does isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggests that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.


Thiazolinone analogues of indolmycin with antiviral and antibacterial activity. Total synthesis of a series of thiazolinone and thiazolidinone analogues of the antibacterial oxazolinone antibiotic indolmycin is described. The synthetic route involves nucleophilic displacement of mesyloxy and chloro groups from methyl 2-substituted-3-(indol-3-yl)propionates 3 and 4 and butyrate 19 with N-substituted thioureas. The formation of the rearranged chloro esters 29, 43, and 44 from beta(RS,RS)-methyl indolmycenate (27), alpha(RS,SR)-methyl 2-hydroxy-3-(2-methylindol-3-yl)butyrate (39), and alpha-methyl 2-hydroxy-3-(indol-3-yl)valerate (41) supports a reaction mechanism involving neighboring group participation by the indole C-3 carbon during nucleophilic displacement on the beta-carbon of a C-3 substituent. Structure-activity relationships are discussed. Although neither indolmycin nor its diastereoisomer isoindolmycin is antiviral, 2-monoalkylaminothiazolinone analogues have in vitro activity against both RNA viruses and bacteria. The most active compound is the sulfur isostere of indolmycin, and only the levorotatory enantiomer 46, with the same absolute stereochemistry as natural indolmycin, has antimicrobial activity.


Another look at learning style inventory and medical career choice. It has been suggested that learning style, as measured by the Learning Style Inventory, can be associated with choice of a particular medical field and that individuals with certain learning styles in making career choices are influenced more than other students by particular learning experiences. In the replication study reported here the Learning Style Inventory was administered to over 200 practicing physicians and medical students. Contrary to the previous findings, the results of this study suggest that there is no association between learning style and career choice in medicine and no association between learning style and the kind of influences which were most important in making a career choice.


Evaluation of medical students during a clinical clerkship in internal medicine. During a three-month clinical clerkship in medicine 175 medical students were evaluated. A proficiency assessment process was developed which included preceptor evaluation of on-the-job performance as well as independent oral and written examinations. Analysis of data from this study disclosed small correlations among the three measurements of clinical competence. Ratings by preceptors, based on direct observations of students, also showed a large intrastudent variation. Although the individual clinical ratings had low reliability, averages taken over a period of time were more consistent. These data have importance not only in the assessment of the clinical competence of medical students but also in other areas of granting medical credentials and certification.


Personality changes and compatibility in the psychiatric resident--supervisor relationship. Seventy-one psychiatric resident-supervisor dyads were studied in terms of Schutz's interpersonal theory of compatibility. Personality changes during the second year of psychiatric residency were also measured by means of Schutz's Fundamental Interpersonal Relations Orientation Scale. Predictions relating compatibility to satisfaction with the dyad and to ratings of competence were not confirmed. Personality changes were found, with residents showing a significant decrease in needs for wanting to be included and for expressing affection. Situational factors are proposed for the personality changes, and personality factors are suggested as influencing the selection of psychiatry as a medical specialization.


Microscopic age changes in the frontal bone of the domestic rabbit. This study reveals age related changes in the microscopic structure of the paired frontal bone of the domestic rabbit. Undecalcified ground sections were prepared from anterior frontal bone slices removed from New Zealand White rabbits ranging from birth to 24 months of age. Included were 40 females, 4 males and 6 rabbits less than 14 days old of unknown sex. The ground sections revealed both qualitative and quantitative age changes. Qualitative changes include change in bone tissue types and developmental processes, and presence or absence of primary and secondary osteones. Quantitative changes were measured by counting primary osteones in the outer table of each frontal bone half within 1.6 mm of the metopic suture. In this region, primary osteones were absent at birth, limited in number at 14 days and generally numerous between one and three months of age. In animals older than three months, numbers of primary osteones generally decreased with increasing age. No animals older than 16 months revealed primary osteones. Possible sources of variability in the relationship between observed primary osteone number and age include ability to recognize primary osteones, methods of sampling and processing bone slices, sex related differences and diseases afflicting specimen. Significance of this study includes increased knowledge of frontal bone growth and histology.


A microscopical study of the innervation of flight muscles in the tsetse fly. The gross morphology of the nervous system supplying the dorsal longitudinal flight muscles of tsetse flies is described. Electron microscopical investigation of the nerves reveals that the dorsal longitudinal muscles are innervated by branches from four main axons. A detailed description of the neuromuscular junctions in the flight muscle is presented.


Survey of continuing education needs for nonemergency physicians in emergency medicine. A questionnaire was mailed to every physician in Iowa (2,551) to determine their need for continued education in emergency medicine. There 884 usable responses (34.7%). Results revealed a low incidence of formal education in emergency medicine, particularly at the undergraduate and graduate levels, with a great incidence of continued education in the field. Approximately half of the responding physicians felt they treat an emergency patient at least once a week. The primary conclusion of the study is that continued education in basic emergency medical care is perceived as being necessary by physicians who are not specialists in emergency medicine, but, nevertheless, treat patients with medical emergencies. Physicians were most interested in education in basic life saving procedures, such as airway maintenance and cardiopulmonary resuscitation.


Emergency, emergentology, emergentologist. No word exists that identifies the branch of knowledge of emergency medicine. The potpourri of names applied to those specializing in emergency medicine creates an aura of amorphism. Emergentology and emergentologist, derived from the Latin emergent, are recommended primarily because they are easily pronounced, appropriately descriptive single words that are obviously related to emergency medicine's foundation word--emergency.


Nonemergency visits to a pediatric emergency department. We examined six factors that may help to explain why parents take their children to hospital emergency departments: arrival time; travel time; who decided the patient should go; did the patient have a physician; did the parent attempt physician contact, and where the parent would have preferred to have gone for treatment. Results indicate that 47% of the nonemergency visits occurred during the time when physicians maintain office hours. Most visits were made by patients living less than 15 minutes away from the hospital. Physicians decided that the patient should go to the emergency department 18% of the time. Patients with a private physician accounted for 80% of the visits. Most parents did not try to contact a physician prior to the visit. Indeed, 46% of the parents preferred to take their children to the emergency department rather than to a physician's office. Finally, 74% of the parents who attempted some contact with a member of the health care system were referred to the emergengy department for care.


Drug injection injuries of the hands: evaluation and treatment. Twenty-six patients with hand infections caused by drug injection were seen at Detroit General Hospital between 1974 and 1976 and were followed up. The duration of drug abuse was 2 to 25 years. The time before the patient sought medical help ranged from three days to 20 weeks. Among the 26 patients were three webspace infections, three finger abscesses, four gangrene of distal phalanx, nine cellulitis and abscess, one ulceration of the thenar eminence, and two ulcerations of the volar aspect. Follow-up was difficult due to unreliability of drug addicts.


Inflammatory pseudotumor of the sternum. A complication of polymer application during sternotomy repair. A case of inflammatory pseudotumor of the sternum resulting from the application of polyurethane foam is discussed. The past use of polymers in bone repair is reviewed.


Successful surgical correction of infradiaphragmatic total anomalous pulmonary venous return into the inferior vena cava. A fourteen-year follow-up. This case report describes the long-term follow-up of a patient who, at 7 weeks of age, underwent surgical correction of infradiaphragmatic total anomalous pulmonary venous return (TAPVR) to the inferior vena cava. Fourteen years after operation, the patient has normal anatomy and nearly normal hemodynamics. The difference between this type of infradiaphragmatic TAPVR with posthepatic drainage is compared with the more common type which drains prehepatically.


Mycobacterium fortuitum epidemics after open-heart surgery. We present the clinical and epidemiological features of Mycobacterium fortuitum epidemics involving 19 patients who underwent open-heart surgery. The source of the infection could not be identified. However, bone wax and homografts utilized at that time have been suspected. The infected patients responded poorly to antibiotic management and their courses in most cases were influenced beneficially by total sternectomy and transplantation of the omentum into the mediastinum. The emergence of M. fortuitum may represent an aggressive bacterial strain resistant to presently used broad-spectrum antibiotic drugs.


Mechanical circulatory support in postoperative cardiogenic shock. A 38-year-old white woman had cardiogenic shock after elective mitral valve replacement and was unresponsive to pressor drugs and intra-aortic balloon counterpulsation. A left ventricular assist device (left ventricle to ascending aorta) was implanted 16 hours after the initial operation and provided circulatory support for 8 days. Improvement in the patient's own cardiac performance was documented, and there were no complications attributable to the assist device. However, intercurrent medical problems resulted in clinical deterioration on the fifth day after operation, and the patient died 8 days after operation. The findings in this patient suggest a potential role for this left ventricular assist device in future cases of acute, intractable, but potentially reversible myocardial failure.


