Heterogenity of serotypes of Neisseria meningitidis that cause endemic disease. Three collections of strains of Neisseria meningitidis that caused meningococcal disease during nonepidemic periods were serotyped to determine whether serotypes that cause endemic disease are more heterogeneous than those responsible for epidemic disease. Thirty-four strains isolated from pediatric patients in Houston, Texas, from February 1977 to March 1978 were of three separate serogroups and 11 serotypes; 27 contemporary (1977-1978) strains from predominantly military populations, obtained nationwide, were of six serogroups and six serotypes, while 11 strains isolated at military posts in the southwest United States from 1970 through 1976 were of four serogroups and five serotypes. Between 9% and 20% of the strains were nontypable, while type II strains which were responsible for the epidemics in the Northern and Western Hemispheres earlier in the 1970's, accounted for only 20%-44% of the strains. In contast to epidemics, which appear to be caused by a single serotype, endemic meningococcal disease appears to be caused by a broad, heterogeneous distribution of serotypes. Thus, development of a serotype-specific vaccine may have limited application to the prevention of endemic meningococcal disease.


In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. Five pairs of juvenile, dengue virus-susceptible rhesus monkeys were given normal or dengue-immune human cord-blood serum injected intravenously to a final dilution of 1:300. The pool of immune human cord-blood serum had a titer of antibody to dengue type 2 virus (D2V) of 1:140 in the plaque-reduction neutralization test and a titer of human monocyte infection enhancement of greater than 1:2,000,000. Fifteen minutes after inoculation of serum, animals were infected with D2V (strain no. 16681). Daily titers of viremia were always higher in the animals that had received antiserum to D2V than in animals that had received normal cord-blood serum. Ratios of infection enhancement ranged from 2.7 to 51.4. The demonstration of antibody dependence of dengue virus infection in subhuman primates--a complex, outbred experimental host--supports the hypothesis that the severity of dengue in humans is regulated by antibody.


Effect of bacille Calmette-Guérin on the immune response of BALB/c mice to a tumor allograft. The effect of dosage and route of inoculation of bacille Calmette-Guérin (BCG) on immune response to allogeneic tumor cells was investigated. BALB/c mice were tested 14 and 21 days after injection of EL-4 lymphoma for spleen-cell cytotoxicity against EL-4 cells in vitro and for complement-dependent, antibody-mediated lysis of tumor cells. BCG treatment had no measurable effect on the antibody-mediated lysis of tumor cells, but spleen-cell cytotoxicity was significantly increased in mice treated with 10(4) or 10(8) BCG by the intraperitoneal route; no such increase occurred when BCG was given by the oral or subcutaneous routes. The cytotoxic effector cells were primarily thymus-derived, since treatment of spleens with rabbit antiserum to mouse brain serum decreased cytotoxicity titers by approximately 90%. Within the framework of these experiments, the intraperitoneal route of BCG inoculation resulted in a more effective immune stimulation than the oral or subcutaneous routes.


Temporomandibular joint meniscectomy--effects on joint structure and masticatory function in macaca fascicularis. The postoperative effects of unilateral temporomandibular joint meniscectomy on joint structure and masticatory function were evaluated in four mature Macaca fascicularis and compared with one control. Mandibular movement during mastication was monitored objectively with an optoelectronic tracking system within four months and again within twelve months postmeniscectomy in each animal. Temporomandibular joint structure was documented radiographically and histologically. Results showed that degenerative joint disease was produced in the postsurgical joint, and that the morphological changes were location-dependent. Fibrous ankylosis was observed histologically in three animals. The contralateral joints were not affected morphologically, except for bony resorption of the articular eminence noted microscopically in one animal. Radiographically, however, the joint appeared normal. Variable alterations in masticatory patterns were observed following unilateral meniscectomy. While there appeared to be an association between temporomandibular joint structure and masticatory function, radiographic and microscopic observation of morphological alterations in the joint did not result in predictable functional limitations in chewing pattern.


Ovarian activity, and total gonadotrophin and gonadotrophin releasing hormone levels in response to some synthetic non-steroidal ovulating agents in the catfish, Heteropneustes fossilis (Bloch). Effects of clomiphene citrate, cyclofenil and prostaglandins (PGE1 and PGF2 alpha) on ovarian 32P uptake, on gonadotrophin levels in the pituitary gland and blood serum and on a gonadotrophin releasing hormone-like (GnRH-like) substance in the hypothalamus were investigated in Heteropneustes fossilis. These drugs were very effective in increasing the serum level of gonadotrophin with a subsequent increase in ovarian 32P uptake in sham-hypophysectomized recipients. All the drugs except cyclofenil failed to stimulate 32P incorporation by the ovary in hypophysectomized fish. Clomiphene citrate and cyclofenil also induced a significant increase in the GnRH-like factor in the hypothalamus of H. fossilis. Such a response was not obtained in fish treated with PGE1 and PGF2 alpha. It seems likely that the action of clomiphene is routed through the hypothalamo-pituitary-ovarian axis and that of prostaglandins directly through the pituitary-ovarian axis. The action of cyclofenil is bimodal; one effect like that of clomiphene and the other direct upon the ovary probably by increasing its sensitivity to the available gonadotrophin.


Identification and purification of a new protein from water-soluble extracts of human adrenal gland. An homogenate of human foetal adrenal gland was subjected to negative immunoabsorption by column chromatography using anti-whole human serum coupled to Sepharose 4B. Two peaks were eluted and used to immunize rabbits. The antisera produced were absorbed and tested for specificity by double immunodiffusion. Two antigens, which appeared to be specific to the adrenal gland, were identified having molecular weights of 25 000 and 65 000 as determined by gel filtration. The lower molecular weight antigen was isolated by physicochemical methods and found to be a protein. The amino acid composition is reported.


A comparison of responding maintained under second-order schedules of intramuscular cocaine injection or food presentation in squirrel monkeys. Key pressing by squirrel monkeys was maintained under second-order schedules of either intramuscular cocaine injection or food presentation. Under one schedule, each completion of a 10-response fixed-ratio unit produced a brief visual stimulus; the first fixed-ratio unit completed after 30 minutes elapsed produced the stimulus paired with either cocaine injection or food presentation. Generally, short pauses followed by high rates of responding were maintained within the fixed-ratio units, and responding was positively accelerated over the 30-minute interval. Under another schedule, each completion of a 3-minute fixed-interval unit produced the brief stimulus; completion of the 10th fixed-interval unit produced the stimulus paired with either cocaine injection or food presentation. Generally, short pauses followed by high rates of responding were maintained within the fixed-ratio units, and responding was positively accelerated over the 30-minute interval. Under another schedule, each completion of a 3-minute fixed-interval unit produced the brief stimulus; completion of the 10th fixed-interval unit produced the stimulus paired with either cocaine injection or food presentation. Rates of responding increased within the fixed-interval units, and to a greater extent over the entire 10 fixed-interval units. Patterns of responding depended more on the schedule of reinforcement than on whether cocaine or food maintained responding. Omitting the brief stimuli following all but the last fixed-ratio or fixed-interval units decreased average rates and altered the patterns of responding. Substituting a visual stimulus that was never paired with cocaine or food following all but the last fixed-ratio or fixed-interval units decreased response rates to a lesser extent and did not substantially alter patterns of responding. When the duration of the paired stimulus was varied from .3 to 30.0 seconds, the highest response rates occurred at intermediate durations (1.0 to 10.0 seconds). The manner in which the stimulus changes affected performances depended more on the schedule of reinforcement than on whether cocaine injection or food presentation maintained responding.


Neurobehavioral effects of methyl N-butyl ketone and methyl N-amyl ketone in rats and monkeys: a summary of NIOSH investigations. The results from four NIOSH investigations concerning the neurobehavioral effects of methyl n-butyl ketone (MBK) and methyl n-amyl ketone (MAK) on experimental animals are summarized. The investigations were initiated following clinical reports of neurologic sequelae in humans exposed to these ketone solvents. In order to explore both acute and chronic effects of MBK and MAK, two general types of studies were conducted: 1) neurophysiologic evaluation of monkeys and rats following chronic inhalation, and 2) behavioral effects in rats following oral or intraperitoneal administration. Results from chronic inhalation studies after 4 months of 1000 ppm MBK exposure (all exposures: 6 hrs/day, 5 days/week) showed the following: decreased motor nerve conduction velocities (NCV) in the ulnar and sciatic-tibial nerves, reduced amplitude of evoked muscle action potentials (MAP), lengthened latency of components of the visual evoked brain potential, decreased body weight, and hindlimb drag. Decrements in sciatic-tibial NCV and MAP amplitude were found after 9 months exposure to 100 ppm MBK. In contrast, exposure to approximately 1000 ppm MAK for 9 months had no adverse affects on neurophysiologic indicators of nervous system integrity. Dose-response investigations of the effects of MBK (oral) and MAK (ip) showed for both solvents a reduction in the response rate of rats trained on a multiple schedule of reinforcement.


An experimental analysis of the effects of d-amphetamine and cocaine on the acquisition and performance of response chains in monkeys. In one component of a multiple schedule of food presentation, monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). Both d-amphetamine and cocaine, at the higher doses, disrupted the behavior in the learning component; the overall response rate decreased, the overall accuracy was impaired (i.e., percent errors increased), and there was less within-session error reduction. The performance component was generally less sensitive than the learning component to the disruptive effects of both drugs on rate and accuracy. After pre-feeding or during an extended session, the response rate decreased in both components, but accuracy was generally unaffected. When the four discriminative stimuli in both components were removed, the behavior was disrupted to a greater extent in the performance component. The disruptive effects of both drugs on behavior in the learning component were attenuated when the drugs were administered during the session after the response chain had been acquired. It was concluded that the greater sensitivity of the learning component to disruptive drug effects is related to the relatively weak stimulus control and/or the lower rate of reinforcement associated with that component.


Specific Lyt 123 cells are involved in protection against Listeria monocytogenes and in delayed-type hypersensitivity to listerial antigens. Specific anti-Lyt antisera and complement were used to determine the Lyt phenotype of peritoneal exudate T lymphocytes from Listeria monocytogenes-immune mice. It was found that Lyt 123+ T cells are crucially involved both in protection against listerial infection and in delayed-type hypersensitivity (DTH) to listerial antigens. Thus, both functions critically depend on a T-cell subclass phenotypically different from that which mediates DTH to noninfectious antigens and help in antibody formation on the one hand, as well as those T cells mediating cytotoxic reactions on the other.


