Double-blind comparison between two new topical corticosteroids, halcinonide 0.1% and clobetasol propionate cream 0.05%. A new steroid, halcinonide, was compared with clobetasol propionate cream in 100 patients with a variety of skin disorders. The study was conducted as a double-blind, paired comparison with the preparations being given twice daily. Results obtained over a 14-day period of therapy showed remarkably similar efficacy for both preparations.


Nucleic acids: interaction with solar UV radiation. Atmospheric pollutants that reduce the amount of ozone in the stratosphere may markedly increase the flux of intermediate-wavelength solar ultraviolet (UV) radiation that reaches the Earth's surface. Like short-wavelength germicidal UV radiation (less than 280 nm), these intermediate UV wavelengths (280-315 nm) can promote photochemical reactions in nucleic acids, leading to the appearance of such products as cyclobutadipyrimidines and single- and double-strand breaks. These photochemical reactions strongly affect the biological activities of the nucleic acids. Computer techniques are now available for predicting the chemical and biological effects of increased in vitro irradiation of purified nucleic acids. However, the effect of increased UV irradiation in vivo is complicated by the presence of sensitizing agents in cells and by the action of nucleic acid repair processes. There is strong evidence that in vivo damage to nucleic acids injures irradiated cells and tissues, but further research is needed to predict quantitatively the physiological consequences of increases in solar UV.


Combined topical pulmonary and systemic gentamicin: The question of safety. Serum levels were measured in 13 subjects who received gentamicin either by inspiratory intermittent positive pressure breathing (IPPB-I) or by tracheal instillation. Only in the latter group were significant serum levels achieved. It is recommended that systemic doses of gentamicin should be reduced and serum levels closely monitored in order to avoid toxicity when the usual 3 to 5 mg/kg of IM or IV gentamicin is conbined with tracheal instillation.


Double-blind comparison of acute bronchial and cardiovascular effects of oral terbutaline and ephedrine. Acute effects of oral terbutaline (5 mg), ephedrine (25 mg) and placebo on bronchial dynamics, heart rate, systolic and diastolic pressure and arterial blood gases at rest were compared over a period of 7 hours in 20 subjects with bronchial asthma using a double-blind crossover technique. Both terbutaline and ephedrine caused significant bronchodilation, but the effect of terbutaline on specific airway conductance (SGA) was significantly greater (peak mean increase in SGA 0.069 vs 0.027 L/sec/cm H2O/L), had an earlier onset (30 minutes vs 1 hour) and lasted longer (7 hours vs 4 hours) than that of ephedrine. Slight but significant increases in arterial Po2 were noted following institution of both ephedrine and terbutaline, suggesting improvement in ventilation-perfusion relationships. Both drugs caused modest but statistically significant increases in heart rate of 8.4-10.9 beats/min and the mean peak increase following terbutaline (8.4 beats/min) was comparable to that following ephedrine. In constrast to ephedrine, terbutaline caused significant, although slight, increases in systolic pressure and decreases in diastolic pressure, indicating that this drug, in the dose recommended for clinical use, is not free of cardiovascular effects.


A computer program for calculation and interpretation of pulmonary function studies. A computer program to calculate and interpret the standard pulmonary function tests has been developed on a programmable calculator system. The program computes both predicted and measured values for static and dynamic lung volumes, airways resistance and diffusing capacity. It then checks for differences between predicted and obtained values and interprets them according to a specific, clinically useful set of diagnostic criteria. By acquisition of a reliable and easy-to-use data processing system, a pulmonary function laboratory can significantly increase the efficiency and accuracy of its day-to-day work.


In vivo comparison of two galenic forms of ampicillin-trihydrate. In order to evaluate a new galenic form of ampicillin-trihydrate, individual blood serum levels and urine excretion of ampicillin-trihydrate were compared in a crossover study after oral absorption of 1-gram captab formulation (this being the new galenic form) versus 2x500 mg of the same product. Analyses performed by two different laboratories indicate that clinically insignificant slightly higher serum concentrations can be obtained with captabs, and that very individual absorption profiles should make one take a sceptic viewpoint as to mean serum concentrations computed from larger series of experiments. To obtain a valid blood serum level in as many patients as possible, a posology of 3-4 captabs, spaced over a 24-hour period is suggested for the treatment of infections with ampicillin-sensitive germs. For less sensitive micro-organisms, one should switch to parenteral therapy or to other antibiotics.


Comparative pharmacokinetics and clinical experience with a new cephalosporin-derivative: cefazolin. In a cross-over study in 12 normal individuals, the pharmacokinetic parameters of cefalotin, cefradine and cefazolin were determined after intravenous injection of 1,000 mg of each substance. The microbiological activities in urine and serum were determined using the agar diffusion test; the pharmacokinetic data were calculated by a computer system on the basis of a Fortran programme. Cefazolin has significantly higher serum concentrations than the other two cephalosporins, distinctly longer serum half-lives, higher protein binding, and smaller apparent volumina of distribution. In 36 inpatients with mainly chronical and acute infections of the urinary tract, we tested the antibacterial effectivity, the compatibility, and the application modalities of cefazolin. In 29 patients we had a satisfactory clinical result, in 25 cases we achieved the elimination of bacteria by the end of the therapy. The compatibility of cefazolin was good; apart from a minor, reversible, liver-specific increase in enzymes in 6 patients, no side effects could be detected.


R factor in Enterobacter cloacae resistant to silver sulfadiazine. A strain of Enterobacter cloacae resistant to silver sulfadiazine was recovered from a unit in which this antimicrobial agent was in use. This strain was found to harbor an R factor responsible for resistance to carbenicillin, kanamycin and ampicillin. These antibiotic resistances were transferable to Escherichia coli by mating. Resistance to silver sulfadiazine was not, however, transmissible.