Aerodynamic relationships associated with normal phonation and paralytic dysphonia. Physiological differences between normal speakers and those with unilateral vocal cord paralysis are presented. Pressure readings taken intraorally and subglotically are compared during phonation of consonants requiring laryngeal closure and those not requiring cord approximation. From our studies, it is apparent that: (1) a significant difference in air pressure patterns exists between normal speakers and those with vocal cord paralysis, (2) the respiratory apparatus tends to alter normally constant airflow in cases of vocal fold paralysis and (3) either voice therapy or teflon cord injection will significantly alter the aerodynamic relationships from the untreated paralyzed state.


Sinusitis, otitis and adenotonsillitis in children: a retrospective study. A retrospective study of 93 cases in which ventilating tubes were required in the therapy of persistent otitis media. Paranasal sinus radiographs, antral washes and cultures of positive washes were used to demonstrate active sinusitis associated with persistent otitis media. Other factors are also of importance, such as allergic or other immune-related disease processes. However, active sinusitis was demonstrated in 25-49% of the cases studied, depending on criteria used.


Monitoring occlusion and accidental extubation of tracheostomy tubes in children. Twelve infants and children with tracheostomies have been monitored for occlusion or accidental extubation in hospital and at home using a thermistor-electronic monitor. The patients ranged from 1 month to 6 years of age and have been monitored for 1 to 16 months. The device sounds an alarm when it fails to sense the warming of air on expiration. It is electrically safe, simple to operate and has been well accepted by parents. The thermistor-monitor has permitted the psychologic and economic advantages of earlier hospital discharge especially for the smaller infants. In two infants, and on three occasions in one, use of the device was life-saving. The device is applicable for use in patients of any age, with endotracheal or tracheostomy tubes.


Guidelines for prognosis in head and neck cancer with nodal metastasis. Patients with squamous cell carcinoma of the head and neck with cervical node metastasis were studied retrospectively to delineate the prognostic significance of certain clinical and histologic parameters. The patients were divided into radiated and non-radiated groups for analysis purposes. A good prognosis was found in non-radiated patients with an active nodal plasmacytic inflammatory response. No prognostic information was obtainable in observing the inflammatory response of nodes altered by radiation effects. Extranodal spread of the tumor indicated a poor prognosis for radiated and non-radiated patients, being more significant in the non-radiated ones. Patients receiving preoperative radiation must be separated from non-radiated patients in evaluating host response parameters for prognostic purposes.


An anatomic study of the hypotympanic branch of Jacobson's nerve. Microscopic dissection of 20 human temporal bones revealed that the nerve of Jacobson gave rise to a hypotympanic branch in 50% of the specimens. The fact that the branch was frequently covered by promontory bone and was difficult to approach by the standard tympanotomy technique may explain the 21% failure rate as reported in the literature.


Experiences with parieto-occipital flaps in hair transplantation. Parieto-occipital flap operations were successfully performed on patients with hereditary or traumatic baldness. The indications for this procedure, the techniques of the operation, and the postoperative morbidity and complications are described.


A technique of nasolabioplasty.

A technique of nasolabioplasty. There are several techniques available for the improvement of the deep nasolabial folds. The standard face-lift operation is the most acceptable and popular technique as it leaves no scars on the face. Occasionally, the aesthetic surgeon encounters patients who, because of economic or health reasons, cannot undergo the face-lift operation. They may also be too old to want a full face-lift. In these individuals, a nasolabioplasty has been found very useful. The operation may also be used as an adjunct to rhytidectomy in patients with persistent sagging of the cheeks and deep nasolabial folds after a face-lift operation. Two incisions are placed on each side; one precisely on the nasolabial groove and the other lateral to the groove. The amount of skin outlined between the two incisions is proportional to the degree of pull desired. The island of skin between the incisions is not removed. Instead, it is de-epithelialized, rolled on itself into a tube and left in situ under the nasolabial fold to minimize recurrent deepening with time. Other techniques of nasolabioplasty are reviewed. The results of the operation in 14 patients are analyzed, and complications are discussed.


Tests for cataglykin activity on a cyanogen bromide fragment of human growth hormone. A peptide having the reputed essential amino acid sequence to show cataglykin-like effects was prepared from human growth hormone (hGH) by cyanogen bromide cleavage and was tested in two systems in which cataglykin has effects. The peptide prolonged the depression of blood glucose concentration brought about by insulin during intravenous insulin tolerance tests in rats. However, the magnitude of the depression caused by insulin was not increased. There was no stimulation by the peptide of glucose uptake by rat hemidiaphragrams in the presence of insulin in vitro. Thus, this peptide does not duplicate the effects of cataglykin.


C-peptide secretion and insulin antibodies as determinants of stability in diabetes mellitus. The relative significance of residual beta-cell secretory activity and human insulin antibodies in determining diabetic stability has been examined in 35 diabetic subjects. The response of plasma C-peptide immunoreactivity following 50 g oral glucose has been used as an index of beta-cell function. Glucose-stimulated C-peptide secretion was observed in 58% of stable diabetics, but in no labile diabetics. When present, C-peptide secretion following a glucose load in diabetics was of smaller amplitude and slower in onset, but more prolonged than in normal subjects. In secretors, stability of diabetes was significantly correlated with the magnitude of the C-peptide response. As a group, labile diabetics had lower insulin antibody levels than stable patients, but stability and antibody levels were not correlated in individual patients. In non-secretors there was no difference in antibody levels between the stable and labile groups. Neither the equilibrium binding affinities nor the dissociation rate constants differed significantly for antibodies from stable and labile diabetics. Thus stability of diabetes depends upon residual beta-cell secretory activity, but not on the concentration or binding characteristics of insulin antibodies.


Spontaneous Fanconi syndrome in the dog. Three dogs with spontaneous renal tubular defects similar to idiopathic Fanconi syndrome are characterized. Renal clearance studies revealed a fractional reabsorption of glucose ranging from 31% to 82%. Abnormal glucose thulium values were present in all dogs. A generalized aminoaciduria occurred in two dogs while one had aminoaciduria characteristic of canine cystinuria. Fractional reabsorption of phosphate ranged from 47% to 79%. In vitro uptake of alpha-methyl-D-glucoside was significantly depressed (p less than 0.001). In vitro uptake of amino isobutyric acid was similar to controls. Renal biopsy revealed nonspecific interstitial change in two dogs and normal histology in the other. These animals represent a useful new model for the study of renal tubular transport defects.


Heparin resistance and decreased hepatic triglyceride hydrolase release during long-term estrogen-progestin treatment. These studies were undertaken to define the mechanism for the depression of post-heparin triglyceride hydrolase activity in women treated with estrogen-progestin oral contraceptives. Six treated and six control women were studied. Total, protamine-inhibited, and protamine-resistant triglyceride hydrolase activities were measured after six different intravenous doses of heparin in each subject in order to determine the dose-response relationships for lipase release. As has been reported during short-term treatment with estrogens, long-term treatment with oral contraceptive agents is accompanied by selective depression of protamine-resistant (hepatic) lipase activity. This depression can be partly reversed by the administration of large heparin doses, but maximally releasing heparin does fail to restore postheparin protamine-resistant activity to control values. These data are compatible with the idea that the releasable pool of hepatic triglyceride hydrolase activity is diminished in women who receive oral contraceptive agents and that the pharmacokinetics of its release are altered in such a way that only relatively high concentrations of heparin displace the enzyme from this pool.


Dose-response studies on the inhibitory effect of thyroid hormones on insulin secretion in the rat. Dose-response studies have been performed to investigate the effect of thyroid hormones on insulin secretion from the rat pancreas with special reference to the time course of the hormone effect, doses of triiodothyronine (T3) and thyroxine (T4), and glucose concentration in the perfusion medium. The prominent effect of thyroid hormones was the inhibition of the late phase of glucose-induced insulin secretion. As the late phase comprises at least 98%-99% of insulin released from the pancreas during a 60-min stimulation period with glucose, 60-min cumulative values were calculated. Both T3 and T4 inhibited insulin secretion and induced concomitant inhibitory effects on plasma cholesterol levels, a parameter of experimental hyperthyroidism. The correlation demonstrates that inhibition of glucose-induced insulin secretion from the pancreas is a specific effect of thyroid hormones. The inhibitory effect of T3 was five times greater than the inhibitory effect of T4. An excess of thyroid hormones induced hyperthyroidism, with its well-known increased incidence of diabetes.