Ethylene oxide: toxicology review and field study results of hospital use. Ethylene oxide (ETO) is used extensively within health care facilities for sterilization of equipment and supplies. Alternative chemicals or processes have, in themselves, serious limitations or health hazards. NIOSH recognizes, therefore, that the continued use of ETO as a gaseous sterilant is highly desirable in many situations. Recent results of tests for mutagenesis have increased the concern for potential health havards associated with exposure to ETO. In order to assess the potential for exposure and associated hazards, NIOSH prepared a "Special Occupational Hazard Review with Control Recommendations for the Use of ETO as a Sterilant in Medical Facilities," DHEW (NIOSH) Publication No. 77-200 (Aug. 1977). An assessment was made of the evidence for toxic effects of ETO, especially with respect to mutagenic, teratogenic, and carcinogenic potentials. Additionally, a limited field survey was conducted by NIOSH to document the use, problems, and potential for human exposure in medical facilities. Based on this review, measures for control of control of occupational exposure have been recommended. The report includes a summary of the airborne ETO concentrations measured within health care facilities as part of the field survery. NIOSH estimates that there are in excess of ten thousand ETO sterilizers in use in U.S. health care facilities, and that approximately 75 thousand workers are potentially exposed to ETO in those facilities. Reasons for the unnecessary exposure of personnel were found to include: improper or inadequate ventilation of sterilizers, aerators, and working spaces; improper handling and/or storage of sterilized items; untrained workers operating some sterilization equipment; improper operating techniques leading to mishandling of some ETO sterilizing equipment; poor design of the sterilization facility; and design limitations of the sterilization equipment.


A role for clonal dominance in the maintenance of allotype suppression? The establishment of immunological memory during the early and complete phase of allotype suppression in the young rabbit has been shown to lead to the preferential production of antibodies with the nonsuppressed allotypic specificity in response to recall injections given after spontaneous or induced release from suppression. It is suggested that this manifestation of clonal dominance, applied to stimulation by environmental antigens, may contribute to the long lasting persistence of allotype imbalance in allotype suppressed rabbits.


Functional analysis of T cells expressing Ia antigens. I. Demonstration of helper T-cell heterogeneity. We have examined the expression of I-region antigens on functional subpopulations of murine T cells. A.TH anti-A.TL (anti-Ik, Sk, Gk) alloantiserum was raised by immunization of recipients with concanavalin A (Con A) stimulated thymic and peripheral T-cell blasts. In contrast to similar antisera made by conventional methods, the anti-Ia blast serum was highly cytotoxic for purified T lymphocytes. Moreover, it reacted in a specific fashion with T cells having particular functions. Treatment of keyhole limpet hemocyanin (KLH)-primed B10.A (H-2 alpha) T cells with this antiserum plus complement resulted in the elimination of helper activity for B-cell responses to trinitrophenyl-KLH. Inhibition was shown to be a result of the selective killing of one type of helper T cell whose activity could be replaced by a factor(s) found in the supernate of Con A-activated spleen cells. A second type of helper cell required for responses to protein-bound antigens appeared to be Ia-. By absorption and analysis on H-2 recombinants, at least two specificities were detectable on helper T cells; one mapping in the I-A subregion and a second in a region(s) to the right of I-J. In addition, the helper T cell(s) involved in the generation of alloreactive cytotoxic lymphocytes was shown to be Ia+, whereas cytotoxic effector cells and their precursors were Ia- with this antiserum. These results provide strong evidence for the selective expression of I-region determinants on T-cell subsets and suggest that T-cell-associated Ia antigens may play an important role in T-lymphocyte function.


The effect of calcium ions on the secretion of quanta evoked by an impulse at nerve terminal release sites. A study has been made of the effects of calcium ions on the number of quanta secreted from all the release sites at an amphibian motor nerve terminal recorded with an intracellular microelectrode (m) compared with the number secreted simultaneously from a small number of release sites recorded with an extracellular microelectrode (me). If the endplate potential was made subthreshold by lowering the external calcium concentration ([Ca]o less than or equal to 0.4 mM), it was possible to find small groups of release sites for which me was comparable to m, indicating considerable nonuniformity in the probability of release of a quantum at different groups of release sites (Pe) in a given [Ca]o. Increasing [Ca]o in the range from 0.25 to 0.4 mM increased the probability of release of a quantum at groups of release sites (Pe), independent of the initial value of Pe, and the dependence of Pe on [Ca]o followed a fourth power relationship. A conditioning impulse enhanced the probability of release of a quantum by a subsequent test impulse at release sites, if Pe was less than 1.0 during the conditioning impulse. It is shown that the present observations regarding the dependence of Pe on [Ca]o and on conditioning impulses can be quantitatively predicted from previous observations regarding the dependence of the binomial parameters m, p, and n on [Ca]o and on conditioning impulses determined with intracellular electrodes, if the probability of secretion of a quantum at a release site (Pj) is different for different release sites and Pj is distributed as a beta random variable.


Light-mediated changes in pigmentation of Pseudomonas aeruginosa cultures. Cultures of Pseudomonas aeruginosa PAO grown under uninterrupted broad-spectrum light showed different pigmentation from dark-grown cultures. Whereas dark-grown bacteria produced pigments which resulted in blue-purple coloured agar, light-grown organisms produced red coloured plates. Extraction and quantification of pigments showed that both dark- and light-grown cultures produced similar concentrations of pyorubrin (red) and pyoverdin (yellow). In contrast, the concentration of pyocyanin (blue) was substantially reduced under certain lighting conditions. This decrease was dependent on both the light intensity and wavelength and occurred with light in the ultraviolet and violet region of the spectrum. After its release from bacteria, pyocyanin was rapidly and nonreversibly photoinactivated with first-order kinetics to produce colourless photoproduct(s).


The intracellular survival and growth of gonococci in human phagocytes. In reassessment of previous tests for intracellular survival, results have been confirmed and additional evidence obtained indicating that some gonococci can survive and multiply in human phagocytes. Use was made of the ability of penicillin to penetrate phagocytes and to kill only actively growing organisms. In microscopic counts on 33 urethral exudate smears, an average of 49% of gonococci were associated with polymorphonuclear phagocytes. The organisms were unevenly distributed amongst the phagocytes, with most cells uninfected and some containing large numbers. Many phagocytes also remained uninfected in tests in vitro with low gonococcal inocula although experiments with large inocula showed that most phagocytes could ingest gonococci. It is proposed that ingestion of one gonococcus may stimulate the phagocytes to take up more. Phagocytes were killed and disintegrated after ingesting large numbers of gonococci and similar effect in vivo may be responsible for the large clumps of organisms seen in urethral exudate. These results underline the probable importance in the pathogenesis of gonorrhoea of intracellular survival in phagocytes.


Complete lysis of glutamic acid-producing bacteria by the use of antibiotics which inhibit the biosynthesis of cell walls. A novel method for obtaining complete lysis of coryneform bacteria has been devised. Bacteria in the late-exponential phase of growth are treated with antibiotics which inhibit biosynthesis of the cell wall. Organisms treated in this way show increased sensitivity to lysis by added lytic enzymes. The preparation of DNA from this group of organisms is thus greatly facilitated.


Delayed effects of subarachnoid haemorrhage on cerebral metabolism and the cerebrovascular response to hypercapnia in the primate. A technique is described for the production of subarachnoid haemorrhage in baboons and their subsequent recovery for chronic study of cerebrovascular reactivity. The baboons make complete neurological recoveries but the response of their cerebral circulation to hypercapnia is impaired one week later. Baseline values of cerebral blood flow and of cerebral oxygen consumption are unaffected at this time. There is no evidence of hypoxic brain damage.


Late effects of subarachnoid haemorrhage on the response of the primate cerebral circulation to drug-induced changes in arterial blood pressure. The ability of the cerebral circulation to maintain a constant level of cerebral blood flow with halothane-induced hypotension and angiotensin-induced hypertension was found to be impaired one week after subarachnoid haemorrhage in the baboon. No evidence of hypoxic brain damage was found. The clinical significance of these findings is discussed.


Bullet injury to the pituitary gland: a rare cause of panhypopituitarism. An unusual case of head injury with a direct bullet injury to the pituitary gland is described. The hormonal profile one month after the injury showed severe panhypopituitatism which did not improve one month after surgical removal of the intrasellar bullet fragment.


Induction of allergic encephalomyelitis in rhesus monkeys treated with anti monkey thymocyte sera. Treatment with rabbit anti-moneky thymus cell sera whether limited (3 days) or extensive (15 days), did not alter the development of experimental allergic encephalomyelitis (EAE) in rhesus monkeys challenged with myelin basic protein or central nervous system tissue (CNS) when compared to similarly challenged control monkeys treated with normal rabbit serum. No consistent difference in disease incidence or intensity as measured by incubation period, neurologic signs or CNS pathology was observed between experimental and control monkeys. This finding is in contrast to previous reports on the efficacy of ATS treatment in prevention of EAE in rodents.


Effect of sequential infection with Plasmodium vivax and P. falciparum in the Aotus trivirgatus monkey. Aotus trivirgatus monkeys with prior experience with Plasmodium vivax were inoculated with P. falciparum via the bites of infected mosquitoes. The animals with prior malaria had higher parasitemias and significantly higher levels of mosquito infectivity than monkeys with no prior P. vivax experience. Monkeys with a history of P. falciparum that were inoculated with P. vivax had essentially the same parasitemias as those with no prior malaria. However, levels of mosquito infectivity were markedly increased in those monkeys with a history of P. falciparum. The results imply that the introduction of another malaria species into a malarious area may result in higher levels of mosquito infection and more rapid establishment and distribution of that species.


Infection and transmission studies with Plasmodium simiovale in the Macaca mulatta monkey. Six different anophelines--Anopheles freeborni, An. b. balabacensis, An. maculatus, An. stephensi, An. atroparvus, and An. quadrimaculatus--were shown to be susceptible to infection with Plasmodium simiovale when fed upon splenectomized Macaca mulatta monkeys between the 1st and 26th days of patent parasitemia. Transmission was obtained via the bites of An. b. balabacensis and An. maculatus mosquitoes. Prepatent periods in M. mulatta monkeys following sporozoite inoculation ranged from 11 to 20 days with a median of 14 days.