Comparative in vitro acitvity of chloramphenicol and thiamphenicol on common aerobic and anaerobic gram-negative bacilli(Salmonella and Shigella excluded). The antibacterial activity of thiamphenicol was compared to that of chloramphenicol against 313 strains of gram-negative bacilli isolated from various clinical specimens. These two antiboitics were equally active against the 106 isolates of Haemophilus MIC equals 0.1 minus 1.56 mu g/ml) and against 40 strains of Bacteroides fragilis (almost all strains being inhibited by 12.5 mug/ml of the two drugs). In contrast, when compared with chloramphenicol, 2-16 times as much of thiamphenicol was required to inhibit Enterobacteriacae, making prediction of the susceptibility of these strains to thiamphenicol on the basis of chloramphenicol testing alone likely to be hazardous. Disc diffusion test using 30-mug discs and 12 mm as cut-off point was a reliable technique to determine susceptibility of bacteria either to chloramphenicol or thiamphenicol. When thiamphenicol discs of greater potency (50 mug) were employed, many strains exhibited wide zones of inhibition although most of them were resistant by the agar dilution method (MIC is greater than 12.5 mug/ml). This practice is not advisable for testing organisms isolated outside of the urinary tract.


Evaluation of antibacterial activities of cephalosporin antibiotics: cefazolin, cephaloridine, cephalothin, and cephalexin. The antibacterial activities of 4 cephalosporin antibiotics, cefazolin, cephaloridine, cephalothin and cephalexin, against 330 isolates of bacteria from patients at National Taiwan University Hospital, were determined by an agar plate dilution technique. Cephalosporins possess strong antibacterial activity against gram-positive bacteria except Enterococci. Staphylococcus aureus is the most susceptible among the organisms tested. More than 90% of Staphylococcus aureus strains are suppressed by cefazolin, cephaloridine and cephalothin at the concentrations of 3.13 mug/ml or less, except that 49.1% are suppressed by cephalexin. The relative potency of cephalosporins against Staphylococcus aureus in decreasing order is cephaloridine, cephalothin, cefazolin, and cephalexin. The gram-negative bacilli, Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis are less susceptible to cephalosporins than the gram-positive cocci. Among the cephalosporins, cefazolin is the most active against the gram-negative pathogens tested. The relative potency of antibacterial activity of cephalosporins against E. coli in decreasing order is cefazolin, cephaloridine, cephalexin, and cephalothin. One hour after the intramuscular injection of 500 mg of cefazolin, the maximum concentration of 33.3 mug/ml is reached in the serum. The sufficient high levels are sustained for 8 hours. Very high concentrations of cefazolin are also found in the urine.


Shigella strains associated with infantile diarrhea in the Kaohsiung area. In 1969 and 1974, 375 Shigella strains were isolated in the Kaohsiung area, and their serotypes and in vitro susceptibility to antimicorbial agents were studied. In 1969, 249 (16.2%) strains were isolated from 1,476 specimens collected from infantile and young children dirrheal cases, whereas 126 strains (11.6%) were isolated from 1,086 specimens in 1969. The isolation rates were higher in May (21.2%), October (20.8%), April (20.6%), August (19.7), November (18.8%) and January (18.5%), than in other months (10.2%-18.0%). Higher incidences of shigellosis appeared in May (22.3%) and April (17.9%) than in the other months during 1974. Shigella sonnei and Shigella flexneri type 2 were most predominant and there was a tendency of increase in number for the former in 1974. From the colicine typing of S. sonnei, it was found that type 8 (40.6%), type 6 (23.4%), and type 12 (17.2%) were the commonly occurring strains associated with the infantile diarrheal disease in the Kaohsiung area. Susceptibility study showed that the resistant rates of S. flexneri to chlroamphenicol (85.5%), streptomycin (81.9%), and tetracycline (61.3%) were much higher than to ampicillin (16.1%), nalidixic acid (14.6%), colistin (4.2%), kanamycin (4.2%), gentamicin (2.8%), cephaloridine (2.4%), and frazolidone (0%). Resistant rates of S. sonnei to 10 antimicrobial agents were as follows: chloramphenicol, 85.9%; tetracycline, 70.2%; streptomycin, 69.9%; nalidixic acid, 16.4%; ampicillin, 13.3%; colistin, 6.3%; kanamycin, 3.9%; gentamicin, 2.5%; cephaloridine, 0%; and frazolidone, 0%.


Non-random chromosome distribution in radial metaphases from the chinese hamster. I. Uncultured cells. Chromosome distribution was analyzed in uncultured radial metaphase cells (corneal epithelium, testicular mitotic cells, cells in the diakinesis, and cells in metaphase II) from the Chinese hamster. The hypothesis of random distribution was rejected at the 0.001 level (chi 2/3 = 31.6).--Homologous association was observed for two pairs of chromosomes (3 and 10) in corneal epithelial cells. It was observed for all four cell types. The chromosomes associated in four groups of similarly sized and shaped chromosomes. While group membership did not appear to vary, position within the group was highly variable.--An elevenpoint model of chromosome relationships was constructed from the data.


Chromomere number and its genetic significance in lampbrush chromosomes. The chromosomes of three species of salamander belonging to the genus Plethodon have been studied with regard to the absolute length of the haploid set of lampbrush chromosomes and the number and distribution of chromomeres per laploid set of lampbrush chromosomes. Each aspect has been considered in relation to the substantial difference in genome size between P. cinereus (C = 20 pg), P. vehiculum (C = 36.8 pg) and P. dunni (C = 38.8 pg). --Karyotype analyses carried out on unfixed preparations of lampbrush chromosomes showed that the absolute length of a haploid complement of lampbrush chromosomes from medium-sized yolky oocytes is much greater for P. vehiculum and P. dunni than for P. cinereus. Nonetheless, the relative dimensions of chromosomes are nearly identical in all three species. --Chromomers were counted along the whole length of the 14th (shortest) bivalent, and the total number of chromomeres in the haploid set of lampbrush chromosomes was determined by extrapolation on the basis of the known relative length of the 14th bivalent in the respective species. Chromomeres were also counted in measured segments of undamaged lampbrush preprations in which all chromosomes could be clearly identified. The average distance between chromomeres (chromomere distribution) was determined and the total chromomere number was estimated on the basis of measured total length of lampbrush chromosomes in a preparation. Chromomere distribution is the same for lampbrush chromosomes from all 3 species, and since P. vehiculum and P. dunni have longer chromosomes than P. cinereus, it is clear that the former 2 species have many more chromomeres (60-70%) per haploid set of lampbrush chromosomes. The term chromomere was used here in the descriptive sense to define a discrete granule of deoxyribonucleoprotein on the axis of a lampbrush chromosome.--These findings are discussed in relation to what is known of the molecular organization of eukaryotic genomes, and in relation to ideas on gene action and transcription in lampbrush chromosomes.