The influence of ethanol on splanchnic and skeletal muscle metabolism in man. Splanchnic and leg exchange of ethanol, acetate, glucose, lactate, pyruvate, glycerol, and free fatty acids was studied in five healthy volunteers before and after a 60-min infusion of ethanol. Leg and splanchnic blood flows were determined simultaneously using a modified indicator dilution technique. The blood alcohol concentration obtained was 1.88 mmoles/liter and splanchnic uptake of ethanol was calculated to be 1.18 mmoles/min. All subjects showed an acetate uptake over the legs with a mean of 0.25 mmole/min. Splanchnic glucose production was attenuated in four of five subjects after ethanol treatment, and glucose uptake by the legs was significantly reduced. The normal splanchnic uptake of lactate was changed by ethanol to a release, and the arterial concentration was nearly doubled. Net leg release of lactate decreased significantly. Splanchnic blood flow and oxygen uptake were uninfluenced by ethanol, whereas leg blood flow decreased from a mean of 0.77 to 0.65 liter/min. It is concluded that, following ethanol treatment, (1) a major part of acetate released from the splanchnic region is taken up by the muscles, (2) leg glucose uptake is decreased by a reduction of the same magnitude as the actate uptake, and (3) leg blood flow is reduced, probably owing to a constriction of muscle vessels.


Are paranoid schizophrenics biologically different from other schizophrenics? Two studies were undertaken to verify the presence of lowered platelet monoamine oxidase activity in chronic schizophrenia. In the first study, a retrospective chart analysis, the mean platelet activity of patients with chronic schizophrenia (7.73+/-0.64 nmol of benzylaldehyde product per 10(8) platelets per hour [S.E.M.]) differed significantly from that of normal controls (12.13+/-0.2, P less than 0.001). Chronic paranoid schizophrenics (4.81+/-0.46) differed significantly from chronic nonparanoid schizophrenics (8.6+/-0.75, P less than 0.03). A separate prospective study confirmed significantly lower values for monoamine oxidase activity in chronic schizophrenic patients diagnosed as paranoid (5.97+/-1.17) or as having secondary paranoid features (6.28+/-0.71) as compared to chronic nonparanoid schizophrenics (9.81+/-0.87, P less than 0.001). Chronic paranoid schizophrenia may be a separate disorder from the other chronic forms of schizophrenia, and this difference may be related, at least in part, to biochemical characteristics.


Effects of leg exercise on insulin absorption in diabetic patients. To examine the effects of leg exercise on insulin absorption from various injection sites, 125I-labelled rapid actin insulin (9 units) was injected subcutaneously into the leg, arm or abdomen of patients with insulin-dependent diabetes before one hour of intermittent leg (bicycle) exercise and on a resting, control day. Insulin disappearance from the leg increased by 135 per cent during the first 10 minutes of leg exercise (P less than 0.05) and remained 50 per cent above resting levels after 60 minutes (P less than 0.02). Leg exercise had no effect on insulin disappearance from the arm, but insulin disappearance from the abdomen was reduced during the post-exercise recovery period (P less than 0.02). As compared to leg injection, arm or abdominal injection reduced the hypoglycemic effect of exercise by 57 per cent (P less than 0.02) and 89 per cent (P less than 0.005), respectively. Leg exercise accelerates insulin absorption from the leg. Arm or abdominal injection avoids this acceleration during leg exercise and reduces exercise-induced hypoglycemia.


Familial azotemia. Impaired urea excretion despite normal renal function. We performed detailed studies of renal function in two of five related patients with normal serum creatinine levels to determine the mechanism of their chronic azotemia. Inulin and para-amino-hippurate clearances, maximum tubular transport of para-aminohippurate, and renal acidification were within normal limits. In addition, renal concentrating and diluting abilities of these patients were similar to those of four normal controls. Urea clearances of both patients during maximum water diuresis (27.6 and 40.8 ml per minute per 1.73 m2) and antidiuresis (5.3 and 4.0), however, were much lower than mean (+/- S.E.M.) values in the normal controls (70.4 +/- 3.7 and 30.0 +/- 3.42 ml per minute per 1.73 m2, respectively). Thus decreased urea excretion despite otherwise normal renal function was responsible for the chronic azotemia of these patients. The genetic defect in renal urea clearance appeared to be inherited as an autosomal dominant trait.


Preservation of function in experimental renal disease by dietary restriction of phosphate. We sought to determine the importance of calcium phosphate deposition in the functional deterioration of damaged or diseased kidneys. Using the remnant-kidney model in rats, we found that dietary phosphate restriction prevented proteinuria, renal calcification, histologic changes, functional deterioration and death in uremia. Histologic examination of the remnant kidney in the nonrestricted animals showed calcium and phosphorus deposits in the cortical tubular cells, basement membranes and interstitium. A similar degree and pattern of calcification have been found in preliminary studies of human end-stage kidneys. Our results suggest that the calcification produced by the altered phosphorus metabolism present in the uremic state incites an inflammatory and fibrotic reaction leading to destruction of the remnant kidney. Phosphate restriction prevents this response in the remnant kidney. The potential applicability of these findings to other forms of experimental renal disease and to clinical uremia remains to be explored.


Circulating immune complexes in steroid-responsive nephrotic syndrome. We analyzed serums from 39 children with steroid-responsive nephrotic syndrome for the presence of circulating soluble immune complexes. Seventeen of 18 children in relapse had raised levels of IgG complexes: median titers were significantly higher in these patients than in control children (P less than 0.001) or in nephrotic children in sustained remission (P less than 0.001). Seven of nine children followed sequentially had raised complex levels in early remission but became normal after six weeks in remission. In contrast to patients with systemic lupus erythematosus these IgG complexes were not able to bind C1q. Serums from five patients in relapse contained complexes intermediate in size (2 to 2.5 X 10(6) daltons) as compared to those seen in systemic lupus erythematosus, and four of the five had small complexes as well (3 to 5 X 10(5) daltons). These findings suggest that immune complexes may have a pathologic role in steroid-responsive nephrotic syndrome, but the mechanism by which proteinuria is effected remains unclear.


Telephone management of acute pediatric illnesses. To evaluate the telephone management of five common acute pediatric problems, a "programmed mother" made unidentified cells to five pediatric nurse practitioners, 28 pediatric house officers and 23 pediatricians in practice. Calls were tape recorded and scored for history taking, disposition and interviewing skill. Nurse practitioners averaged 79.6 per cent of the total possible theoretical score for history taking, house officers 69.1 per cent, and practicing pediatricians 52.6 per cent (P less than 0.001). For disposition, nurse practitioners averaged 71.1 per cent of the maximum score, in contrast to 60.1 per cent for house officers and 58.9 per cent for practicing pediatricians. Similarly, nurse practitioners had significantly higher (P less than 0.001) scores for interviewing skills. No significant differences were found among house officers in the first, second and third years in history taking, disposition or interviewing skills. We conclude that pediatric nurse practitioners manage common pediatric problems by telephone better than house officers or practicing pediatricians and that better training for this aspect of practice is needed.


Effect of lithium on neutrophil mass and production. We measured the effect of lithium on the blood neutrophil mass and neutrophil production, using standard di-isopropylfluorophosphate (DF32P) methods. In 12 lithium-treated patients the total blood neutrophil pool was 105 (42 to 270) x 10(7) cells per kilogram (median and 95 per cent limits) as compared with 61 (27 to 138 x 10(7) in 71 controls (P less than 0.001). The neutrophil turnover rate, a measure of effective neutrophil production, was 230 (108 to 380) x 10(7) cells per kilogram per day in the lithium-treated group and 160 (62 to 400) x 10(7) in the controls (P less than 0.05). Neutrophil migration into skin lesions ranged from 34 to 469 x 10(5) cells per day in the lithium-treated patients, as compared with 1.7 to 68 x 10(5) in 10 controls. Lithium causes enlargement of the total circulating neutrophil mass and accelerates neutrophil production without impairing neutrophil migration into skin lesions.