Aspects of the sporogonic development of Leucocytozoon tawaki of the Fiordland crested penguin in its primary vector, Austrosimulium ungulatum: an ultrastructural study. Early oocysts of Leucocytozoon tawaki Fallis, Bisset and Allison were located between the basal lamina and the midgut epithelium of the vector, Austrosimulium ungulatum. The spherical oocysts were surrounded by an amorphous, electron-dense wall and contained a large, central core of closely spaced dense particles, the crystalloid inclusion. Around the latter were many concentrically arranged cisternae of granular endoplasmic reticulum. A few large, poorly defined nuclei, some of which contained spindle apparatus, were seen. Sporozoite formation occurred around the peripheral cytoplasm of maturing oocysts. The sporozoite pellicle was subtended by 30 microtubules which appeared to originate from the most posterior of 3 dense, polar rings. Each forming sporozoite contained a central nucleus, mitochondrion, and a crystalloid inclusion both anterior and posterior to the nucleus. The nature and significance of the crystalloid in Leucocytozoan species and other apicomplexans is discussed with special reference to similar viruslike inclusions in the sporogonic stages of certain species of Plasmodium.


Studies on the West African I strain of Plasmodium falciparum in Aotus trivirgatus monkeys. The West African I strain of Plasmodium falciparum was isolated from a commercial airline pilot who had an overnight stay in Nigeria. Once established in the Aotus trivirgatus griseimembra monkey, the parasite produced high parasitemias and readily infected mosquitoes. Anopheles freeborni and An. maculatus mosquitoes transmitted the infection to additional animals. Infected salivary glands were also seen in An. culcifacies. Comparative infectivity studies indicated the most susceptible mosquito to be An. freeborni, followed by An. culicifacies, An. maculatus, and An. balabacensis balabacensis. Only 2 An. albimanus mosquitoes were infected out of 450 examined. The one A. t. trivirgatus monkey inoculated with this strain had very low levels of parasitemia.


Extraordinary hyperbilirubinemia in a neonate with idiopathic hypertrophic pyloric stenosis. This case describes an extraordinarily elevated total bilirubin level that reverted to normal 9 1/2 wk after Fredet-Ramstedt pyloromyotomy. Although the etiology of jaundice occurring in patients with IHPS remains uncertain, theories implicating inhibition of the glucuronyl transferase system have been proposed. Infants with IHPS have a documented hypergastrinemia. An hypothesis is offered, illustrated by this case, to explain the inhibition of the glucuronyl transferase system with resultant hyperbilirubinemia by the hypergastrinemia of idiopathic hypertrophic pyloric stenosis.


A safer system for percutaneous subclavian venous catheterization in newborn infants. Percutaneous infraclavicular cannulation of the subclavian vein in even the tiniest infants can be performed with safety and ease using a plastic cannula metal needle stylet and following plastic catheter. This route for achieving superior vena caval catheterization provides a most satisfactory method for central pressure monitoring, long term antibiotic administration, total parenteral nutrition, and exchange transfusion. Few serious complications have been noted in over a hundred infant cannulations. The procedure can be performed in the intensive care nursery with a success rate of over 95%. Sepsis rates in clean cases are acceptably low. Most sepsis is due to other clearly identifiable sources of infection in these already critically ill infants.


N-Benzoyl derivatives of amino acids and amino acid analogs as growth inhibitors in microbial antitumor screen. Twenty-seven N-benzoyl derivatives of amino acids and amino acid analogs were prepared and tested for growth-inhibitory activity in a microbial antitumor screen. Of these, 19 showed some inhibitory capacity, from a modest 13% to a potent 96% at 1 mg/ml. The activities of the "modest" inhibitors were comparable to those of most inhibitory chloracetyl and trifluoroacetyl derivatives reported earlier. The intermediate inhibitors were as active as N-chloroacetyl-beta-hydroxy-D-norleucine isomer B, the most active acyl derivative noted previously. The most active compounds in this study were N-benzoyl-p-chloro-DL-phenylalanine and N-benzoyl-m-fluoro-DL-phenylalanine, which inhibited the test organism almost completely under the assay conditions.


Kinetics of drug-drug interactions: biliary excretion of iodoxamic acid and iopanoic acid in rhesus monkeys. The dynamic method originally developed for studying the capacity-limited kinetics of the cholecystographic agents iodoxamic acid and iopanoic acid was applied to study the in vivo interactions of these two compounds following coadminstration in the monkey. Results indicate that these interactions are complex. The compounds appear to compete for plasma protein binding sites as well as for binding sites on intrahepatic proteins. The biliary excretion data apparently fit the "ligand exclusion" model in which iopanoic acid acts as an inhibitor and competes with iodoxamic acid for binding to either of two identical sites within the liver. This competition probably is the rate-limiting step in the liver's overall elimination of these radiographic contrast agents.


Effects of morphine, pentazocine and cyclazocine alone and in combination with naloxone on electric shock titration in the squirrel monkey. The effects of morphine, pentazocine and cyclazocine were examined on a discrete-trial shock titration procedure. Monkeys received continuous shock during 15-sec shock periods. If the monkey did not respond during the shock period, shock remained on for 15 sec and then increased by one increment on the next 15-sec shock period. If five responses were made during the shock period, the shock was immediately terminated for 15 sec during which the chamber was dark (time out). After the 15-sec time out period, the shock resumed at the next lower intensity. Morphine, pentazocine and cyclazocine altered patterns and rates of responding similarly. At a low dose, pentazocine, cyclazocine and morphine decreased median shock levels and increased rates of responding in the presence and in the absence of shock (i.e., during time out). These effects were observed over a wider dose range with pentazocine and cyclazocine than with morphine; moreover, decreases in median shock level and increases in rates of responding in the absence of shock were of greater magnitude after pentazocine and cyclazocine than after morphine. At higher doses, morphine, pentazocine and cyclazocine increased median shock levels and decreased rates of responding in the absence of shock. Rates of responding in the presence of shock were either unchanged or decreased very slightly, suggesting that increases in the intensity at which shock is maintained under shock titration procedures is not necessarily due to decreases in rates of responding. In contrast, naloxone had very little behavioral effect when administered alone. The effects of morphine were antagonized by a dose of naloxone as low as 0.01 mg/kg, whereas higher doses of naloxone were required to antagonize the effects of pentazocine and cyclazocine.


Possible mechanism of the inhibitory effect of ouabain on renin secretion from rat renal cortical slices. 1. The effects of ouabain on renin secretion by rat renal cortical slices were studied. 2. Renin secretion was inhibited by 10(-3) M-ouabain in the presence of free Ca (10(-4) to 2.6 x 10(-3) M). Inhibition was blocked at Ca less than 10(-8) M. 3. The effect of free Ca on ouabain-inhibition was shown to be independent of the presence of EGTA, completely reversible, and unrelated to passive leakage of renin from non-viable cells, as assessed by simultaneous release of lactate dehydrogenase activity (LDH). 4. It is proposed that, as a result of inhibition of Na, K-ATPase by ouabain, (a) intracellular Na increases in the renin-secreting juxtaglomerular cells, (b) intracellular Ca increases, via an Na-Ca exchange mechanism, and (c) that Ca accumulation, in some unknown manner, inhibits renin secretion.


The role of the flocculus of the monkey in saccadic eye movements. 1. Purkinje cell discharges were recorded from the flocculus of monkeys either spontaneously making saccadic eye movements (saccades) or trained to fixate a small visual target presented on a tangent screen. In the trained monkeys, saccades of known magnitude and direction were induced by changing the position of the fixation target. 2. Among 513 Purkinje cells, 343 units (66.9%) paused during saccades in all directions (286 units) or in particular directions (57 units). In most units, there were intimate temporal relationships between the beginnings of pauses and saccades, and between the ends of pasuses and saccades. 3. The pause in activity preceded saccades by an average of 9.6 msec, with a maximum lead time of 30 msec. In a fraction of the units (7.6%), the pause started after the onset of saccades. 4. There were 104 units (20.3%) which showed bursts during saccades in all directions (eighty-two units) or in particular directions (twenty-two units). 5. In sixty-six units (12.8%) a burst was associated with saccades in one direction and a pause in the opposite direction. 6. The burst in the burst and burst-pause units preceded saccades by an average of 3.8 msec. There was no significant difference in the lead times between these two groups of units. 7. There was a linear relationship between the duration of the pause in Purkinje cell activity and that of the accompanying saccade. A linear relationship was also seen between the pause duration and the magnitude of saccade.


The role of the flocculus of the monkey in fixation and smooth pursuit eye movements. 1. Purkinje cell discharges were recorded from the flocculus of monkeys trained to fixate a small visual target and to track the target when moved slowly. 2. A striking feature of Purkinje cell activity during the steady fixation was a high rate of tonic discharges with regular interspike intervals. The average discharge rate in the whole population of Purkinje cells ranged from 37 to 145 spikes/sec. The coefficient of variation of the interspike intervals was typically smaller than 0.5 in most units. 3. In 43.9% of the Purkinje cells, tonic levels of activity changed by more than 20% of the average background activity with shifts of gaze. 4. In some Purkinje cells, especially in most burst-pause units, discharge rates during steady fixation were proportional to eye positions in one plane, implicating these cells as sources of eye position information to their target cells. 5. When the monkey tracked a sinusoidally oscillating target, the activity of some Purkinje cells was clearly modulated in phase with the eye velocity. 6. In the other Purkinje cells exhibiting smooth pursuit modulation, the activity curve appeared with a phase shift. When these cells were tested with sinusoidal target movements at different frequencies, but with a constant magnitude, the peak firing rates were proportional to the frequencies of the excursions, i.e. the velocities. 7. The flocculus thus provides the oculomotor system with eye position information during fixation and with velocity information during smooth pursuit and participates in the control of oculomotor functions stabilizing retinal images.