In situ hybridization of ribosomal DNA labelled with 125iodine to metaphase and lampbrush chromosomes from newts. Methods are described for in situ hybridization of ribosomal DNA from Xenopus laevis, labelled in vitro with 125iodine, to mitotic and lampbrush chromosomes from Triturus cristatus carnifex. The hybridization reaction was carried out in a mixture containing 50% formamide, 4 X SSC, 0.1 M KI, at 37 degrees C, or in 2 X SSC, 0.1 M KI at 65 degrees C. Autoradiographs of mitotic metaphases from 2 males showed labelling over the middle of the short arm of one chromosome IX in each metaphase. In some cases, a region near the end of a longer chromosome was also labelled. In a lampbrush preparations, labelling was confined to a region identified as about 53 units, near the middle of the short arm of both halves of bivalent IX. The usefulness of the technique and the significance of the labelling of only 1 of the 2 chromosomes IX in mitotic preparations are discussed.


[Identification of the genetic sex chromosomes in the monogenic blowfly Chrysomya rufifacies (Calliphoridae, Diptera)]. Previous investigations have shown the sex determination in the monogenic blowfly Chrysomya rufifacies to be controlled by a cytologically not discernible homogametry-heterogamety mechanism in the female. Female-producing (thelygenic) females are assumed to be heterozygous for a dominant female sex realizer (F') with sex-predetermining properties, while male-producing (arrhenogenic) females as well as males are supposed to be homozygous for the recessive allele (f). In order to identify the genetic sex chromosomes of C. rufifacies among its five pairs of long euchromatic chromosomes (nos. 1-5) plus one pair of small heterochromatic ones (no. 6), all chromosomes were marked by reciprocal translocations induced by X-ray treatment of adult males. The inheritance of thirteen different heteroxygous translocations has been analyzed. All of the translocations (eleven) between two of the four longer chromosomes did not show sex-linked inheritance, thus demonstrating the autosomal character of the chromosomes nos 1, 2, 3 and 4. The same is true for the translocation T6 (2/6). Therefore the small heterochromatic chromosome no. 6, corresponding to the morphlogically differentiated six chromosomes within the amphogenic calliphorid species, remains without sex determining function in the monogenic fly. This could be confirmed by the analysis of monosomic (monosomy-6) and trisomic (trisomy-6) individuals, which resulted from meiotic non-disfunction in T6/+ translocation heterozygotes. Contrary to these translocations, the heteroxygous 5/2 translocation (T14) exhibited sex-linked inheritance: There was but a very low frequency (0,76 per cent) of recombinants resulting from crossing-over between F'/f and the translocation breakage point in theylgenic F1 T14/+females. The sex-linked inheritance of T14 was confirmed by the progeny of a thelygenic F1 T14/+ female crossed to a homozygous T14/T14 translocation male.Among the offspring of that F1 T14/+ female, which had received the translocation from its father, all of the F2 T14/+ females were thelygenic compared to their arrhenogenic T14/T14 sisters. These results prove that the chromosomes of pair no. 5 genetically act as X'X-XX sex chromosomes in C. rufifacies.


The bacterial phosphoenolpyruvate: sugar phosphotransferase system. The bacterial phosphotransferase system participates in diverse physiological phenomena; its best characterized function is in the group translocation of sugars that are substrates of the system. Such sugars are phosphorylated as they are translocated across the cell membrane. Isolation of different proteins of the phosphotransferase system and reconstitution of the complex shows that in the net transfer of the phosphoryl group from phosphoenolpyruvate to a given sugar the phosphoryl group is sequentially transferred from one protein to another. In all cases so far studied, with one important exception, the phosphoryl group is linked to the proteins through a nitrogen atom in the imidazole ring of a histidyl residue. In the exceptional protein, the phosphoryl group is linked to a carboxy group. An additional function of the phosphotransferase system is to regulate the uptake of sugars that cannot be phosphorylated.


The origin of force in skeletal muscle.

The origin of force in skeletal muscle. Since the proposal and rapid acceptance of the sliding-filament theory in 1953-1954, numerous suggestions have been made for the cause of the sliding movement. When the amount of overlap is varied by altering the initial length, the maximum tension is directly proportional to, but the speed of shortening under zero load is independent of, the amount of overlap. This suggests strongly that a relative force between thick and thin filaments is produced by independent force-generators distributed within each overlap zone. These force-generators are identified with projections (cross-bridges) on the thick filament, each consisting of part of a myosin molecule. Measurements of the 'tension transients' when the length of a stimulated muscle fibre is suddenly altered show that the range of action of each cross-bridge is 10-15 nm. The travel within a single contraction may be many times greater, so each cross-bridge must act cyclically by attaching, exerting a force and detaching. Details of the tension transients suggest that each cross-bridge makes its movement in two or three steps, each with a potential energy change a few times kT. Each cross-bridge contains also an elastic element in series. It is sufficient, on present evidence, to postulate that the only action of ATP is to dissociate the cross-bridge from the thin filament after it has completed its stroke.


The effect of methylphenidate on sensory perception in varying degrees of hyperkinetic behaviour. In a double-blind study of methylphenidate, hyperkinetic children of varying levels of age and degree of hyperactivity were assessed on subtests of the Illinois Test of Psycholinguistic Ability (ITPA). The ITPA was supplemented with a combination of monosensory, bisensory, and trisensory stimuli presentations. Methylphenidate improved the ITPA's visual, auditory and tactile age scores of children who exhibited a more marked degree of hyperkinetic behaviour. That improvement was also observed in the recognition of sensory stimuli presented in a monosensory fashion. Similarly, the children with a more marked degree of hyperkinesis improved their stimuli recognition rate significantly on methylphenidate when stimuli were presented to bisensory and trisensory perceptual modalities simultaneously. It was concluded that drug improvement on sensory perception seemed to be more related to the degree of hyperkinetic behavior manifested than to chronological age. Further research of degree of hyperkinesis, age-level, sensory modality and drug administration was suggested.