Circulating immune complexes and complement activation in primary biliary cirrhosis. We evaluated 20 patients with primary biliary cirrhosis and seven controls with extrahepatic biliary obstruction for presence of circulating immune complexes, having found serologic evidence of alternate complement-pathway activation in eight of the 20. Immune complexes were isolated by cryoprecipitation from serum and measured directly by the sensitive Raji-cell radioimmunoassay. Cryoproteins, found in high concentrations in 90 per cent of the patients with cirrhosis but undetectable in the controls, were composed of IgM (60 per cent), IgG-IgM (25 per cent) and IgA-IgM (5 per cent) and were capable of activating the complement system in vitro. Immune complexes detected by the Raji assay were found in 95 per cent of the patients with cirrhosis and circulated in exceedingly high concentrations (474 microgram per milliliter; range, 16.2 to 2192) but were absent in the controls. Furthermore, the alternate complement pathway was activated in eight cirrhotic patients. These complement-fixing immune complexes differ from immune complexes isolated from other types of liver diseases and may be important in the pathogenesis of primary biliary cirrhosis.


Peritoneal dialysis in rabbits. A study of transperitoneal theophylline flux and peritoneal permeability. Since vasodilators can restore toward normal the decreased peritoneal clearances associated with vascular disease, the influence of aminophylline on peritoneal solute transport was studied in unanesthetized rabbits. Mean control creatinine clearance was 0.56 ml/kg/min and urea clearance 0.80 ml/kg/min. Neither intraperitoneal nor intravenous aminophylline increased peritoneal clearances, nor did the ratio creatinine clearance/urea clearance change from the control value, 0.70. Bidirectional flux of theophylline occurred at clearances of 0.70 ml/kg/min efflux and 0.64 ml/min influx. The removal rate of theophylline was 0.05% min, allowing therapeutic removal of excess aminophylline and warranting supplemental therapy during dialysis if therapeutic theophylline concentrations are required. As the intraperitoneal aminophylline was well tolerated, this route can be considered for therapeutic administration.


Revision of light-microscopic kidney biopsy diagnosis in glomerular disease. Paraffin-embedded kidney biopsies sent to our laboratory in 1967 were re-embedded in Epon and studied with electron and light microscopy (1-micrometer thick sections). Of 28 biopsies with enough material 18 were cases with clinical suspicion and symptoms of glomerular disease. In electron microscopy all of these were shown to be of glomerular origin by demonstrating either dark deposits in or at the basement membrane, or amyloid fibrils, or areas with retraction of the foot processes of the epithelial cells. Original light microscopy in 1967 had given proof of glomerular origin in 9 of these 18 cases. Light microscopy of plastic sections of these originally paraffin-embedded biopsies was also helpful in diagnosis and showed deposits in 9 out of 14 cases with ultrastructural deposits. The study shows that considerable benefits can be gained through re-embedding biopsies in plastic, especially in cases with minor alterations.


High concentration of sweat calcium, magnesium and phosphate in chronic renal failure. Sweat collected from the forearm of chronic renal failure and control patients, after iontophoretic stimulation with pilocarpine, was analyzed for Na, K, Cl, Mg, phosphate and urea. Concentrations of Ca, Mg and phosphate in sweat from chronic renal failure patients were significantly elevated (p less than 0.05) as compared to controls, while the concentrations of Na, K, and Cl were normal. The mean sweat rates and apparent skin conductivities were lower in uremics, but not significantly different from controls (0.05 less than p less than 0.10). Tentatively it is concluded that the increase of Ca, Mg and phosphate in uremic sweat is due to an increase in the secretion of these electrolytes in the secretory portion of the sweat gland, while the reabsorptive duct is normal.


Binding of hippurate in normal plasma and in uremic plasma pre- and postdialysis. The protein binding of 14C-hippurate has been measured by conventional ultrafiltration techniques in the plasma of normal subjects and in uremic subjects pre- and postdialysis. In addition, the clearance of 14C-hippurate was determined in vitro in both isotonic saline and plasma to assess binding limitations on hippurate removal during dialysis. Binding levels of hippurate in normal subjects of 68+/-1.8% (n = 5) were significantly higher than either postdialysis (48.3+/-15.4%; n = 7) or predialysis (36.6+/-11.7%; n = 7) levels in the same uremic subjects. Actual levels of plasma hippurate were, however, considerably greater in uremics (24.7+/-11.2 mg/dl' n = 7) than in normal subjects (congruent to 0.5 mg%). The difference in hippurate binding between pre- and postdialysis samples in uremics was significantly different from zero (p less than 0.01, t = 5.36), indicating depletion of competitive site-binding species during dialysis. The saline clearance of hippuric acid (99.1 +/-0.5 ml/min; n = 6) under standard conditions in a capillary dialyzer (CDAK-4) was consistent with the expected clearance of a solute of its molecular weight. Hippurate clearance in citrated plasma, where binding was determined as 50+/-3%, was 65+/-0.7 ml/min (n = 6), in good agreement with a theoretically predicted clearance of 60 ml/min for this level of binding. High serum levels of hippurate and its derivatives, may depress effective function of various organs. In addition to the normal dietary intake of hippurate and its precursors, patients on dialysis receive a further burden of hippurate precursor in the form of benzyl alcohol, the common preservative in heparin solutions. The large body burdens of hippurate in dialysis patients, coupled with its impaired removal on dialysis due to binding, point to the necessity for a through investigation of the potential toxicity of this compound.


Serial studies of the renin system in rats with glycerol-induced renal failure. Serial changes in plasma of renin concentration (PRC), renin-substrate concentration (PSC) and renin activity (PRA) were followed in rats during glycerol-induced acute renal failure. There was an early but transient increase in PRC and a more delayed and prolonged rise in PSC. PRA began to rise a few hours after glycerol administration at the expense of increases in renin, but by 24 h the high activity was maintained largely by increases in renin-substrate. No correlations between PSC, PRC, or PRA changes and severity of renal failure could be demonstrated. These results suggest that these changes are not causally related to the development of kidney failure.


Red  blood cell Li+ to plasma Li+ ratios. Are they related to plasma Li+ concentrations? The relationship between the lithium ratio (ratio of lithium in blood cells to that in plasma) and plasma lithium concentration was examined in a group of male inpatients taking lithium carbonate for affective disorders. The lithium ratio was found to increase in the majority of these patients as plasma lithium concentration increased. However, the magnitude of variation of the lithium ratio with plasma lithium concentration observed in these patients is not sufficient to seriously affect the value of determining the lithium ratio in the clinical situation.


[Uptake of tryptophan and tyrosine in some cases of manic depressive psychosis and schizophrenia (author's transl)]. The uptake of tryptophan and tyrosine by the brain has been studied in 6 manic-depressive patients and in 8 schizophrenics. In an attempt to saturate the blood-brain transport mechanisms, this uptake has been evaluated by measuring the arteriovenous differences (arterial plasma-internal jugular plasma) of these two amino acids before and after perfusion with L-dopa and L-5-HTP. Considering a positive difference as an uptake and a negative one as an outflow, results show (1) in melancholia an uptake of tryptophan and an outflow of tyrosine; (2) in mania an uptake of tyrosine and an outflow of tryptophan, and (3) in schizophrenia an outflow of tryptophan accompanied with either an uptake or an outflow of tyrosine. In addition, the kinetics of tryptophan binding to plasma proteins and the ratio of tryptophan/tyrosine uptake are different in manic-depressive illness and in schizophrenia. These results support the view that a disturbance in the blood-brain transport mechanisms of tryptophan and tyrosine could be involved in the physiopathology of manic-depressive illness and schizophrenia.


Discriminant  analysis of EEG in children with situational, learning and impulse disorders. Neurological and EEG findings were studied in 113 children diagnosed as adjustment reaction, behavior disorder, and minimal brain dysfunction (MBD). The MBD patients were subdivided into MBD behavior and MBD learning groups, thus yielding four patient groups in all. The presence of soft neurological signs and abnormal EEG examinations increased in stepwise fashion from the adjustment reaction group to the behavior disorder group, to the MBD behavior group, to the MBD learning group. The EEG records were rated on 16 variables, including amounts and frequencies of a variety of normal EEG features as well as abnormal features. The EEG ratings were then subject to a discriminant analysis. Three discriminant functions were found to be necessary to describe the relation of the four groups. The functions were identified as cortical maturity, cortical abnormality, and cortical reactivity. This implies that the groups do not just differ along one dimension, but along three dimensions. The discriminant program correctly classified 53% of the patients.