Processing of eye movement signals in the flocculus of the monkey. 1. Extracellular recordings were made from afferents to the Purkinje cells of the flocculus of monkeys either spontaneously making saccadic eye movements (saccades) or trained to fixate a small visual target projected on a tangent screen. In the trained monkeys, saccades of known magnitude and direction were induced by changing the position of the fixation target. 2. Among a population of 108 units, eight were climbing fibres, seventy-one were mossy fibres, and twenty-nine were non-Purkinje cells. Based on their discharge patterns the latter two groups of units were categorized into one of four classes. 3. Long-lead burst units (twenty-two units) exhibited saccade-related discharges substantially before saccade onset (average: 113 msec). Most of these (twenty units) discharged for saccades in a particular direction, while the remainder exhibited discharges for saccades in all directions. All units were essentially silent between saccades. 4. Burst units (twenty-seven units) started discharging slightly before saccades (average: 6.9 msec). Discharges were associated with saccades in all directions (sixteen units) or in preferred directions (eleven units) and were not observed during periods of fixation. 5. Burst-tonic units (twenty-two units) were characterized by saccade-related burst and position-related intersaccadic tonic activity. 6. Tonic units (thirty-seven units) exhibited position-related tonic activity. The position-related activity in both burst-tonic and tonic units was observed only for fixation points within a specified region. The units were silent for fixation positions outside this region of preferred fixation.


Origin and developmental patterns of lactase and other glycosidases in sheep amniotic and allantoic fluid. Intestinal lactase activity (with its associated cellobiase, 4-methylumbelliferyl-beta-galactosidase and -beta-glucosidase activities) was used as a specific intestinal marker enzyme to study the release of protein and enzymes of intestinal origin in sheep amniotic fluid during gestation. In amniotic fluid, intestinal lactase activity peaked at 66--85 days of gestation and then decreased with gestation. This enzyme activity was very low or absent in allantoic fluid throughout gestation suggesting that there is no important transfer of amniotic fluid lactase towards the allantoic cavity. Maltase and 4-methylumbelliferyl-alpha-glucosidase showed no statistically significant variation with gestation in both amniotic and allantoic fluid whereas alpha-galactosidase and N-acetyl-beta-hexosaminidase which were first higher in allantoic than in amniotic fluid increased in amniotic fluid to reach allantoic fluid levels near term. Such patterns are consistent with the suggestion that the fetal urine is a source of alpha-galactosidase and N-acety-beta-hexosaminidase activities and that sheep urine is first accumulated in the allantoic sac via the urachus up to 86--90 days of gestation and thereafter passes more and more into the amniotic sac.


Primaquine analogues: derivatives of 4-amino-2-methoxyacridine. Based on the antimalarial activity of primaquine (1a) and its 4-methyl analogue 1b, 4-aminoacridinyl analogues, 4-[(4-amino-1-methylbutyl)amino]-2-methoxyacridine (2a) and 4-[(4-amino-1-methylbutyl)amino]-2-methoxy-9-methylacridine (2b), were prepared and evaluated as potential tissue schizonticidal agents. These compounds were found to be substantially less active than primaquine against Plasmodium cynomolgi in the rhesus monkey. The antileishmanial activity in hamsters of 4-[[6-(diethylamino)hexyl]amino]-2-methoxy-9-methylacridine (2d) was found to be considerably less than that of 8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4-methylquinoline (1c).


3-[(1,2,3-Thiadiazol-5-ylthio)methyl]cephalosporins. The syntheses of ten 3-](1,2,3-thiadiazol-5-ylthio)methyl]cephalosporins, made by displacement of the 3'-acetoxy group by the novel thiol derivatives, potassium 1,2,3-thiadiazole-5-thiolate and dipotassium 1,2,3-thiadiazole-4-carboxylate-5-thiolate, are described. Several of the compounds showed good in vitro antibacterial activity against both Gram-positive and Gram-negative organisms. The subcutaneous in vivo activities against Staphylococcus aureus were generally less than that of cafazolin. Four of the compounds were administered orally and all were active; the 7 beta-(thiophen-2-acetamido) and 7 beta-(D-2-amino-2-phenylacetamido)-3-[(1,2,3-thiadiazol-5-ylthio)methyl] compounds were equally active by either route, with a PD50 of ca. 1 mg/kg.


Folate antagonists. 15. 2,3-Diamino-6-(2-naphthylsulfonyl)quinazoline and related 2,4-diamino-6-[(phenyl and naphthyl)sulfinyl and sulfonyl]quinazolines, a potent new class of antimetabolites with phenomenal antimalarial activity. Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.


Genetic polymorphisms in diabetics and non-diabetics. Phenotype distributions of some genetic polymorphisms are reported in a sample of 721 diabetics and 515 non-diabetic, non-blood donor controls. Reference is also made, in the case of the ABO and Rhesus systems, to previously published results for blood donors resident in the Durham area. Non-insulin-taking diabetics show an increased frequency of blood group A1 (and A1 + A2) when compared with controls. This difference is particularly marked in male diabetics. When diabetics are compared with age matched controls, the difference is confined to the older cases. It is proposed that this effect is predominantly the result of a deficiency of group A1 in controls rather than the result of increased susceptibility to the disease among A1 people. No association with any of the Rhesus phenotypes is shown. In non-diabetics, the results suggest an enhanced survival value for the rr genotype. No significant associations are seen when the MNSs, Kell, Lewis, Duffy, haptoglobin, red cell acid phosphatase, phosphoglucomutase, adenylate kinase, and adenosine deaminase distributions in these groups of subjects are compared.-


A new estimate of sequence divergence of mitochondrial DNA using restriction endonuclease mappings. A new estimate of the sequence divergence of mitochondrial DNA in related species using restriction enzyme maps is constructed. The estimate is derived assuming a simple Posisson-like model for the evolutionary process and is chosen to maximize an expression which is a reasonable approximation to the true likelihood of the restriction map data. Using this estimate, four sets of mitochondrial DNA data are analyzed and discussed.


Effects of oral and intramuscular carbaryl administrations on repeated chain acquisition in monkeys. A type of learning task was utilized to determine the effective dose of carbaryl on Macaca fascicularis for both oral and in routes of administration. Monkeys were required to press four buttons in a set order; the order was changed daily. A baseline reversal design was utilized to test all animals several times at each concentration. The im carbaryl injections resulted in consistent, statistically reliable decrements in total session time and increases in errors at 5 and 10 mg/kg for the 4 animals in this section of the experiment, but produced no change in performance at 1 mg/kg. Errors increased in 3 of 4 monkeys after 3 mg/kg injections. Oral doses as high as 50 mg/kg were not consistently effective in changing performance on the task in any of 5 animals included in this section of the experiment. Some support was given to the suggestion that monkeys are more tolerant of carbaryl than are rats. These are the first reported effects (other than the LD50) of carbaryl in monkeys.


Testicular function among carbaryl-exposed exployees. A cohort of 101 male carbaryl production workers with at least 1 yr experience in the carbaryl area was selected from employment records. Of these individuals, 47 provided satifactory semen samples for analysis; 36 of the 47 provided blood for hormone assay. There were no major age or employment-status differences between those who agreed to participate and those who did not. In the absence of sufficiently detailed industrial hygiene exposure data, a subjective exposure classification was developed. No apparent relationships were found between sperm count and exposure category or years worked in classifications based on carbaryl exposure. Also, no relationship was found between fathering children and exposure to carbaryl. When the sperm-count distribution of the carbaryl-exposed workers was compared with a distribution of sperm counts representing a nonexposed (control) population, no overall differences were observed that could be related to carbaryl exposure. There was a small excess in the number of sperm counts less than 20 million per milliliter among the carbaryl-exposed men, but the excess was not significant at alpha = 0.05.


Peripelvic new bone formation following straddle injuries in hemophiliac patients: report of two cases. Of 123 patients suffering from either Haemophilia A or B examined at our clinic two were found with peripelvic new bone formation following straddle injuries. An awareness of the possibility of peripelvic ossification should prompt immediate treatment to stop hemorrhage into soft tissues in such cases.


Viral genome RNA serves as messenger early in the infectious cycle of murine leukemia virus. When NIH/3T3 mouse fibroblasts were infected with the Moloney strain of murine leukemia virus, part of the viral genome RNA molecules were detected in polyribosomes of the infected cells early in the infectious cycle. The binding appears to be specific, since we could demonstrate the release of viral RNA from polyribosomes with EDTA. Moreover, when infection occurred in the presence of cycloheximide, most viral RNA molecules were detected in the free cytoplasm. Size analysis on polyribosomal viral RNA molecules indicated that two size class molecules, 38S and 23S, are present in polyribosomes at 3 h after infection. Analysis of the polyriboadenylate [poly(rA)] content of viral RNA extracted from infected polyribosomes demonstrated that such molecules bind with greatest abundance at 3 h after infection, as has been detected with total viral RNA. No molecules lacking poly(rA) stretches could be detected in polyribosomes. Furthermore, when a similar analysis was performed on unbound molecules present in the free cytoplasm, identical results were obtained. We conclude that no selection towards poly(rA)-containing viral molecules is evident on binding to polyribosomes. These findings suggest that the incoming viral genome of the Moloney strain of murine leukemia virus may serve as a messenger for the synthesis of one or more virus-specific proteins early after infection of mouse fibroblasts.


Clonal analysis of mammalian cell cultures persistently infected with Japanese encephalitis virus. More than 200 cells were cloned from populations of mammalian cells persistently infected with Japanese encephalitis virus. Only four cloned cultures contained cells that had viral antigen measurable by immunofluorescence and that released infectious virus, yet all clones harbored virus-specific RNA. Superinfection of cloned cells with wild-type Japanese encephalitis virus did not produce cytopathic effects, but resulted in production of viral antigen and infectious virus in formerly nonproducing clones. Cocultivation of nonproducer clone cells with normally permissive cells did not induce virus production, nor did treatment of nonproducer clones with various inhibitors of DNA, RNA, or protein synthesis. It is suggested that the cloning procedure may have selected for a particular subpopulation of cells and that defective virus is also involved in establishment and maintenance of persistent infection.


Characterization of a bacteriophage related to R-type pyocins. A bacteriophage with a contractile tail which shows very similar features to R-type pyocins was isolated and characterized. This phage, named PS17,was purified by DEAE-cellulose chromatography and CsCl density gradient centrifugation. It was a DNA-containing phage, and the density of the purified particles in CsCl was found to be 1.468. DNA from this phage had a density of 1.720 in CsCl, indicating its guanine plus cytosine content to be 61.2%. The head was polyhedral, 69 nm in diameter, and the tail was 150 nm in length. This phage was neutralized by antiserum preparations against five R-type pyocins, and the antiserum against this phage was active in neutralizing R-type pyocins. The properties of this phage, PS17, were compared with another similar phage, PS3, which was previously reported.