Loxapine succinate: a controlled double-blind study in chronic schizophrenia. Loxapine succinate was compared to chlorpromazine in a 12-week double-blind study of 50 hospitalized chronic schizophrenic patients. Statistical analyses of BPRS scores showed significant improvemement for several items and factors in both groups of patients. Both drugs significantly decreased severity of illness on the CGI scale. On the NOSIE scale, "manifest psychosis" was improved significantly with chlorpromazine and "global severity" with loxapine succinate. There were no significant treatment differences in BPRS, CGI, or Nosie items or factors or in the reduction of overall psychopathology. The side effects associated with the study drugs differed little with respect to incidence, number, severity, and type. The most frequently reported symptoms in both groups were behavioral, extrapyramidal, and sedative. Analyses of vital signs and clinical laboratory data revealed no evidence of serious untoward effects.


The treatment of cluster headaches with prednisone. Nineteen patients obstinate with cluster headaches whose pain was not mitigated by standard treatment (Methysergide, caffeine, ergotamine preparation, phenobarbital and analgesics) underwent a double blind control study with single crossover for the evaluation of prednisone therapy. Compared to placebo, a single oral dose of prednisone in 17 cases produced sustained improvement. Maintenance administration of prednisone was also effective in decreasing the frequency of attacks; however a single dose of the steroid when headaches began was effective.


A foreign body (chicken bone) in the rectum causing extensive perirectal and scrotal abscess: report of a case. A case of foreign-body perforation of the rectum with extensive necrotizing fasciitis is presented and the literature briefly reviewed. The peculiarity of the case was brought out because of the nature of the foreign body(chicken bone) and the extensiveness of the process. The increases risk of swallowing a foreign body if dentures are worn is pointed out.


[Infection with "enteritis salmonella" at non-intestinal sites (author's transl)]. So-called "enteritis Salmonella" was isolated in five cases from extra-intestinal specimens (about 3% of all primary Salmonella isolations in one year). The organisms were: S. typhimurium, S. enteritidis, S. java, S. panama, and S. infantis. In four of the five cases the clinical picture was not that of a Salmonella infection. Focal manifestations were a knee-joint empyema after long-term treatment with glucocorticoids, pleuritis in Hodgkin's disease, osteomyelitis of the head of the tibia, and meningitis in a child. In a 72-year-old man, acute renal failure occurred after enteritis, following which the Salmonella was isolated from the respiratory tract for many weeks.


[Pseudo-LE syndrome after treatment with Venopyronum dragees] (author's transl). During the past three years a pseudo-LE syndrome (with antimitochondrial antibodies) was diagnosed in 14 patients. Information from the patients and their doctors disclosed that twelve of them had taken Venopyronum dragees over a period of two months to five years before onset of first symptoms. Two of the patients died of nonspecific myocarditis. Clinical investigations strongly suggest that the drug may have played a role in the pathogenesis of the pseudo-LE syndrome which is likely to take a severe course if, as in the two patients, the cardiovascular system is involved.


Naproxen: a review of its pharmacological properties and therapeutic efficacy and use. Naproxen2, (+)-6-methoxy-alpha-methyl-2-naphthalene acetic acid, is a new non-steroidal anti=inflammatory agent advocated for use in rheumatiod arthritis, degenerative joint disease and ankylosing spondylitis. Published data suggest that in rheumatiod arthritis, naproxen 500mg daily comparable in efficacy with moderate doses of aspirin (3.6 to 4g daily) or 150mg daily of indomethacin, but generally causes fewer and milder side-effects than these drugs at the dosages used and can be given less frequently (12-hourly). Encouraging intial results have been reproted from its use in other inflammatory joint disorders, including acute gout and juvenile rheumatiod arthritis. It has compared favourably with indomethacin in ostioarthrosis of the hip of knee. Its exact place in the management of ankylosing spondylitis remains to be determined.


Clotrimazole: a review of its antifungal activity and therapeutic efficacy. Clotrimazole 2, a synthetic imidazole derivative, is primarily used locally in the treatment of vaginal and skin infections due to yeasts and dermatophytes. In vitro, it is most active against Candida spp., Trichophyton spp., Microsporum spp. and Malazzesia fuffur (Pityrosporon orbiculare). In addition, it has some in vitro activity against certain Gram-positive bacteria, and at very high concentrations has activity against Trichomonas spp. In the treatment of vaginal candidiasis, clotrimazole vaginal tablets have produced cure rates comparable with those of conventional nystatin vaginal tablets. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets - nystatin dosage forms preferred by some clinicians. Cootrimazole has also been successful in patients who had failed to respond to other antifungal agents such as nystatin and amphotericin B. Results in trichomonal vaginitis are not impressive. Skin infections caused by Candida or dermatophytes have been effectively treated with topical application of clotrimazole. In comparative trials, clotrimazole cream has been as effective as Whitfield's ointment and tolnaftate in the treatment of dermatophytoses, and as effective as nystatin in cutaneous candidiasis. Clotrimazole topical preparations are generally well tolerated, but local irritation has necessitated withdrawal of therapy in a few cases. Candidal septicemia and urinary and pulmonary candidiasis have been cured with oral clotrimazole therapy. Results in other types of serious fungal infections, including pulmonary aspergillosis, have been disappointing. A limiting factor in oral clotrimazole therapy is the high incidence of gastro-intestinal disturbances and neurological reactions.


Ihibition of the pre-ovulatory proestrous gonadotropin surge, ovulation and pregnancy with a peptide analogue of luteinizing hormone releasing hormone. D-[PHE]-2-D[ALA]-6-LRH (Wy-18,185), an analogue of synthetic hypothalamic LRH, was evaluated for its anti-fertility properties. The compound dampens the preovulatory proestrous surge of serum LH and FSH in rats, is an active anti-ovulatory agent in both rats and rabbits and prevents pregnancy when administered pre-coitally to rats. Additionally, the compound suppresses the ovulatory event in rats only during the cycle in which it is acutely administered, does not interfere with the rat vaginal cycle and is devoid of any effects on body, ovarian and uterine weights when given acutely. The compound is a moderate LRH agonist in rats but does not induce ovulation in rats or rabbits.