An ultradian rhythm of reaction time measurements in man. Repeated measurements of reaction times were made individually in 53 healthy subjects at 60-sec intervals and continued for 30 min. The subject's visual perceptual task each minute was to determine the momentary cessation of the second hand of a clock and his reaction times were automatically recorded. The results showed that the subject's reaction times followed a free-running cycle ranging in frequency between 4 and 15 min when their reaction times were submitted to spectral analysis and autocorrelograms obtained. Error scores during the procedure showed significant correlations with chronological age but not with gender. The biological implications of these oscillations are discussed.


Alcohol, prolonged isolation and barbiturate sedation in two strains of mice. Mice subjected to prolonged socioenvironmental deprivation gradually develop hyperirritability and hyperreactivity to physical stimuli. This heightened neuroexcitability may or may not debouch into aggressiveness according to strain and sex of the animals, and it is accompanied by a reduced sensitivity to CNS depressants. Socioenvironmental deprivation or isolation is shown to decrease the sensitivity either to pentobarbital or to ethanol potentiation of pentobarbital sleeping time in male mice from two different strains.


Hormones, electrolytes, and cerebrospinal fluid proteins in manic-melancholic patients. The concentrations of insulin and thyroid hormones, tryptophan, electrolytes, urea, plasma proteins in the cerebrospinal fluid, and glucose in blood and cerebrospinal fluid in manic-melancholic patients were studied. As control groups served patients suffering from other psychiatric disorders as well as neurological and orthopedic patients. Apart from the blood values of thyroid hormones, the results showed no differences between the various diagnostic groups, neither in the abnormal states nor when recovered. For blood thyroxine and free thyroxine index, a statistically significant differences was seen in unipolar (melancholic) patients, namely a decrease concomitant with the clinical improvement. A tendency in the opposite direction of the thyroxine values was found in bipolar (melancholic) patients. In the manic group a marked decrease in the thyroxine values was obtained in the lithium-treated patients.


Protein depletion and energy retention in rats with ventromedial hypothalamic lesions. The catabolic effect of bilateral lesions in the ventromedial are of the hypothalamus (VMH) was studied in nitrogen-balance experiments and compared with the effect of a sham-operation in control animals. A transitory (24 h) increase in urine nitrogen was found in the controls, while in the lesioned animals, a persistent increase was found as long as the animals were fed. Fasting (48 h) eliminated the difference in urea excretion between the groups. Food-dependent effects of the VMH lesion are suggested. The changes in body and organ composition of VMH-lesioned animals, kept for 4 months on a food intake close to normal, were studied. The massive increase of body lipids and marked decrease of body protein and water was primarily due to increased subcutaneous-and abdominal-fat, and reduced skeletal and skin protein. An almost normal composition of the liver and close to normal amounts of protein in the viscera demonstrate that at least some tissues in VMH animals are able to maintain a normal protein content. Hyperphagia as a means to counteract the increased amino acid catabolism and to sustain the lean body mass is discussed.


[Effect of gum guar in diet on nitrogen balance, protein metabolism and food transit time in rats]. The addition of 5% gum guar to a diet containing 10% casein did not change the overall N retention of young rats but induced a significant shift in the N excretion from urine to feces, resulting in a markedly decreased apparent protein digestibility. The increase in total fecal dry matter over control values accounted for only 30% of the ingested gum guar implying that 70% was absorbed, possibly after being degraded by intestinal micro-organisms. The elimination of 14C activity following oral application of 14C protein indicated an accelerated turnover of amino acids during the first 3 h. After 25 h no difference between experimental and control animals was evident with respect to 14C activity remaining in the carcass. The transit time of food, as determined by neutron activation analysis of an Ytterbium marker, was somewhat decreased in the presence of gum guar.


Albumin metabolism and gastric surgery.

Albumin metabolism and gastric surgery. Albumin metabolism was followed in 7 patients suffering from benign gastric diseases. The study was performed using human serum albumin-125 I before gastric surgery and after operation. The total albumin pool decreased after the operation by about 15%. The decrease in extravascular albumin pool was stronger (by about 19%) than the decrease in intravascular albumin pool (at about 11%). The causes of changes in albumin metabolism after surgery are discussed.


Utilization of 35S from radioactive methionine or sulfate in the detoxification of cyanide by rats. Weanling rats were fed a semipurified diet based on 10% casein and 1,500 ppm potassium cyanide. The diet was supplemented with varying levels of DL-methionine and/or potassium sulfate such that all diets were iso-sulfurous except for the basal which had no additional sulfur. The animals were fed for 2 weeks after which half of the rats in all groups except the basal were used in a radioactive study. Urine was collected and analyzed for thiocyanate. Animals which received labeled methionine were more efficient in producing labeled thiocyanate than those which received labeled sodium sulfate, although the latter did contribute to the detoxification of cyanide. Increases due to additional methionine were larger for weight gain, feed consumption, and urinary and plasma thiocyanate than with supplemental sulfate.


[Comparative study of effects of tannic acid and oxidized tannic acid on growth, body composition and biological utilization of nutriments in rats]. The nutritional effects of oxidized tannic acid in rats have been compared with the effects of tannic acid supplemented or not with a reductor: sodium sulfite. The results indicate that in the group which ingested oxidized tannic acid, fecal nitrogen excretion is lower than in the group which ingested tannic acid; its action on growth is mainly exerted by reduction of the retention coefficient; urinary nitrogen excretion being increased. With regard to the other groups of animals, oxidized tannic acid decreases the weight gain of the thymus and slightly increases the weight gain of the heart. Sulfite supplementation does not change the effects of tannic acid on growth; nevertheless, a higher weight gain of the kidneys is noted.


Homeostatic adjustments in zinc digestion to widely varying dietary zinc intake. A 15-day Zn balance study was conducted with 36 growing rats maintained on a casein diet with 18.2 microgram Zn/g from day 0 to 3. Thereafter, six rats each were given the diet with the following variates of Zn content (microgram Zn/g): 5.6, 10.6, 18.2, 39, 70, 141. Zn digestion adjusted to the change in dietary Zn intake within the first 6 days via control of the extent of intestinal Zn absorption and fecal excretion of endogenous Zn. From day 9 to 15, mean apparent Zn digestion ranged from 92 to 18% and Zn absorption from 100 to 34% in an inverse relation to Zn intake. At the supply of 39 and 70 microgram Zn/g of diet, fecal excretion of endogenous Zn amounted to nearly one fourth of the dietary Zn intake. Reduction of intestinal absorption became the major factor to confine Zn accretion by the body when Zn intake was in great excess above requirement. Endogenous fecal Zn excretion exhibited its greatest homeostatic response in the range of optimum Zn intake. Zn excretion via the kidneys did not partake in Zn homeostasis, except that it was a major drain of body Zn compared to the intestinal route at low Zn intakes.


Influence of hyperthyroidism on the rate of ethanol metabolism in man. The rate of ethanol metabolism was studied in 3 hyperthyroidism patients without therapy and in 2 after 1 week of treatment with propylthiouracil and reserpine. The rate of ethanol metabolism (mg/kg/h +/- SEM) was 386 +/- 57 in the 3 hyperthyroid patients,  184.5 +/- 2.5 in the 2 treated patients and 159 +/- 15 in 12 euthyroid non-alcoholic subjects. The results suggest that hyperthyroidism markedly increases ethanol metabolism.


Intersexual differences in the serum-free amino acid pattern of young adults, normal obese aged subjects. In a group of ethnically homogeneous subjects, intersexual differences and the effect of ageing on the pattern of serum free amino acid were studied. The amount of the amino acids: valine, isoleucine, leucine, tyrosine, phenylalanine, glutamic acid and ornithine was significantly greater in young males than in young females. Such intersexual differences were not observed in aged subjects. When comparing a group of aged obese females with a control group, no difference in the pattern of serum free amino acid was observed.


Rat hepatic lysine-2-oxoglutarate reductase activity. Induction by lysine, glucagon and cycloheximide administration. The activity of hepatic lysine-2-oxoglutarate reductase was determined in white female rats maintained on one of two dietary lysine levels (0.23 and 0.54% in diets A and B, respectively). The high dietary lysine increased the enzyme activity (p less than 0.05) twofold compared with the activity obtained with the diet A (67 vs. 27 mumol saccharopine/30 min/g liver protein). Repeated intraperitoneal injection of glucagon (259 microgram/100 g body weight/day) showed a short initial drop in the enzyme activity, followed by a marked rise, which remained above the basal level after withdrawal of the drug. Repeated injections of cycloheximide increased the enzyme activity, and the findings suggested that the apparent increase was due to the inhibition of the system responsible for the degradation of the enzyme. The individual free amino acids of the livers varied as a function of treatment. The ratio of E/N amino acids was found to be a good measure of the physiological condition of the animal, with the lowest value in animals treated with cycloheximide.