Bactericidal activity of the tail of Pseudomonas aeruginosa bacteriophage PS17. The tail of bacteriophage PS17 of Pseudomonas aeruginosa was shown to be bactericidal, and its properties were compared with those of pyocin R1. Temperature-sensitive mutants were isolated from PS17, and the products at nonpermissive temperature were morphologically characterized. Bactericidal substances were found in the lysates of such mutants that were defective in the head formation but not in the tail formation. Phage tails were purified from the lysate of one such mutant, and its chemical and biological properties were studied. Isolated tails killed sensitive cells by a single-hit process and repressed the uptake of leucine in sensitive cells. These results were consistent with the previous findings on the serological and morphological relationship between PS17 and pyocin R1. However, certain differences were also shown between them in shape and protein composition.


Management of bladder diverticula by transurethral resection: re-evaluation of an old technique. Many surgical techniques have been described for bladder diverticulectomy, including extravesical, intravesical or combined procedures. An alternative therapeutic technique not widely recognized is transurethral resection of the diverticular neck. We have used this procedure on 6 patients, either to promote emptying of a diverticulum or to permit adequate endoscopic examination. Each operation was successful and there were no complications. We herein describe this technique and recommend its use in selected patients.


Studies of the toxicity of an intravenous fat emulsion. i. Hematologic changes and survival after administration of a soybean oil (FE-S15) in beagles. The potential toxicity of FE-S15 (B. Braun-Melsungen), a soybean-oil fat emulsion used in parenteral nutrition, was studied in dogs. Forty pure-bred beagles, in two experimental groups (FE-S15 at 9 and 4 g/kg/day) and two corresponding control groups (receiving Dextrose-Ringer's solution), were given daily infusions for 28 days via a central venous catheter. Vital signs and hematologic, biochemical, and bacteriologic changes were monitored closely. When compared with control groups, no significant weight loss was observed in either group; the food intake decreased only in animals receiving fat in high doses. Hemoglobin and hematocrit decreased in all groups during infusion, the greatest fall observed in the group receiving high-dose fat infusion where the hematocrit declined from 45.5% to 31.7%. This decrease was significantly different from the controls only during one observation period. Clinical signs, such as lethargy, vomiting, diarrhea, loss of appetite and fever were observed infrequently in both experimental and control animals, more often in those treated with high-dose fat infusion. It appears that the fat emulsion FE-S15 causes only minor side effects but otherwise is well tolerated in dogs at a potentially toxic level.


New synthetic substrates for parenteral feeding. The glycerol esters of short and medium chain fatty acids are predicted to become important in future nutritional therapy. These compounds provide a mixture of carbohydrate and "carnitine-independent" fat which, together, can serve more tissues than either substrate alone. Medium chain triglycerides are available for enteral feeding, and water-soluble monoglycerides are suggested for parenteral feeding. Two monoglycerides have been tested by continuous infusion into the rat and dog. Experimental evidence indicates rapid ester hydrolysis by endogenous mechanisms which release the basic components of the glycerides. Nutritional tests with these glycerides have produced results at least comparable to glucose as an energy source, and no toxicity has yet been noted. The data suggest that further investigations should be conducted on the benefits of these compounds.


Studies of the toxicity of an intravenous fat emulsion. II. Blood chemical changes after administration of a soybean oil (FE-S15) in beagles. Biochemical changes were monitored during fat infusion as part of an evaluation of the toxicity that accompanies the intravenous administration of a new soybean oil emulsion in dogs. Beagles were given FE-S15 at 9 and 4 g/kg/day for 28 days via a central venous catheter. The total serum lipid, triglyceride, and phospholipid concentrations of the animals receiving fat in high doses increased 3 to 4 times in comparison to that of the control group; cholesterol increased 5 times. The rise of serum lipid fractions was proportionally smaller in animals receiving the low dose fat infusion. All values returned to the control range 2 wks after termination of the infusion. The serum protein level fell from 6.5 to 5.1 g/dl in animals given 9 g/kg/day fat while animals receiving 4 g/kg/day had a significant increase to 8.4 g/dl (day 27). In comparison with the control groups, the animals receiving low dose fat infusion also had a significant rise in serum albumin and, to a lesser degree, in alpha and beta globulins. A rise in alkaline phosphatase activity was observed in all dogs receiving fat infusion, but was significantly different from the controls only in animals on high dose fat infusion. None of the other monitored biochemical serum values were affected by the administered fat and there was no evidence of disturbance in liver function.


Metabolic response to postoperative parenteral nutrition in infants. Thirty-five infants who had tracheoesophageal fistula, esophageal stenosis, anal  atresia, or Hirschsprung's disease were managed with various types of parenteral solution after their radical operations. The infants were divided into 6 groups and given 1) the usual low calorie infusion consisting of 5% glucose, water, and electrolytes, 2) high calorie formula consisting of 21 g/kg/day glucose, and 4 g/kg/day synthesized crystalline L-amino acids, 3) solutions without phosphate, 4) solutions of Cal/N ratio 200 providing 4 g/kg/day amino acids, 5) solutions of Cal/N ratio 400 providing 2 g/kg/day amino acids, and 6) a regimen containing fat emulsion. Nitrogen (N) and phosphorus (P) balances, blood urea nitrogen (BUN), blood glucose, plasma phosphate, immunoreactive insulin (IRI), and non-esterified fatty acid (NEFA) values were investigated. Parenteral solutions, providing 100 Cal/kg/day of Cal/N ratio 200, yielded sufficient positive N balance (120 mg/kg/day average). High calorie solutions without phosphate caused marked hypophosphatemia (0.3 mEq/1) with undetectable P in 24-hr urine. P balance correlated with N balance. Solutions of Cal/N 400 induced a lower BUN level, although there was a cumulative negative N balance. Solutions of Cal/N 200 induced higher levels of IRI and lower glucose than those of Cal/N 400. Increased IRI response and remarkedly decreased NEFA levels were seen in the group administered solutions without fat. Solutions with fat emulsion suppressed IRI response and improved the level of plasma NEFA.


Home parenteral nutrition: an alternative approach to the management of complicated gastrointestinal fistulas not responding to conventional medical or surgical therapy. Twelve patients, 9 with enterocutaneous fistulas and 3 with enterovaginal fistulas, were placed on a home parenteral nutrition (HPN) program after conventional inpatient total parenteral nutrition with bowel rest and/or surgical attempts at fistula closure failed. Fistula closure was achieved (in 66%) after from 28 to 400 days on the program. Six closed spontaneously while 2 were closed surgically. Underlying inflammation in the bowel and the persistence of fistula drainage beyond 180 days were indicative of poor prognosis for closure. Number, location, and volume of drainage were not useful prognostic indices. HPN offers an alternative approach in the management of "intractable" gastrointestinal fistulas.


Therapeutic and economic implications of emergency department evaluation for venous thrombosis. Records of 160 emergency department patients with lower extremity complaints were reviewed to determine the economic and therapeutic impact of noninvasive venous impedance testing. Venograms obtained in 86 extremities were used to determine diagnostic accuracy. The incidence of pulmonary thromboembolic events, postphlebitic syndrome and complications of anticoagulation was ascertained. Outflow impedance testing correctly identified all patients with deep venous thrombosis and overall diagnostic accuracy was 95% (41/43 patients). In 123 patients (33 positive results, 90 negative) therapeutic decisions were based solely on impedance test results. Examination required 20 to 30 minutres at a cost of $35. Follow-up ranging from 4 to 60 weeks failed to reveal documented thromboembolic complications or recurrence of lower extremity symptoms. In 37 patients (six positive results, 31 negative) impedance test results were ignored and inpatient workup, including invasive venography, was undertaken. Hospital charges for these patients averaged $1,500. In addition to its ease of performance and high degree of accuracy, comparison with inpatient evaluation documents its cost effectiveness. Impedance testing for emergency department evaluation of suspected deep vein thrombosis appears appropriate.


Vascularization of premalignant lesions in carcinogen-treated hamster cheek pouch. Of 27 lesions induced in Syrian golden hamsters by 12 applications of 0.5% 7,12-dimethylbenz[a]anthracene in liquid paraffin, 14 showed a static phase of at least 28 days' duration in their life history. Ten static lesions resumed growth, and this was accompanied by clinically obvious vascularization in 8 cases, 7 of which culminated in carcinomas by the end of the study. Because the wall of the normal hamster cheek pouch possesses small nodules whose histologic structure closely resembles that of hyperplastic epithelium, they could be misinterpreted as a product of carcinogenesis.


Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by N-2-fluorenylacetamide in rats. The effects of inducers of liver microsomal enzymes on the induction of hyperplastic liver nodules by N-2-fluorenylacetamide (2-FAA) were studied in male F344 rats. The rats were fed a diet containing 200 ppm 2-FAA for 2 weeks and then given test chemicals for the following 8 weeks. Partial hepatectomies were performed at the end of the third week of the experiment. The compounds were tested, and their concentrations (in ppm) in the diet were as follows: 1,000 polychlorinated biphenyls (PCB), 500 PCB, 500 PCB plus 70 3-methylcholanthrene (MCA); 500 PCB plus 500 phenobarbital, 70 MCA, 500 phenobarbital, 500 phenobarbital plus 500 beta-naphthoflavone, and 2,500 3-(3,5-dichlorophenyl)-5,5-dimethyloxazoline-dione-2,4 (DDOD). All experimental groups developed significantly greater numbers and total areas of hyperplastic nodules than did the controls. In groups treated similarly with the test chemicals but without partial hepatectomy, the numbers and total areas of hyperplastic nodules were significantly less than those in the experimental groups with partial hepatectomy. Administration of test chemicals except 2-FAA to partially hepatectomized rats did not induce hyperplastic nodules. The present results showed the early detection of the enhancing effect on induction of hyperplastic liver nodules by a system consisting of the following three procedures: 1) 2-FAA feeding; 2) administration of test chemicals, and 3) partial hepatectomy during administration of test chemicals. In this system DDOD enhanced the induction of hyperplastic nodules of the liver.


[Macro-creatine kinase; circulating immunoglobulin enzyme complexes as cause of elevated CK-activities (author's transl)]. We report a case of a woman (58 years old) with persistent and elevated CK activities and without corresponding clinical signs. For seven months CK-B activity was determined above normal by an inhibition test. By exclusion chromatography, ion-exchange chromatography, electrophoresis of CK isoenzymes and immunological methods we were able to explain this phenomenon as Macro CK consisting of immunoglobulin G bound CK-BB.