Studies on the mechanism controlling growth hormone release induced by chlorpromazine in the anesthetized rat. In intact urethane-anesthetized rats, plasma growth hormone (GH) levels were low but increased significantly following intravenous injection of chlorpromazine.  Plasma GH levels were significantly elevated in rats with hypothalamic cuts such as complete  deafferentiation, anterior cut and antero-lateral cut, whereas plasma GH levels in rats with posterior cut or postero-lateral cut were not significantly different from those in rats with sham-operation.  Intravenous injection of chlorpromazine caused an increase of plasma GH in rats with any type of hypothalamic cut.  However, the maximum increments of plasma GH following chlorpromazine were larger in rats with antero-lateral cut and smaller in rats with posterior cut than in rats with sham-operation.  These results suggest that extrahypothalamic inhibiting and stimulating neurons influence the regulatory mechanism of rat GH secretion through anterior and posterior routes to the hypothalamus respectively.


Effect of prostaglandin F2alpha upon ovulation and LH, FSH and prolactin secretion in chlorpromazine blocked rats. The ovulation-inducing and LH, FSH and protein releasing activities of prostaglandin F2alpha (PG F2alpha) were investigated, using the female rats which had ovulation blocked by chlorpromazine (CPZ). Serum LH, FSH and prolactin concentrations were measured with NIAMD-rat-radioimmunoassay kits. The number of ova present in the fallopian tubes was investigated microscopically. Subcutaneous injection of 0.4-1.6 mg of PG F2alpha at 3:00 p.m. to CPZ-blocked proestrous rats induced ovulation in 80% of the animals during presumptive estrus. However, the percentage of ovulating rats was reduced in 40-60% of the animals when the same doses of PG F2alpha were injected intravenously. All control animals receiving the vehicle alone did not ovulate. The number of ova was not related to the dose of PG F2alpha, but the percentage of ovulating rats was. The serum LH peak was observed 10 min after the intravenous injection and 60-180 min after the subcutaneous injection of PG F2alpha. The peak in serum FSH and prolactin occurred simultaneously 180 min after both subcutaneous and intravenous injection of PG F2alpha. It is concluded from these data that PG F2alpha at dose levels used, may directly affect the hypothalamo-pituitary axis and consequently induce ovulation. These results further support the conception that the prostaglandins (PGs) have a central effect stimulating LH, FSH and prolactin release from the anterior pituitary.


Specific and nonspecific multiple unit activities during the onset of pentylentetrazol seizures. I. Intact animals. A quantitative evaluation of specific and nonspecific multiple unit activity (MUA) before and during pentylenetetrazol-induced EEG tonic-clonic discharges (OTCD) was made at four levels of the CNS: cortical, thalamic, mesencephalic, and pontine. In addition, MUA of sciatic nerve was recorded to detect possible spinal cord efferent discharges. At all levels, sustained increase in specific and nonspecific multiple unit activity preceded EEG and sciatic nerve discharges induced by  pentylenetetrazol. Increments in nonspecific MUA occurred sooner and were larger than those of specific MUA, and increments in mesencephalic nonspecific MUA occurred sooner and were larger than those of other cortical, thalamic, and pontine nonspecific MUAs. This sequence of neuronal activation suggests that pentylenetetrazol seizures are initiated in nonspecific structures at the mesencephalic level.


Effects of hippocampal afterdischarges on Purkinje cell activity. Hippocampal afterdischarges can induce increased Purkinje cell activity that characteristically shows a pronounced acceleration during the period of the afterdischarges. Increased Purkinje cell activity may continue for many seconds after termination of the hippocampal activity. Typical frequency histograms are presented. A short period of hippocampal afterdischarges (under 25 sec) may occur with few if any alterations in cerebral activity and vice versa. However, such afterdischarges can produce changes in cerebellar activity as shown by enhanced Purkinje cell activity. These data support the view that the nucleus tegmenti pontis may be prominently involved in relaying hippocampal afterdischarges to the cerebellum whereas much of the neocortical seizure activity is relayed trough the pons, inferior olive, and lateral reticular nucleus, rather than through nucleus tegmenti pontis. EEG tracings taken from these areas illustrate the findings.


Increased cholesterol-ester formation during forced cholesterol synthesis in rat hepatocytes. By comparing the incorporation of 3H20 and [14C]mevalonate into cholesterol in suspensions of rat hepatocytes, it was calculated that the cholesterol biosynthesis could be stimulated 4--7-fold by addition of mevalonate. The addition of 3.3--6.7 mM mevalonate also caused a 5--6-fold increase in the proportion of newly synthesized cholesterol that was esterifield. The esterification of radioactive cholesterol, entering the cells by exchange with surrounding plasma lipoproteins was also increased, indicating that a true increase in the rate of cholesterol ester formation rather than a more selective utilization of newly synthesized cholesterol for esterification, occurred. The increase in cholesterol esterification was not abolished by cycloheximide, indicating that it did not require an increased synthesis of cholesterol esterifying enzyme. Instead the data suggest that the supply of cholesterol to the esterifiable pool may be an important factor, regulating the rate of cholesterol ester formation in rat liver. The addition of 0.5 mM oleic acid to the medium did not increase the degree of cholesterol esterification significantly, whereas 2 mM oleic acid bound to 1% albumin increased the proportion of newly synthesized cholesterol that was esterified, by about 70%. The cells secreted radioactive cholesterol esters into the medium. Cycloheximide inhibited this secretion to about 80% but did not affect the rate at which newly synthesized cholesterol was transferred to surrounding plasma lipoproteins.


Stimultaneous purification of Escherichia coli termination factor rho, RNAase III and RNAase H. This communication describes a method for the stimultaneous purification of Escherichia coli termination factor rho, RNAase III and RNAase H, which is rapid, reproducible and high in yield. Depending on how cells are grown 0.5 to 1 mg of RNAase III, 1 to 2 mg of RNAase H and 1 to 2 mg of rho are obtained from 100 g wet cells. RNAase III and rho are pure proteins, and RNAase H 80% pure. In addition it is shown that pure RNAase III degrades only RNA. RNA duplexes, and is responsible for the sizing of early T7 mRNA. The active form of RNAase III is composed of two identical subunits having a molecular weight of 23 500. Native RNAase H which specifically hydrolyses the RNA moiety of an RNA. DNA hybrid, is a single polypeptide chain with a molecular weight of 21 000 The amino acid composition of termination factor rho is also reported.