Lipid metabolism in the vitamin-B12-deprived rat. Rats were deprived of vitamin B12 in order to study the effect of this deprivation on the metabolism of lipids in the liver and the nervous system. Serum vitamin B12 concentrations of 102.7 and 78 pg/ml were found at sacrifice after 5 and 6 months, respectively. Neurological testing failed to reveal signs of neuropathy. The total liver lipids were decreased in the vitamin-B12-deprived animals, but no changes were detected in the lipid concentration or in the phospholipid composition of the nervous system. Some animals were given propionate, and in these, contrary to expectations, pentadecanoic acid and heptadecanoic acid were found in smaller amounts in the liver triglycerides of the vitamin B12-deprived rats than in the control rats. This could be due to the inhibitory effect of methylmalonyl CoA on fatty-acid synthesis, demonstrated by others in vitro.


Vitamin B12 deprivation in the rat: effects on folate metabolism with emphasis on the nervous system. Rats were subjected to deprivation of vitamin B12 in order to induce neuropathy and to study effect on folate metabolism. Plasma vitamin B12 concentrations were maintained at about 100 pg/ml for 5 months. Neurological testing failed to reveal signs of neuropathy. Vitamin B12 deprivation induced high plasma folate levels but had no effects on the levels of total folate in the liver or the nervous system, probably because of an adequate methionine supply. If the rats were starved, a smaller proportion of 5-methyltetrahydrofolate was found both in liver and brain of the vitamin-B12-deprived animals. The folate concentration in the cerebrospinal fluid was lower than in the plasma but the values were correlated. There was a striking similarity between the liver and the brain in the way of handling 3H-folic acid and 14C-methyltetrahydrofolic acid. However, both substances showed a higher specific activity in the brain than in the liver, indicating a more dynamic state of brain folate.


Androgen and estrogen formation in women with ovarian hyperthecosis. Women with ovarian hyperthecosis were studied and found to have a plasma testosterone production rate of 2.1 mg/day, a value eight times greater than that of nonhirsute, ovulatory women. The severity of hirsutism and virilization in these women was more closely correlated with the amount of testosterone produced than with plasma testosterone concentrations. The mean plasma production rates of androstenedione in these women, 8.6 mg/day, was more than three times that found in young women with no evidence of androgen excess. There was a marked gradient between ovarian and peripheral venous plasma concentrations for both C19 steroids. Following ovarian wedge resection or oophorectomy, there was a precipitous fall in the peripheral venous concentrations of these steroids. These observations support the view that the major source of excess androstenedione and testosterone secretion in these subjects was the ovaries. The rate of estrone formation in these women, 106-345 microgram/day, was the result of extraglandular aromatization of plasma androstenedione.


Estrogen excretion patterns in induced ovulation. Observation of response to gonadotropins in the treatment of anovulation has allowed us to define the estrogen excretion pattern which leads to a successful single pregnancy. The typical pattern shows a low pretreatment urinary total estrogen excretion; treatment with gonadotropins, of human pituitary origin, is continued for about 14 days. There is a predictable rate of rise of preovulatory estrogen excretion (30 microgram/24 hr2). Human choronic gonadotropin--about 4000 IU--should be given when an estrogen excretion of 75-100 microgram/24 hr has been obtained. The use of this pattern of ovarian response is put forward as a useful guide in the planning of gonadotropin therapy.


Chemotherapy in ovarian carcinoma recurrent after radiation therapy. Fifty-seven patients referred to Roswell Park Memorial Institute between 1971-1975 with Stage III or IV epithelial ovarian cancer treated with prior radiation therapy were randomly allocated to treatment with melphalan, 5-fluorouracil (5-Fu) plus melphalan (FUME), actinomycin-D plus 5-fluorouracil plus melphalan (ACFUME), actinomycin-D, or 5-fluorouracil plus cyclophosphamide (ACFUCY). These patients receiving 5-FU plus melphalan had longer median duration of survival with better quality of life. Combination chemotherapeutic agents effected significantly. better responses (P less than 0.05) than single agent chemotherapy. The ACFUME and ACFUCY combinations resulted in higher incidence of severe and life-threatening toxicity. Patients showing complete response had maximum median duration of survival.


The fallability of X-chromatin as a screening test for anomalies of the X chromosome. In 13 of 148 patients suspected of anomalies of the X chromosome, the X-chromatin test was misleading. Therefore, if an anomaly is suspected, a karyotype as well as an X-chromatin study is indicated.


Comparison of fetal maturity evaluation with ultrasonic biparietal diameter and amniotic fluid lecithin-sphingomyelin ratio. Fetal head biparietal (BP) measurements by ultrasonic techniques and amniotic fluid lecithin-sphingomyelin (L/S) ratios were simultaneously determined (within 2 days) on 84 occasions in 72 women. Using the criteria for maturity of an L/S ratio of 2.0 or more or a BP measurement of 9.0 cm or more, there was agreement between these test results in 66.7% of the cases. The BP incorrectly predicted the L/S ratio 33.3% of the time, with a false positive rate of 27.3% and a false negative rate of 6.0%. If an L/S ratio of 1.5 were used as the critical determinant, the BP false positive rate remained high (9.5%). A high false negative error (21.4%) occurred if a BP value of 9.3 cm was used. These results suggest that ultrasonic BP measurements should not be used as the only criteria of fetal maturity in the management of high-risk pregnancies.


Duration of colposcopic changes associated with trichomonas vaginitis. The possibility that an abnormal Papanicolaou smear of the uterine cervix may be associated with vaginitis due to trichomonas vaginalis has been known for some time. Since colposcopy is being used with increased frequency to evaluate patients with cytologic abnormalities noted on the cervical smear and the colposcopic changes produced by trichomonal vaginitis are quite typical, a study was designed to evaluate the duration of these changes after effective eradication of the parasite. Among 12 patients in whom the infection was successfully treated, none showed evidence of colposcopically detected abnormalities due to the trichomonal vaginitis at 2 weeks and again at 4 weeks after initiation of therapy.


Suppression of puerperal lactation by metergoline. Based on the known stimulatory effect of serotonin on prolactin secretion, a trial of suppression of puerperal lactation by a potent serotonin antagonist, metergoline, was carried out in 30 puerperal women who did not want to nurse. The drug was administered orally at the dose of 4 mg tid for 5 days to all subjects, starting between 24 and 72 hours from delivery. Lactation was either prevented or rapidly suppressed in all subjects. Rebound of lactation after the end of treatment was observed in 10% of cases. Metergoline administration was associated with a significant suppression of the plasma prolactin levels.


A rapid method for the presurgical cleansing of hands. A new rapid method of presurgical cleansing of the hands has been evaluated in a clinical setting. The effectiveness of a 90 second jet wash has been compared with a standard 10-minute presurgical scrub. Bacteriologic cultures were obtained from the fingertips of interns, residents, and staff of the Department of Obstetrics and Gynecology of the Walter Reed Army Medical Center before and after 90-second jet washings and 10-minute conventional scrubs. The results showed that the 90-second jet wash was more effective in degerming the hands than the 10-minute standard brush scrub. Other advantages of the new method, such as the amount of time saved, the standardization of cleansing, and reduced skin irritation are discussed.


A new topical hemostatic agent in gynecologic surgery. Experiences with a topical hemostatic agent, microfibrillar collagen (MFC), material made from beef hide dermis are recounted. Topical hemostasis is facilitated by virtue of its fibrillar structure forming a sticky matrix for platelet aggregation. The material was used in women undergoing cervical conization to determine its absorption at hysterectomy 6 weeks later. In another group, it was used as the sole hemostatic agent at conization and compared with a control group in which conventional sutures were used. A larger group who underwent abdominal hysterectomy allowed comparison between MFC on the bladder muscularis and conventional suture ligature in terms of blood loss, operating time success of method used, and complications.


New observations on the physiology of menstruation. Endometrium was studies histologically, histochemically, and ultrastructurally in a series of biopsies taken from 3 normal, ovulating patients on Days 1-9 of the cycle. The occurrence of ovulation and the adequacy of progesterone were determined by radioimmunoassay. The most striking feature of menstruating endometrium was its vigorous attempt to survive. This was manifested by lysosomal activity, lipid accumulation, expulsion of glycoproteins, and the uptake of stromal debris by epithelial cells for passage to the uterine cavity. Regression, rather than cell death, was the chief event of menstruation. While some cells of the spongiosa underwent necrosis, the vast majority remained viable and underwent remodeling to participate in the new cycle. These studies may lead to further understanding of the process of menstruation and the pathophysiology of anovulatory bleeding and irregular shedding of the endometrium.