Spontaneous zinc deficiency in marmosets, saguinus mystax. Moustached marmosets, Saguinus mystax, developed alopecia, skin lesions and general debilitation approximately 6 months after being brought into our laboratory. These lesions resembled the signs of zinc deficiency in pigs, rats and squirrel monkeys. The marmosets were fed a commercial monkey diet containing 150 parts per million zinc and about 100 g of apples and oranges per week. The addition of 40 parts per million zinc to the drinking water brought about improvement in hair coat and skin condition.


The occurrence of a bilateral mandibular mast cell neoplasm in a mouse with lymphocytic leukemia. A 7-month-old female mouse was killed after developing lethargy, rough hair coat and enlarged superficial lymph nodes. Postmortem and histologic examination revealed lymphocytic leukemia involving several organs and a bilateral mast cell neoplasm in the mandible.


Corynebacterium equi in the cottontop marmoset (Saguinus oedipus): a case report. A wild-caught cottontop marmoset died after a short illness characterized by loss of appetite, loss of weight and general unthriftiness. Necropsy revealed a large thoracic abscess from which Corynebacterium equi was recovered.


A rapid procedure for shortening canine teeth of nonhuman primates. A modified pulp cap procedure was utilized to shorten canine teeth of nonhuman primates. A temporary cap was made by cutting the tooth with a diamond-faced cutting disc, making a conical cavity in the tooth with a carbide dental burr, and filling the cavity with a rapid-hardening filler material. A permanent pulp cap was made by repeating the above technique, making three anchor holes, connecting the holes with a furrow, and capping with quick-setting dental restorative material or amalgam. These procedures provided a simple, rapid and uncomplicated alternative to canine tooth extraction.


Reproduction of wild-caught marmosets (Saguinus labiatus labiatus) under laboratory conditions. The reproductive performance of marmosets (Saguinus labiatus labiatus) was evaluated under laboratory conditions. Nineteen of 22 (86%) male-female pairs produced 32 live births during the first 18 months in the laboratory. The reproductive performance and survival rates were comparable to those of other Saguinus species maintained under similar conditions.


A spontaneous outbreak of polychlorinated biphenyl (PCB) toxicity in rhesus monkeys (Macaca mulatta): clinical observations. A spontaneous, progressive disease occurred in a large domestic breeding colony of rhesus monkeys (Macaca mulatta). The disease was characterized by slow but continuous weight loss, alopecia, acne, facial edema, diarrhea and trauma from other monkeys. Breeding efficiency was impaired with a high incidence of abortions and stillbirths. Live offspring were small and unthrifty contributing to a high infant mortality rate. The cause of this disease was polychlorinated biphenyls (PCSs) which were present in the concrete sealant on the cage floors. Removing the sealant and resurfacing the floors alleviated the problem.


A spontaneous outbreak of polycholorinated biphenyl (PCB) toxicity in rhesus monkeys (Macaca mulatta): toxicopathology. Polychlorinated biphenyls (PCBs) were shown to be the cause of a wasting syndrome and reproductive dysfunction in a group of rhesus monkeys (Macaca mulatta). The polychlorinated biphenyls were found by gas chromatographic analysis in high amounts in the superficial layers of concrete slab floors in the housing facility. The concrete sealant was suspected as the original source although it is not known whether it contained polychlorinated biphenyls before it was applied or if it was contaminated later. Histopathologic findings for the most part were confined to epithelial tissues where squamous metaplasia of several glandular tissues was observed. A striking finding was severe hypertrophy of the glandular stomach and a similar but less severe lesion in the colon. The lesions may be related in part to impaired vitamin A metabolism, but not to a dietary deficiency.


Diagnosis of the mucopolysaccharidoses using cultured skin fibroblasts and amniotic fluid cells. Assay of alpha-L-iduronidase, heparin sulphamidase, N-acetyl-alpha-D-glucosaminidase, arylsulphatase B, alpha-L-fucosidase, beta-glucuronidase, beta-galactosidase and alpha-D-mannosidase in cultured cells is described. Activities in deficient fibroblast strains are compared to control fibroblast strains. The first case of Sanfilippo B in the United Kingdom is reported. A comparison of enzyme activities in cultured fibroblasts and amniotic fluid cells is made.


Phenylketonuria in Indian children.

Phenylketonuria in Indian children. Three untreated phenylketonuric Indian children aged respectively 3 1/2 years, 1 1/2 years and 1 year showed rapid neurological deterioration. Plasma, cerebrospinal fluid and urine phenylalanine concentrations were significantly raised and the phenylalanine-tyrosine ratio was high. Analysis of a biopsy of the right frontal lobe of the brain in one case showed the myeline lipids--cerebroside and sulphatide--to be decreased. The total cerebroside in white matter was low. Light microscopy showed marked pallor of the white matter of the brain and extensive spongy degeneration. Ultrastructurally these spongy vesicles are located between the lamellae of the myelin sheath.


Osteogenesis imperfecta: evidence for the existence of an abnormal amino acid sequence in the molecule of dermal collagen. A collagen-type pattern of peptide and amino acid spots was obtained when partial hydrolysates of normal human dermis were examined by a specially developed thin-layer chromatographic (TLC) 'finger-printing' technique. The pattern was consistent and independent of age and sex. Two clinically similar cases of osteogenesis imperfecta congenita gave identical patterns which differed in specific regions from those given by their age-matched, normal controls. A single case of osteogenesis imperfecta tarda showed the same overall pattern as the congenita cases. It is concluded that an abnormal amino acid sequence occurs in the collagen molecule of both types of osteogenesis imperfecta.


Biochemical and clinical studies of a new case of alpha-aminoadipic aciduria. A mentally retarded, 10-year-old female with obesity, hypotonia, clumsiness and mild ocular abnormalities excreted in her urine large amounts of alpha-aminoadipic acid. Amino acid analyser studies and gas-liquid chromatography--mass spectrometry (GC--MS) confirmed the presence of alpha-aminoadipic acid in both urine and plasma but, in contrast to most other patients with this disorder, failed to demonstrate significant levels of alpha-ketoadipic acid in urine. Other known causes of alpha-aminoadipic aciduria were eliminated by showing that levels of lysine, saccharopine and pipecolic acid in plasma and urine were normal and that the activity of glutaryl-CoA dehydrogenase was also normal. Loading with L-lysine and L-tryptophan both increased the concentration of alpha-aminoadipic acid in blood and urine compatible with the primary deficiency of alpha-ketoadipate dehydrogenase, in spite of the absence of alpha-ketoadipic aciduria. Dietary restriction of lysine and administration of vitamins B1 and B6 were unsuccessful in correcting the biochemical abnormality.


Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome. A male boy is described, who suffered from an intractable diarrhoea and several infections and who died in a severe marasmic state at the age of 8 months. Immunological studies revealed a block in the normal differentiation of B cells to Ig-producing plasma cells. After the age of 5 months, however, this block disappeared, leading to a dramatic increase in circulating Ig, most pronounced in the IgM class. In the intestine, plasma cells could only be detected after the age of 5 months, and then with a marked preponderance of IgM cells. Our results thus indicate a reversible block in the normal maturation of B cells in our patient. An older brother may have had a similar disease, suggesting a possible genetic basis for the disorder.


Biochemical studies of a human low-activity galactose-1-phosphate uridyl transferase variant. A low activity galactose-1-phosphate uridyl transferase (transferase) variant in a newborn infant has been demonstrated by biochemical studies in erythrocytes and cultured skin fibroblasts. The newborn infant was a galactosaemic suspect identified in a neonatal metabolic screening programme. On breast feeding, he did well without clinical symptoms of galactosaemia during the first 15 days of life. However, substantial amounts of erythrocyte galactose-1-phosphate and urinary galactitol corresponding to the levels in untreated galactosaemic patients, along with mild amino aciduria, were found. The transferase activity, as measured by a sensitive micro kinetic radioisotopic method, was about 7--10% of the normal. On starch gel electrophoresis, the enzyme from the haemolysate had similar mobility as the normal in Tris--glycine buffer, pH 8.8 and phosphate buffer, pH 7.0, but had a slower mobility than that of the normal in the histidine buffer, pH 7.8. The mobility difference was much clearer in a semipurified enzyme preparation. The transferase enzyme in the haemolysate appeared to be more heat labile.


Secondary metabolic changes in fibroblasts from six patients with hereditary lactic acidosis. Studies on fibroblasts from patients with lactic acidosis of different causes showed secondary metabolic changes in pathways of glucose metabolism. These secondary changes may be important clues to the diagnosis of the many different types of hereditary lactic acidosis.


Fructose load test--an in vivo screening test designed to assess pyruvate dehydrogenase activity and interconversion. An in vivo screening test is described, which is designed to assess the activity and interconversion of the human pyruvate dehydrogenase complex. Oral fructose was administered to six healthy subjects following (a) an overnight fast and (b) an oral glucose load. The rise in blood pyruvate and lactate levels following fructose was almost twice as great in the fasted state compared to the fed (post-glucose) state. It is proposed that this difference is due to the conversion of pyruvate dehydrogenase to its active form, following feeding.


Prenatal and postnatal diagnostic difficulties in a family with rare alleles of the galactose-1-phosphate uridyl transferase locus. Whole-blood galactose-1-phosphate uridyl transferase (Gal-PUT) (EC 2.7.7.12) activity was absent in a newborn boy with galactosaemic symptoms. The symptoms disappeared on a galactose free diet. In the next pregnancy prenatal diagnosis was performed. Gal-PUT activity was measured by isotope technique and Gal-PUT genotype was determined by gel electrophoresis. The mother was shown to be heterozygous Duarte/heterozygous Los Angeles, the father heterozygous Duarte/heterozygous galactosaemia. The fetus had the same genotype as the father. A normal girl without galactosaemic symptoms was born. Reinvestigation of the index case showed that he was also heterozygous Duarte/heterozygous galactosaemia. It is concluded that the activity of Gal-PUT should always be measured by isotope technique to prove the diagnosis of heteditary galactosaemia. Furthermore, Gal-PUT-genotyping in families with rare alleles is essential for safe prenatal diagnosis.


Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport? A child is described who presented in the neonatal period with feeding difficulties, severe neurological abnormalities, lens dislocation of the eyes and dysmorphic symptoms of the head. Routine laboratory investigations revealed a decreased serum urate and a positive sulphite reaction of the urine. Subsequent chromatographic examinations showed xanthinuria and increased excretion of S-sulphocysteine and taurine to be present. In addition, high thiosulphate and low sulphate excretions in the urine were observed. Xanthine oxidase deficiency was demonstrated in a jejunal biopsy specimen, whereas the excretion of sulphur containing substances was considered to be characteristic of sulphite oxidase deficiency. This new combination of defects may be the result of malfunctioning of both enzymes, possibly caused by alterations in the essential molybdenum containing active centre of the enzymes, which they share in common.