Studies on energy-linked reactions: genetic analysis of venturicidin-resistant mutants. Genetic analysis of venturicidin-resistant mutants has revealed the presence of both nuclear and mitochondrial genes responsible for determining venturicidin sensitivity/resistance in Saccharomyces cerevisiae. Recombination studies show that the mutation with phenotype VENR is situated at mitochondrial locus OL I and is therefore extremely useful of future genetic manipulations as it gives a unique phenotype to this locus distinguishable from the second oligomycin locus OL II. The mutations with phenotype VENR OLYR are linked to oligomycin locus OL I and have been allocated a new mitochondrial locus, namely OL III. Three factor croses involving the venturicidin mutations at loci OL I and OL III have shown them to freely recombine with the other mitochondrial loci R I, R III and OL II. The mitochondrial genetic map is therefore represented as four 'recombinational linkage groups'. A fifth linkage group is also specified for mutants with phenotype VENR TETR, and is probably located on a separate DNA molecule from the four other groups.


Glyceraldehyde phosphate at the reducing terminus of Salmonella Q haptens. Salmonella montevideo. The O antigen polysaccharide of Salmonella montevideo was isolated from a core-defective mutant by the phenol/water procedure, and was suspected to contain phosphomonester and cyclic phosphodiester at its reducing end in anology to the O hapten from Salmonella typhimurium (Kent and Obsborn, 1968. Therefore, it was chromatographed on a DEAE-cellulose column. Whereas one part eluted with water the other part of the polysaccharide could only be eluted with buffer. Both fractions were further purified on Sephadex G100 and contained mannose, glucose, N-acetylglucosamine and phosphate in a molar ratio of 4:1:1: less than 0.1. In order to specifically label the reducing end phosphate was removed enzymatically, or the presumed cyclic diester was cleaved by mild hydrolysis, and the fractions were reduced with sodium horo[3H]hydride. Both fractions yield mainly [3H]glycerol after hydrolysis and paper chromatogaphy. In addition, [3H]mannitol and [H]monohydroxyacetone could be identified by paper chromatography and were concluded to be the result of phosphate migration and beta-elimination reactions taking place during the isolation procedure and the various treatments prior to sodium boro[3H]hydride reduction. These findings in addition to periodate oxidation studies indicated that the O antigen polysaccharide of Salmonella montevideo had glyceraldehyde phosphate at its reducing end. From the incorporation of 3H into the polysaccharide the O antigen was calculated to consist of about 19 repeating units of 6 sugar residues each.


Ribosomal RNA genes in the amoebal and plasmodial forms of the slime mould Physarum polycephalum. 1. The degree of homology between ribosomal RNA isolated from microplasmodia and amoebae of the slime mould Physarum polycephalum has been determined by competive hybridisation of the RNA from the two sources to homologous DNA in solution. The extent of competition was measured both by hybridisation to saturation and by following the kinetics of hybrid formation. In each case competition was found to be 100%, indicating that the ribosomal RNAs from the two, quite different vegetative forms of the organism exhibit a high degree of homology and are probably transcribed from the same genes. 2. The relationship between the amount of nuclear DNA that codes for ribosomal RNA (rDNA) and ploidy has been investigated in three strains of P. polycephalum which exhibit a 1:2:5 variation in the amount of DNA per nucleus. Ribosomal RNA saturation values were determined by hybridisation to DNA isolated from prophase nuclei of plasmodia. The proportion of rDNA was found to be constant at 0.16--0.18% of the total genome in the three strains.


The effects of overloading in density-gradient centrifugation. The effects of overloading of the sample zone in density gradient centrifugation have been studied by use of a three-component shelf-lavered sample in which the total protein concentration was increased by addition of different amounts of albumin. It is found that overloading of the gradient gives rise to particle movements which are not predictable from the Svedberg equation. The two typical effects of overloading are dislocation of the zone mass centres and changes in the zone shapes. It is found that the magnitude of the calculated sedimentation coefficients increases nearly linearly with increasing sample load. The changes in zone shapes are found to depend on the specific load and two different patterns may be distinguished. The zone of the sample component which causes the overloading is defined as primarily overloaded and the others as secondarily overloaded. In primarily overloaded zones the original Gaussian shape is lost, while in secondarily overloaded zones the Gaussian zone shape is maintained, although a zone broadening is seen. Extreme high loads are found to be able to divide single zones. As a whole these experiments show that evidence for a non-overloaded set of experimental conditions must be provided, when density gradient centrifugation is used for determination of sedimentation coefficients. For preparative gradient centrifugations the power of resolution will decrease with increasing sample load. A simple method to detect overloading in density gradient centrifugations is described.


The "hidden ligand" of the galactose-binding protein. Following tryptophan fluorescence of the galactose-binding during dissociation of the ligand it has been found that glucose dissociates with a half life of less than 5 s. Similarly, fast dissociation was also observed by following release of radioactively labelled glucose from Sepharose-coupled galactose-binding protein upon dilution. Accordingly, a previous claim that the galactose-binding protein contains glucose as a non-dissociable "hidden ligand" [G. Richarme and A. Kepes (1974) Eur. J. Biochem. 45, 127-133] has to be reinterpreted


Purification and characterization of a new factor which restores protein synthesis in  a conditionally lethal mutant of Escherichia coli. The mutant Escherichia coli strain, N4316, has a temperature-sensitive defect in a protein factor required for translation in vitro of bacteriophage f2 RNA. We have purified the normal counterpart of this factor from a wild-type strain, using as an assay its ability to restore the activity of mutant extracts at non-permissive temperature. Our final preparation is free of known initiation, propagation, and release factors, proving that the factor is a new component required for translation. The new factor has a molecular weight of 95000 with preliminary data suggesting a subunit structure. 70% of this protein is found in the soluble-cell fraction, the rest being associated with 70-S ribosomes. Kinetic analyses indicate that the factor acts early in translation. Expression of the defect is highly dependent on the Mg2+ concentration, no temperature-sensitivity being apparent at 15 mM Mg2+. At lower Mg2+ concentrations, the defect is expressed only with natural mRNAs such as f2 RNA, and not with artifical polymers such as poly(U). This specificity suggests that the factor may function in events coded by special sequences in the natural messengers