Endometrial biopsy interpretation. Shortcomings and problems in current gynecologic practice. The analysis of 345 endometrial biopsies was carried out with special regard to the relation between pathologic findings and presenting symptoms or complaints. Only 52.4% of the biopsies showed microscopic features possibly related to the complaints. Endometrial polyps and chronic endometritis were diagnosed in 21.1 and 9.8%, respectively, of the entire study group. The currently accepted definitions of dysfunctional uterine bleeding raise the question whether endometrial polyps and atypical secretory changes may or may not be included in the syndrome.


Therapy of heavy drinking during pregnancy. A survey of patients registering at the Boston City Hospital Prenatal Clinic had demonstrated that 9 percent were heavy drinkers. To reduce the health hazards to mothers and children, treatment of heavy alcohol use was integrated with prenatal care. A pediatric neurologist independently examined 322 offspring, including 42 whose mothers were heavy drinkers. Frequency of congenital anomalies, growth retardation, or functional abnormalities among these 42 was twice that of infants born to abstinent or moderate drinking mothers P less than .001). Within that group of 42, there were 15 whose mothers were able to abstain or reduce alcohol intake during the third trimester. These 15 demonstrated fewer abnormalities than those 27 whose mothers had continued heavy drinking (P less than .001). Since pregnant women can be motivated to reduce heavy drinking, treatment programs can benefit both mothers and infants.


Plasma prostaglandins in pregnancy.

Plasma prostaglandins in pregnancy. Plasma prostaglandins were determined by radioimmunoassay in 92 pregnant and 14 nonpregnant women. There was significant elevation of PGA-like material in the first trimester of pregnancy (1744 pg/ml) over that seen in nonpregnant women (576 pg/ml) with continuation of that elevation in the second and third trimesters. No significant difference existed among PGE levels of the nonpregnant group (251 pg/ml) and the first two trimesters of pregnancy (384 pg/ml and 294 pg/ml); the PGE level of the third trimester group (443 pg/ml) was significantly elevated over that of the nonpregnant group. PGF levels remained constant during all trimesters (135 pg/ml, 144 pg/ml, and 130 pg/ml) but exhibited plasma concentrations significantly higher than the nonpregnant group (78 pg/ml). Potential role (s) of prostaglandins as mediators of cardiovascular and renal changes of pregnancy are discussed.


Amniotic fluid analysis. Its role in maternal neonatal infection. Indirect evidence suggests that amnionitis, in the absence of maternal symptoms, contributes to neonatal morbidity. The incidence is unknown because diagnostic techniques are not available. A quantitative amniotic fluid analysis of bacteria, white blood cells, and lactic dehydrogenase levels was performed during labor among 28 patients considered to be a risk for infection. Thirteen of 16 patients with bacterial colony counts greater than 10(3)/ml subsequently developed maternal infection had a premature delivery, neonatal sepsis, or a combination of these factors. Maternal fever was a late sign in clinical infection and was frequently absent in cases of premature delivery associated with microbiologic evidence of amnionitis. Amniotic fluid analysis may be of value in diagnosing unrecognized amnionitis among patients delivering prematurely and those requiring nonelective cesarean section.


Osteogenesis imperfecta as a complication of pregnancy. Osteogenesis imperfecta is a complex disorder that rarely complicates pregancy. The successful obstetric management of a patient with severe osteogensis imperfecta is presented along with a detailed review of maternal osteogenesis imperfecta in the recent English literature. A review of the disease process, its complications, and associated disorders is presented.


Inidcations for prenatal diagnosis in relatives of patients with neural tube defects. We have reviewed the family histories of children with neural tube defects to determine which relatives are at sufficient risk to be offered amniocentesis for prenatal diagnosis. The recurrence risks for sibs was 6%; therefore, women with one affected child should be made aware of the availability of this test for monitoring subsequent pregnancies. The empiric recurrence risks for various groups of second and third degree relative exceeds 1% only for mothers' sisters' children. The lower values for the other groups may reflect either true biologic differences of reporting biases. Unit the matter is clarified, all sibs of affected children and all sibs of the parents of affected children should be informed of the availability of amniocentesis for monitoring their (or their spouse's) pregnancies.


Induction of labor in the high-risk pregnancy with PGF 2 alpha. The induction of labor in the high-risk patient is accompanied by an increased incidence of cesarean section partly due to failed induction. A series of 50 high-risk patients induced with intravenous prostaglandin F 2 alpha is presented. Forty-five were successfully induced, 35 of whom delivered vaginally. Failed inductions occurred in 5 patients. The overall success rate was 90%, and cesarean section rate was 25.5%. There was an increased incidence of late decelerations in the PGF 2 alpha groups as compared to spontaneous and Pitocin-stimulated labors. While the success was high, the use of a drug which itself may caused fetal cardiovascular changes is not desirable, especially in those pregnancies already at risk.


Absence of capillary microangiopathy in oral contraceptive users with glucose intolerance. The possible vascular hazard associated with carbohydrate intolerance produced by long-term use of oral contraceptives was investigated by examining the capillary basement membrane thickness in quadriceps muscle biopsies, a highly sensitive and reliable indicator of diabetic microangiopathy. The average basement thickness  of 18 long-term (4-9 years) contraceptive users with diminished carbohydrate tolerance was 1644 A, compared to normal pregnant women (1711 A) prediabetic pregnant women (1854 A), and overt diabetic women (2593 A). Contraceptive steroid-induced carbohydrate intolerance appears to carry little, if any, increased risk for the development of diabetic vascular disease, even as assessed by the sensitive electron microscopic technique.


Endometrial adenocarcinoma and the Stein-Leventhal syndrome. Six cases of adenocarcinoma of the endometrium associated with the Stein-Leventhal syndrome are presented. The average age of the patients was 27.8 years. All patients were treated surgically; 2 had preoperative intracavitary irradiation, and 1 had postoperative intravaginal cesium-137 application. At follow-up, ranging from 1 to 15 years, all patients are alive and free of disease. Almost 90% of endometrial adenocarcinoma in association with the Stein-Leventhal syndrome is well differentiated, and appropriate treatment is associated with a good prognosis. Conservative therapy carries the risk of progression of the cancer to more advanced stages and has very little to offer for future fertility. It is suggested that these patients be treated as are any other patients with endometrial cancer.


Meconium screening for cystic fibrosis.

Meconium screening for cystic fibrosis. In our hands, the BMC-Test Meconium has been a significant step towards the goal of developing an ideal newborn screening test for CF. It is easily performed, is highly specific, has reasonably high sensitivity, and--given its limitation of identifying only patients with CF who have intrauterine pancreatic insufficiency--is the best method of screening newborns for CF that has been devised to date. Many technical problems remain to be solved before the test can be endorsed without reservation. Because the test, as currently constituted, does not identify all potential subjects for further testing who might have CF, it should not be made mandatory. It is, however, better than other available screening methods for CF and can be praised for that benefit. The concept has indicated a valuable new direction for mass-screening possibilities and perhaps can, by future modification, be made sensitive enough to warrant universal usage.


The use of new antibiotic agents for chronic pulmonary disease. Modern advances in the development of antimicrobial agents and in chemotherapy have made available potent aminoglycoside antibiotics, with more effective ones to come. Their effectiveness against P. aeruginosa is a great contribution to patients with cystic fibrosis and other chronic disorders. The development of carbenicillin has augmented the effectiveness of the aminoglycoside antibiotics. Ticarcillin is similar to carbenicillin and will play a similar role in antibiotic therapy. The cephalosporins serve as alternative agents principally for their antistaphylococcal activity. We are urgently in need of a potent antibiotic agent against P. aeruginosa that can be given by the oral route. The TMP-SMX combination is a potent chemotherapeutic agent that can be administered by the oral route. It is effective in the treatment of P. carinii pneumonia, which is very common owing to the extended survival of patients with leukemia and other malignancies or with allografts who are prone to develop infections with immunosuppressive therapy.


Atypical mycobacteria.