Metabolic inhibitors of host-tissue origin in Mycobacterium leprae. It is not clear why host-derived bacteria are metabolically inert, compared to organisms grown in vitro. o-Diphenoloxidase is the only metabolic property proven to be present in Mycobacterium leprae separated from infected human as well as animal (mouse and armadillo) tissues. However, highly concentrated suspensions of M. leprae obtained from the organs of experimentally infected armadillos showed little or extremely low o-diphenoloxidase, while the organisms bound 14C-labeled dopa. When these preparations were diluted, they readily oxidized D-dopa to pigment. The activity remained unaltered by washing the suspensions with dilute alkali or acetone and ether, indicating that it is an intrinsic property of the bacilli. Treatment with different proteases relieved the inhibition, and resulted in a 100% stimulation of O-diphenoloxidase in the bacilli. Evidently, the M. leprae suspensions obtained from infected tissues contain an inhibitory material which is protein in nature, and the metabolic inertness sometimes observed in host-grown bacteria may not be due to loss of enzymes or metabolites from the organisms.


Superstructures of wet inactive chromatin and the chromosome surface. Superpacking of chromatin and the surface features of metaphase chromosomes have been studied by SiO replication of wet, unstained, and unfixed specimens in an exceedingly thin (less than or equal to nm) aqueous layer, keeping them wet. Hydrophilic Formvar substrates allow controlled thinning of the aqueous layer covering the wet specimens. Whole mounts of chromatin and chromosomes were prepared by applying a microsurface spreading method to swollen nuclei and mitotic cells at metaphase. The highest level of nucleosome folding of the inactive chromatin in chicken erythrocytes and rat liver nuclei is basically a second-order superhelical organization (width 150--200 nm, pitch distance 50--150 nm) of the elementary nucleosome filament. In unfavorable environments (as determined by ionic agents, fixative, and dehydrating agetns) this superstructure collapses into chains of superbeads and beads. Formalin (10%) apparently attacks at discrete sites of chromatin, which are then separated into superbeads. The latter consist of 4--6 nucleosomes and seemingly correspond to successive turns of an original solenoidal coil (width 30--35 nm), which forms the superhilical organization. When this organization is unfolded, eg, in 1--2 mM EDTA, DNAse-sensitive filaments (diameter 1.7 nm) are seen to be wrapped around the nucleosomes. The wet chromosomes in each metaphase spread are held to each other by smooth microtubular fibers, 20--20 nm in diameter. Before they enter into a chromsome, these fibers branch into 9--13 protofilaments, each 5 nm wide. The chromosome surface contains a dense distribution of subunits about 10--25 nm in diameter. This size distribution corresponds to that of nucleosomes and their superbeads. Distinct from this beaded chromosome surface are several smooth, 23--30-nm-diameter fibers, which are longitudinal at the centromere and seem to continue into the chromatid structure. The surface replicas of dried chromosomes do not show these features, which are revealed only in wet chromosomes.


RNA synthesis during spore germination in Bacillus subtilis. We have analyzed the RNA synthesized during spore germination in Bacillus subtilis. Early in germination there is little incorporation of [3H]uridine into RNA. A large increase in incorporation into RNA was found at 45--60 min into germination which was in part due to increases in the specific activity of the UTP pool. When corrected for specific activity changes, the instantaneous rate of RNA synthesis showed a seven to tenfold increase between 30 and 45 min of germination. Polyacrylamide gel electrophoresis studies showed that the RNA synthesized during germination appeared very similar to the RNA made during vegetative growth. DNA-RNA hybridization studies indicated that mRNA and rRNA were synthesized throughout germination. Their relative proportions remained constant and were very similar to the composition of RNA synthesized during vegetative growth.


Restriction of plasmid-mediated transformation in Bacillus subtilis 168. When plasmids carrying leucine genes of Bacillus subtilis 168 were isolated from a restriction and modification deficient (r-m-) strain and used for transformation of a restricting strain B. subtilis 168 leu recE4, the number of transformants was greatly reduced. Transformation of rec+ strain (transformation by integration of the donor DNA into the chromosome) with the plasmids was not affected irrespective of whether the recipient carried the r+ or r- phenotype. These results show that the plasmid-mediated transformation is subject to the host controlled restriction and suggest that r-m- strains should be used for construction of recombinant DNA molecules in B. subtilis 168.


Induction of bacteriolytic enzyme from pyocinogenic Pseudomonas aeruginosa and its enzymatic properties. Mitomycin C induced a pyocinogenic Pseudomonas aeruginosa P15 to produce a bacteriolytic enzyme, PR1-lysozyme, together with pyocin R1. No significant accumulation of the enzyme was observed inside the induced cells. The enzyme was partially purified by acrinol treatment and Amberlie CG-50 column chromatography. The mode of action of the enzyme on the host bacterial cells as well as on Micrococcus lysodeikticus cells or peptidoglycan isolated from Salmonella typhimurium, was compared with that of hen egg-white lysozyme or phage lambda-lysozyme. It is suggested that PR1-lysozyme should be classified as a glycosidase, rather than an amidase or an endopeptidase.


Glycosyltransferases of Streptococcus mutans strain Ingbritt. The glycosyltransferases of S. mutans strain Ingbritt have been resolved by SDS-polyacrylamide gel electrophoresis, followed by incubation in the presence of non-ionic detergent to restore enzyme activity. A group of high molecular weight proteins synthesizing glucans has been identified, as well as three distinct fructan-synthesizing activities. The glucan-forming enzymes have been purified by affinity chromatography on insoluble glucan, followed by gel chromatography in SDS, and antiserum to the purified enzymes has shown that they are antigenically identical within serotypes c, e and f, and cross-react strongly with serotype b.


Nitrogenase activity of Rhizobium sp. strains in pure culture in relation to extracellular polysaccharide composition and antigenic affinity. Five strains of slow-growing Rhizobium sp. (strains CB756, 32HI, CB562, CB627 and QA549) out of seventy examined developed appreciable nitrogenase activity in pure culture. CB756 and 32HI were serologically indistinguishable and each produced 6-deoxy-L-talose as a major component of its extracellular polysaccharide. They did not share these properties with CB562, CB627 or QA549.


The rubro-olivo-cerebellar teaching circuit. The hypothesis proposes a neural teaching circuit, and invokes the parvocellular Red Nucleus as the key nucleus in that circuit acting on the inferior olivary nucleus to maintain the efficiency of motor learning in primates, while acknowledging the inferior olive to be the key nucleus by which learning instructions go to Purkinje cells in the cerebellar cortex. Anatomical, physiological and pathological data is reviewed in an attempt to attribute a function to the evasive parvocellular Red Nucleus.


Is the selenium drinking water standard justified? Four cases are presented which suggest that the present U.S.E.P.A. drinking water standard for selenium of 10 micrograms/L in inappropriate. The rationale upon which this standard is based is that selenium is carcinogenic, induces dental caries formation, and is highly toxic to animals. However, a critical assessment of this literature can not support these claims. Case no. 1 demonstrates that there is insufficient evidence to classify selenium as a carcinogen. Data derived from the three respective groups of researchers claiming a carcinogenic effect induced by selenium are obscure due to 1) the inability to accurately identify malignancies, 2) the apparent opposite effects of different selenium compounds, and 3) the lack of proper controls. Case no. 2 reviews recent evidence that selenium reduces the incidence of cancer in laboratory animals and in man, an effect which can probably be attributed to the antioxidant properties of selenium compounds. Case no. 3 provides evidence which does not permit the classification of selenium as a cariogenic element. Epidemiological studies supporting such a claim are inadequate since they lack properly matched control groups. Animal data do not support this link as well. Case no. 4 is a review of studies which clearly demonstrate the essentiality of selenium, an aspect of selenium metabolism that was not considered when the 10 micrograms/L standard was promulgated. In light of the four cases presented and an assessment of selenium toxicity in man, it is concluded that the 10 micrograms/L standard can not be justified. Instead, it is suggested that 50 micrograms/L selenium should provide sufficient protection from the toxic effects of this element. This is consistent with the current state of knowledge with respect to the potential adverse health effects associated with selenium.


Oropharyngeal microflora in Aboriginal and non-Aboriginal Australian children. An indicator of environmental contamination. Faecal microorganisms, not normally resident in the oropharynx, were isolated much more often from Aboriginal than non-Aboriginal Australian children. This is almost certainly due to differences in standards of hygiene and living in these two groups, and is an important factor in contributing to the common and serious problem of gastrointestinal infections in young Aborigines. In the non-Aboriginal group, the isolations of faecal organisms were much more common from infants and from children under the age of two years when compared with older children; this is probably due to the readiness of spreading microorganisms from the gastrointestinal tract to the mouth in the younger children.


Adaptation of thymidine utilization to changing rates of DNA synthesis in the cell cycle. In synchronous cultures of P-815 murine mastocytoma and of Chinese hamster ovary (CHO) cells, the relative contribution of exogenous thymidine to DNA synthesis was studied by comparing rates of (3H)thymidine incorporation with the rate of DNA synthesis as derived from incorporation of (3H)thymidine (10(-5) M) in the presence of amethopterin. In synchronous P-815 cultures, time-dependent variations of DNA synthesis rates were in close agreement with those of (3H)thymidine incorporation rates at concentrations of the precursor ranging from 5 x 10(-8) to 10(-5) M. Similarly, in synchronous CHO cell cultures prepared by two different methods, time-dependent changes in DNA synthesis rate were almost identical with those of the rate of incorporation of (3H)thymidine supplied at 5 x 10(-8) M. Thus, at a given thymidine concentration in the medium, the proportion of thymine residues in DNA that were derived from exogenous thymidine remained nearly constant, even though rates of cellular DNA synthesis underwent pronounced changes. This indicates that in the synchronous culture systems used, utilization of exogenous thymidine is efficiently adapted to changing rates of DNA synthesis.