Topology of binding sites for carbamyl phosphate in aspartate transcarbamylase from Escherichia coli. The use of pyridoxal phosphate as covalent probe. Pyridoxal phosphate, a competitive inhibitor of aspartate transcarbamylase, binds to six sites in the catalytic and to twelve sites in the regulatory subunits of this hexameric protein. The properties of its association to the active sites of the enzyme are very similar to those observed with one of its substrates, carbamyl phosphate. It tightly binds to one half of the sites in the absence of succinate, an analogue of the second substrate. Since pyridoxal phosphate can be linked covalently to the protein by reduction, the distribution of the high affinity binding sites on catalytic trimers was studied after dissociation of modified holoenzyme. Electrophoresis of isolated subunits under non-denaturing conditions revealed four distinct bands, corresponding to trimers containing 0 to 3 pyridoxal phosphate derivatives. The distribution among the four species as a function of ligand concentration in the absence of succinate indicates that in the native oligomer, pyridoxal phosphate (and by extrapolation, carbamyl phosphate) binds to both catalytic trimers, rather than to three sites on a single subunit.


Digestion with matrix-bound proteases as a possible probe for the topography of the DNA-dependent RNA polymerase from Escherichia coli. DNA-dependent RNA polymerase lacking subunit sigma was digested with matrix-bound chymotrypsin or trypsin in the presence of 0.4 M NaCl in the monomeric form or at low ionic strength in the oligomeric form. Sigma-containing polymerase was digested in the same way. The course of proteolysis was followed by polyacrylamide gel electrophoresis after dissociation of the enzyme with detergent into subunits and the fragments produced by the hydrolysis. The following results were obtained. (a) The large subunits beta and beta' are cleaved with a much higher rate in the monomeric than in the oligomeric polymerase. (b) Both large subunits are hydrolysed with the same rate. (c) Subunit alpha is hydrolysed almost with the same rate in the monomeric and oligomeric form of polymerase. (d) The same was found for subunit sigma. (e) These effects were independent of the substrate specificity of the protease used. (f) Subunit sigma is much more susceptible to chymotrypsin than to trypsin. (g) Subunit sigma protects the large subunits beta and beta' against tryptic cleavage. These results can be explained in terms of a tentative model for the topography of the protomer-protomer interactions in RNA polymerase. According to this model subunits beta and beta' contain two sites for isologous interactions of protomers. One site can be blocked by attachment of subunit sigma. Subunits alpha and sigma do not participate directly in the association.


Metabolism of the phosphatidylglycerol molecular species in Escherichia coli. The fractionation, turnover and biosynthesis of the phosphatidylglycerol molecular species of Escherichia coli were studied. Monoacetyldiglycerides derived from phosphatidylglycerol were separated into five subfractions; cis-vaccenyl-palmitoleyl, cis-vaccenyl-cis-vaccenyl, palmityl-palmitoleyl, palmityl-cis-vaccenyl and the disaturated molecular species on a silica gel plate impregnated with silver nitrate. Individual molecular species had different turnover rates. The palmityl-cis-vaccenyl species was metabolized faster than the others. Disaturated species were rather stable. Various phosphatidylglycerol molecular species were synthesized in the presence of sn-glycerol 3-phosphate, palmityl-CoA, palmitoleyl-CoA, cis-vaccenyl-CoA and CTP by the E. coli membrane particulate fraction. When only the proportion of palmityl-CoA among the three acyl-CoAs was increased, the molecular species containing the palmityl residue were increased. Similar results were obtained with the other acyl-CoAs. However, a temperature-sensitive incorporation of unsaturated and saturated fatty acids into phosphatidylglycerol molecular species was observed with no change in the proportions of the three acyl-CoAs, completely reflecting the in vivo unsaturated/saturated ratio.


No correlation between native and denatured forms of tRNA(Trp) form Escherichia coli and the resistant and sensitive molecules characterised by phosphorolysis.  Two classes of conformation characterised by phosphorolysis in both native and denatured tRNA(Trp). Some tRNA molecules in solution are sensitive to attack by polynucleotide phosphorylase while others are resistant, even with pure species of tRNA. Further analysis of this behaviour has revealed an underlying microheterogeneity in tRNA structure. In order to clarify the relation between the sensitive and resistant classes of tRNA, and the native and denatured forms with respect to amino acid acceptance, the phosphorolysis of tRNATrp from Escherichia coli has been investigated. Native tRNATrp is similar to species examined previously: resistant and sensitive classes are observed and the sensitive proportion increases with temperature. At 20 degrees C both native and denatured tRNATrp are stable under phosphorolysis conditions, and denaturated tRNATrp is found also to possess resistant and sensitive classes. About 10% of both native and denatured tRNATrp is rapidly phosphorolysed at 20 degrees C, but the rate of conversion of resistant denatured tRNATrp to the sensitive class is about twice as fact as for the native form. Thus it can be concluded that the sensitive molecules of tRNATrp attacked by polynucleotide phosphorylase are not due to denaturation.


Cerebral aspergillosis with special reference to cerebrospinal fluid findings. A case of cerebral aspergillosis in a 69-year-old diabetic man is reported. The disease, initially presenting as headache and vertigo, was caused by Aspergillus fumigatus. Seven CSF specimens were examined. The main findings included decreased glucose and increased protein concentrations, leukocyte reaction and one positive culture for A. fumigatus. Neuropathological examination revealed granulomatous leptomeningitis and typical fungal hyphae. The process probably lasted for more than 1 year and was an important contributing factor to two brain stem infarcts.


Association between myasthenia gravis and malignant lymphoma. A reticulum cell sarcoma was diagnosed in a myasthenic patient 14 years after the first manifestations of myasthenia gravis. The association of myasthenia and malignancy, especially lymphoreticular, is discussed in view of an increasing number of similar reports in the literature. It is suggested that autoimmune diseases, myasthenia gravis and malignant processes might have a common underlying abnormal immune state related to thymic pathology.


Kuru-plaques in creutzfeldt-jakob disease. A case of Creutzfeldt-Jakob disease of cerebellar type is reported. In this case the cerebellar cortex exhibited classical Kuru-plaques. From a comparison of this finding with 50 cerebella from senile patients and patients with cerebellar atrophies it is concluded that the Kuru-plaque is specific for Creutzfeldt-Jakob disease, possible even for its cerebellar variant.