Atypical mycobacteria. The atypical mycobacteria are common human saprophytes. Their presence, particularly in a healthy person, is not associated with disease. In the child they cause two conditions, cervical adenitis and swimming-pool granuloma. Both of these diseases tend to be localized and nonprogressive. The former can be treated with reasonably nontoxic drugs; if this falls, total excision can be employed. The latter is best left to heal by itself. Occasionally, the atypical mycobacteria will cause widespread systemic disease, particularly in the patient whose immunity has been compromised.


Studies on the mechanism of reflex vasodilatation. The cholinergic component in the baroreceptorial reflex in the dog. This study was designed to investigate whether the cholinergic system is involved in the genesis of the reflex vasodilatation which follows the systemic hypertension induced by fast intravenous injection of norepinephrine in the dog. Accordingly, in 7 dogs the gracilis muscle was isolated and perfused and the reflex evoked. The analysis of the integrated areas of vasodilatation after atropine pretreatment showed a significant decrease of the reflex response in the perfused circulation. In fact, the mean value of the integrated areas of vasodilatation which was 66 +/- 8 mm Hg/min in the control condition, was reduced to 45 +/- 4 mm Hg/min after administration of atropine in the gracilis artery; meanwhile the integrated areas of systemic hypertension did not show any change. Phentolamine intra-arterial administration completely abolished the reflex. These results suggest the existence of a cholinergic component in the reflex vasodilatation induced by transitory baroreceptorial stimulation.


Sex differences in diazepam protein binding in patients with renal insufficiency. Sex differences in the extent of binding of diazepam to plasma protein were assessed in a series of patients with renal insufficiency previously described by Kangas et al. Among identifiable independent variables, sex alone accounted for the greatest proportion of variability in percent unbound diazepam (r = 0.33), whereas age and serum creatinine accounted for practically none. The mean (+/- SE) percent unbound among females (10.8 +/- 2.8%) was larger (p less than 0.1) than among males (5.8 +/- 1.3%). Since only the unbound fraction of diazepam in plasma is available for pharmacologic activity, the intensity and duration of diazepam's clinical action in patients with renal insufficiency might differ between males and females.


Plasma levels and protein binding of phenytoin during exercise in man: the effect of elevated free fatty acids. Five healthy subjects performed submaximal physical exercise approximately 20 h after a single oral dose of phenytoin (5 mg/kg of the sodium salt). The plasma levels of free fatty acids (FFA) increased 2- to 3-fold in the post-exercise period. In spite of this, the degree of plasma binding of phenytoin and its total concentration in plasma were unaffected. Thus FFA at the levels reached (1.5-2.9 mEq/l), did not displace phenytoin from its binding sites on albumin. Furthermore, during the FFA peak the plasma protein binding of warfarin, as measured in vitro, did not decrease as compared to the pre-exercise period. These findings contrast to previous observations in rats and dogs, where FFA caused a considerable displacement of warfarin and phenytoin at relatively low FFA/albumin molar ratios.


Effects of isoprenaline and orciprenaline on the vascular bed of the mouse placenta. High doses of isoprenaline or orciprenaline decreased the rate of transfer of tritium-labelled water from mother to fetus. The effect was blocked by propranolol. Maternal blood spaces of the placental labyrinth in the treated animals were congested with masses of red blood cells. These observations suggest that the placental circulation is impaired by high doses of beta-sympathomimetic drugs.


Effect of cartilage bone-marrow extract on articular cartilage collagen formation. Cartilage bone-marrow extract has stimulated the collagen formation of articular as well as sternal cartilage collagen in chick embryo. Collagen biosynthesis has been stimulated also in other investigated tissues, i.e. in cornea and sclera of chick embryo as well as in sponge granuloma of rats, where mainly formation of collagen type I was stimulated. Glycosaminoglycans formation has also been increased after administration of cartilage bone-marrow extract.


Influence of hexobendine, dipyridamole, dilazep, lidoflazine, inosine and purine riboside on adenosine uptake by the isolated epithelium of guinea pig jejunum. The uptake of (14C)adenosine by isolated epithelium of guinea pig jejunum, administered on the blood side, was inhibited by hexobendine, dipyridamole, dilazep and lidoflazine. On the lumen side, however, weak inhibition was observed with lidoflazine only and no significant change was recorded with hexobendine, dipyridamole or dilazep. This difference was not altered when the degradation of hexobendine by the jejunal epithelium was blocked by physostigmine. When adenosine uptake was already reduced by purine riboside, further addition of hexobendine, dipyridamole, dilazep or lidoflazine caused divergent changes depending on the side of administration. Adenosine uptake was further diminished on the blood side, but raised towards control values on the lumen side. By contrast, inosine inhibited adenosine uptake on both sides of the epithleium. The results suggest that the mechanism of adenosine uptake is different on either side with respect to inhibition characteristics, corresponding to differences in morphology and function of the two sides of the intestinal epithelium.


Cholinergic receptor mechanisms in amphibian vasoconstrictor responses. The four choline esters, namely acetylcholine, carbachol, methacholine and bethanechol, produced constriction of frog's perfused systemic blood vessels, acetylcholine and carbachol being more potent than methacholine and bethanechol. Pentolinium and dihydroergotamine, in submaximal receptor-blocking doses, also produced a uniform partial inhibition of all choline esters and other agonists including the direct-acting barium chloride. On the other hand atropine markedly inhibited the responses of the four choline esters without affecting the adrenaline and barium responses. Compound AHR-602, a specific ganglionic muscarinic excitatory receptor stimulant, did not produce any effect in these experiments. Eserine in higher doses produced slight vasoconstriction and markedly potentiated acetylcholine responses, but it inhibited partially those of the other three choline esters without significantly affecting adrenaline and barium responses. The results provide strong evidence in favor of involvement of the postganglionic muscarinic receptors only in vasoconstriction after choline esters. There seems to be a considerable nonspecific inhibitory activity in ganglionic and alpha-adrenergic blockers in their submaximal receptor-blocking doses. It may be that in frog the adrenergic and nicotinic receptors are not as well differentiated as muscarinic receptors are. The ganglionic muscarinic receptors also seem to be absent in the frog.


A behavioral and autonomic nervous system study of chronic imipramine administration to conscious dogs. The clinically effective antidepressant imipramine, an iminodibenzyl structure, was examined in two experimental methods which had previously demonstrated high prediction ability in descerning and categorizing potential psychotherapeutic drugs. The chronic administration of imipramine produced a significant reduction in the scores of aberrant behavioral response evoked by the fixed-dose with Ditran seen as early as 1 week after treatment was initiated and continuing through the 8-week treatment duration. This chronic per oral treatment with impramine was also associated with a significant potentiation of mean arterial pressure responses to fixed-dose treatment with serotonin, noradrenaline, yohimbine and adrenaline, while significantly inhibiting the histamine-induced depressor response. The results of this study support the speculation that, in dogs, the clinically effective antidepressants antagonize or reverse the Ditran-induced response and produce an associated response of sympathetic nervous system arousal or sensitization.


Effect of secretin on mucinous secretion by the isolated canine stomach perfused extracorporeally. Principal glycoproteins, uronic acid and amino acids were determined in canine gastric secretion, obtained from isolated canine stomachs perfused extracorporeally with homologous blood. Gastric secretion was collected during intraarterial infusion of pentagastrin alone for 3 h, and of secretin + pentagastrin for the next 3 h. Secretin produced a significant increase in the output of D-galactose, D-glucosamine, L-fucose, D-glucose, total sugars, total sulfate and uronic acid. Secretin had no significant effect on the output of most of amino acids of gastric secretion.


EMG feedback as a muscle reeducation technique: a controlled study. In an effort to evaluate the efficacy and function of EMG feedback in muscle reeducation, improvement of the abductor function of the abductor hallucis muscle was studied under three training conditions involving 1) EMG feedback, 2) sensory stimulation or 3) equal time for unassisted practice; and a fourth, control condition involving testing without training. Active range of motion was measured before and after training to assess ability to use the muscle as an abductor. EMG activity was quantified for a 1-minute test contraction to evaluate ability to maintain and maximize a voluntary contraction of the target muscle. The results indicated that EMG feedback was highly effective when subjects had little initial use of the target muscle. EMG feedback improved the ability of these subjects to maintain and maximize voluntary muscle contractions, as demonstrated on the EMG measure. EMG feedback did not add to the learning situation when only a relatively brief, phasic contraction was required, as on the range-of-motion measure; similar gains were made with equivalent practive without EMG feedback. When subjects already had considerable use of the target muscle prior to training, EMG feedback may have actually interfered with training; in this case unassisted practice was more effective.