[Options in dietary treatment by oral and parenteral balanced nutrition (author's transl)]. Balanced nutrition is an important tool in the treatment of several pediatric disorders. Its application is based on the knowledge of normal metabolism and of the pathophysiology in metabolic disorders. The principles of oral balanced dietary treatment are discussed in relation to phenylketonuria and renal insufficiency. In case of unability to ingest foods by the oral-enteral route parenteral nutrition becomes necessary. The indications, principles and hazards of parenteral nutrition are discussed, especially the type of amino acid solution required. It is pointed out that xylit and sorbitol containing solutions should be abandoned completely since there are no indications for its use but potential hazards by toxic side effects.


[Schimmelpenning-Feuerstein-Mims-syndrome (author's transl)]. The clinical picture of the Schimmelpenning-Feuerstein-Mims (or nevus sebaceus linearis) syndrome is described. The syndrome especially its excessive formes, is a relatively rare, but typical biotype of the neuroectodermal phakomatosis disorders. Symptomes are multiple widespread linear sebaceus nevi, seizures and mental retardation, ECG anomalies and ocular dysplasia and dystrophia, which can cause blindness.


[Artherogenesis. Experimental investigations on the pathogenesis of obliterating arteriopathies in mini-pigs (author's transl)]. The principal objective of our experiments was to obtain information on the initial processes involved in the pathogenesis of obliterating arteriopathies or arteriosclerosis. We thereby concentrate on the formal pathogenesis, which we intend to elucidate by discussing the basic data and with preliminary radioimmunoassay examinations using angiopathy-models on the mini-pig. Very early in artherogenesis, an adhesion of thrombocytes in viscous metamorphose to the apparently intact arterial walls is always detectable and is followed by the formation of an intima-plaque.


[Take-off and landing--stresses for the pilot (author's transl)]. Methodologically it is possible to assess roughly the intensity of strains due to flying stress by means of measuring the pilot's various individually very different stress reactions. Take-off and especially landing are stresses for the pilot. They differ according to the operational and other accompanying circumstances, the quality of the pilot's training and the flight pattern. If the stress exceeds the individual capacities considerably, a disproportion may arise known in aeronautics as "pilot's error". The stresses described can be effectively reduced by a close cooperation of technicians and physicians.


[Legionaire's disease (author's transl)]. In a review of all cases of legionaire's disease known so far the epidemiology, diagnosis and therapy of this disease are discussed. Risk factors have been shown to be stays in hotels and hospitals, especially if the rooms were subject to faulty air conditioning, water containers or to earthworks. Furthermore, the male sex and an immunosuppressive therapy were established as risk factors. The diagnosis can only be confirmed by increased titer in the indirect fluorescence test. Erythromycin and Rifampicin (as a supplementary medication) have proved the antibiotics of choice.


[The diagnosis of visceral leishmaniasis (carried in) (author's transl)]. Five cases of Kala-Azar carried in from the Mediterranean area between May 1977 and March 1979 suggest that in this age of mass tourism these diseases, considered by us as rarities until now, may become more common. In all cases considerable difficulties in diagnosis were first encountered. Serology was always indicative, the indirect fluorescence antibody test (IFAT) being found very reliable. In 4 of the 5 cases the identity of the pathogen was previously established by different methods.


[Epidemiology of hospital-acquired urinary tract infections (author's transl)]. Among hospital-acquired infections, urinary tract infections are the widest spread. The most common pathogenic agents are E. coli, Enterococci and Proteus mirabilis. Indwelling bladder catheters account for about 70% of infections. Suprapubic urine drainage can reduce the incidence of urinary tract infections by approximatively 50%.


[Hospital acquired urinary tract infection (author's transl)]. To explain hospital acquired urinary tract infections in a Urological Clinic, 3691 case histories were evaluated. About 15% of iatrogenic infections were found, among them 7% bacteremias and 0.9% of cases with urosepsis. Autoinfection and intermittent infections should be differentiated. The iatrogenic infection can be prevented by avoiding certain diagnostic and operative interventions, observation of asepsis and exact indication, the autoinfection and intermittend infection by shortening the period of hospitalization. The observed different risk of infection of individual organ systems had its origin, not in a low defense potency but in the operative technique used.


[Concentrations of cefradine in renal tissue (author's transl)]. After a single bolus injection of two grams of cefradine the concentrations of antibiotic in serum and renal tissues of 21 patients were estimated. After 30 minutes the mean serum concentrations were 159 microgram/ml, after 60 mins 62 microgram/ml and after 95 mins 22 microgram/ml. The tissue concentrations in normal renal tissue (group I) after 30 minutes were 348 microgram/ml and with tissue of chronically inflamed kidneys (group II) 118 microgram/ml in the same period. After 90 minutes the concentrations of group I were 214 microgram/g, and in group II 28 microgram/g, e.g. 8 times lower. The estimated cefradine concentrations in serum and in normal and impaired renal tissue within the time interval of 10 to 90 minutes are above the minimal inhibition concentrations for most cefradine sensitive pathogens.


[Urinary tract infections. Therapeutic failures and course monitoring (author's transl)]. The proportion of reinfections and relapses in urinary tract infections amounts to about 35-70%. Hydrokinetic conditions (e.g. size of bladder, frequency of micturition, rate of multiplication of the pathogens, adhesiveness of bacteria) not seldom lead to a discrepancy between the in vivo response of the pathogen to the chemotherapeutic agent and the corresponding MIC determined in vitro. Ten causes for the therapeutic failure are discussed in greater detail. Monitoring the course in good time with due regard to the risks is essential. A scheme for microbiological monitoring investigations before beginning therapy, during treatment and after discontinuing the medicament, as well as for long term therapy is suggested.


[The development of transfusion medicine (author's transl)]. The development of transfusion medicine started from the attempts to transfuse blood in animals in the 17th century and the first fruits were seen in the second half of the 19th century. About 1800, however, Blundell introduced a new development which brought fundamental changes with the elucidation of the problems of defibrination, the phenomenon of hemolysis and coagulation. At the beginning of the 20th century the serological problems were solved by Landsteiner's discoveries. The introduction of anticoagulation permitted the conservation of blood and led to the discontinuation of direct blood transfusion in favour of indirect transfusion of conserved blood. This considerably enlarged the functions and possibilites of transfusion medicine which opened into the development of blood component therapy with its opportunities for optimal care of the patients.


[Ileovesical fistula in Crohn's disease (author's transl)]. Ileovesical fistulae are rare in Crohn's disease and may occur at any age and any stage of the disease. Typical diagnostic pointers are pneumaturia and fecaluria. Cystoscopy and the cystogram are important pointers to the diagnosis. Resection of the intestine and partial resection of the urinary bladder is the treatment of choice and leads to healing, as is demonstrated in the discussion of a case.


[Epidemiology of Hospital-acquired infections in surgery (author's transl)]. The incidence of hospital-acquired infections in surgery fluctuates between 1.5 and 29%, the average infection is 5%. The most frequent hospital infections are: urinary tract infections, wound infections, respiratory tract infections, sepsis and infections of the skin. Escherichia coli and Staphylococcus aureus are most commonly isolated from the nosocomial infections. Hospital infections in surgery are of endogenous origin, i.e. from the organisms of the body itself (e. g. wound infections after intestinal interventions) or exogenous from direct or indrect contact. The most frequent route of transmission is by hands. Almost half of all hospital-acquired infections have their origin in surgery. Standards of prevention of hospital-acquired infections in surgery departments are described.


[Clinical experience with acute mesenteric vascular occlusion (author's transl)]. Between 1964 and 1978 twenty patients suffering from acute mesenteric vascular occlusion were treated in the surgical department (University of Münster). The average duration of the anamnesis until their hospitalization was 3.1 days and the actual operation was performed 11.35 hours later on the average. In only 15% of the cases had a correct preoperative diagnosis been given. As regards the frequency of causation, 60% of the mesenteric vascular occlusions were caused by a mesenteric arterioembolism, 20% by a mesenteric venous embolism, 10% by a mesenteric arterial thrombosis and 10% by a non-obstructive occlusion. In a post cardiac infarction condition was the predisposing factor in 50% of all cases, valvular defect in 33.5% and tachyarrhythmia in 16.6%. The causes found for the mesenteric venous tbrombosis were insufficiency of the right heart, absolute bradyarrhythmia, recurrent venous thrombosis of the leg, and myeloproliferative syndromes.


[Complement: function. Biological significance and clinical aspects (author's transl)]. The term complement comprises approximately twenty serum proteins. Activation of these components can be started by antigen-antibody complexes or even without the participation of antibodies. The activated complement proteins bring about a number of important biological actions. They produce vigorous local inflammatory reactions, exert phagocytosis--increase effects, destroy microbial and animal cells and affect the immune response to antigen stimulus. Congenital lack of individual complement components may considerably impair the antimicrobial defense or even be the cause of excessive inflammatory reactions. The activation of complement may also have harmful effects on the organism.


[Diagnostic significance of cholinesterase determination in human serum (author's transl)]. The differential diagnostic importance of CHE determination in searching for and observing the course of liver diseases is emphasized in the literature within the small and large enzyme pattern (eg. Gergs 1976). In chronic hepatitis and cirrhosis normal or almost normal values suggest a favorable prognosis. Greatly reduced CHE points to limitation of liver function and a severe form of the disease suggesting toxic influences and considerable deficiency. Rapidly falling CHE activity both in acute hepatitis and in chronic inflammations of the liver point to the danger of threatening hepatic coma.


[Diagnosis and differential diagnosis of acute hepatic prophyrias (author's transl)]. Diagnosis of porphyria is a clinical and biochemical procedure. Acute hepatic porphyrias are molecular regulation diseases which are characterized by a relative enzyme deficiency of the ferro-chelatase chain and an induction of hepatic delta-aminoacid synthase. There are indistinct clinical and pathobiochemical transitions between the three acute hepatic types of porphyria: acute intermittent porphyria, hereditary coproporphyria and porphyria variegata. They develop a similar acute clinical syndrome. The differential diagnosis is made possible by a differentiation of porphyrins and porphyrin precursers in the urine and the porphyrines in the stool and by the determination of uroporphyrinogen synthase activity in the erythrocytes.


[Citrate concentration in samples for physiological coagulation investigations (author's transl)]. Citrate determination in coagulation blood samples sometimes end considerable deviations from the prescribed end concentration. Only a part of these samples can be recognized in the laboratory by simple inspection, in the undiscovered cases faulty results must be reckoned with. The citrate end concentration is more reproducible under routine conditions when a special sampling apparatus (Citrate-Monocuvette) is used.