Facilitation through hyperventilation of therapeutic effect of pyrithioxin in cerebral infarct patients. A method of treatment consisting in administration of a neurodynamic drug, pyrithioxin, combined with a short period of hyperventilation (HV) was applied in cerebral infarct patients with hemiplegia. The combination was superior to pyrithioxin alone for the motor recovery of these patients. In some cases, it induced immediately a partial restoration of motility. The combination constantly brought about an increase in urinary excretion of norepinephrine and vanilmandelic acid, which failed to occur after pyrithioxin or HV alone. HV appears to facilitate the neural effects of the drug by promoting its transfer into the CNS.


His bundle electrograms in patients with congestive cardiomyopathy. His bundle electrograms were obtained at rest and during atrial pacing in 16 patients with congestive cardiomyopathy. Increments in heart rate during atrial pacing were associated with progressive increases in the A-H interval in all patients. Three patients had abnormal conduction (prolonged P-H) proximal to the His bundle; atrial pacing resulted in second degree A-V block (A-H block) in these three patients at paced rates below 130/min; these three patients were on digitalis at the time of the study. Two patients ahd left bundle branch block associated with a prolonged H-V interval suggesting a conduction disturbance in the contralateral bundle system either at or distal to the branching portion of the His bundle. Two patients had H-V prolongation in the presence of a normal QRS duration which suggests delay in the bundle of His. Two patients with normal H-V intervals had marked prolongation of the total intraventricular conduction time (H-S prolongation). The His bundle electrogram uncovered abnormalities in atrioventricular conduction not apparent on the standard electrocardiogram and has allowed expansion of our knowledge regarding the electrophysiologic features of congestive cardiomyopathy.


A new method for the evaluation of analgesic activity using adjuvant-induced arthritis in the rat. A bioassay was developed for the assessment of analgesic activity by using pain resulting from a reproducible pathological condition. The vocalization displayed by rats with adjuvant-induced polyarthritis was defined as an expression of pain, and a decrease of this response was established as specifically demonstrating analgesic activity. This method was capable of detecting the analgesic activity of morphine-like and narcotic antagonist-type analgesics, as well as the activity of the antipyretic analgesics. The relative potencies of known analgesic agents determined with this technique closely approximated the potencies of these analgesics in man. The instrumentation for recording and measuring the vocal response of arthritic rats is described.


Impaired radioprotective capacity and reduced proliferative rate of bone marrow from neonatally thymectomized mice;. The colony forming capacity of bone marrow from neonatally thymectomized mice is reduced in comparison with that of normal animalsmin addition to this quantitative change, we observed that the bone marrow of thymectomized animals has a reduced radioprotective effect upon inoculation into lethally irradiated recipient mice. It was also found that the cellularity of spleen colonies derived from bone marrow of thymectomized animals is lower than that of intact controls. In vitro uptake of 3H-thymidine into cells of spleen colonies, and rate of DNA synthesis measured in vitro were found to be reduced in cells derived from bone marrow of thymectomized donors; The initially observed reduction in colony forming capactiy of bone marrow from neonatally thymectomized mice could be reversed by thymus reimplantation=


alpha-Methylnoradrenaline induced hypotension and bradycardia after administration into the area of the nucleus tractus solitarii. Bilateral injections of alpha-methylnoradrenaline into the area of the nucleus tractus solitarii of the brain stem caused a dose-dependent decrease of systemic arterial blood pressure and heart rate of anesthetized rats. The effects were prevented and even reversed by a preceding injection of the alpha-adrenoceptor blocking agent phentolamine. Pressor doses of angiotensin II and of arginine-vasopressin at the same site failed to drcrease blood pressure and heart rate.


Behavioral functions of narcotic antagonists: response-drug contingencies. Behavioral effects of the narcotic antagonist naloxone are discussed in terms of stimulus functions. As an eliciting stimulus, the effects of naloxone depend on prior administration of narcotic. Administered independently of responding, naloxone can increase or decrease rates of narcotic-reinforced responding depending on the dose of naloxone. When naloxone is administered as a consequence of narcotic self-injection, the further probability of that behavior is reduced; thus, naloxone can function as a punishing stimulus. As a negatively-reinforcing stimulus, naloxone can maintain behavior which terminates or prevents delivery in morphine-dependent monkeys. In animals with previous naloxone avoidance-escape experience, unavoidable-inescapable injection of naloxone produce increases in avoidance-escape response rates. In these animals, responding subsequently can be maintained, at least temporarily, when naloxone is administered only as the consequence of responding.


Effect of methyldopa treatment on peripheral sympathetic nerve function in the dog. Administration of methyldopa (100 mg/kg, p.o. twice daily for 3 days) to mongrel dogs produced a significant decrease in the mean blood pressure (MBP) and heart rate (HR). Chronotropic responses to cardioaccelerator nerve stimulation and vasoconstrictor responses to lumbar sympathetic nerve stimulation were significantly attenuated in the treated dogs. Pressor and chronotropic responses to bilateral carotid occlusion (BCO) and tyramine were also markedly reduced following treatment with methyldopa, which is consistent with the clinical findings that chronic methyldopa treatment in hypertensive patients impairs cardiovascular reflexes. Methylnorepinephrine (MNE) was significantly less potent than norepinephrine (NE) in producing an increase in MBP or hindleg perfusion pressure, while the chronotropic and inotropic potency of MNE was about equal to NE. These results indicate that treatment with methyldopa in the dog does indeed produce an impairment of peripheral sympathetic neuronal function to certain organs and this peripheral effect of the drug may be of importance in accounting for its antihypertensive action in the dog.


Catecholamines and drug-behavior interactions. The effects of several drugs on schedule-controlled operant behavior depend on the baseline rate of responding and on the nature of the environmental conditions that maintain the behavior. For example, the effects of amphetamine and alpha-methylpara-tyrosine (alphaMT) on operant performances depend to a large extent on the rate at which organisms respond under nondrug control conditions. A neurochemical mechanism for these rate-dependent effects has not been established. However, several lines of evidence suggest that catecholamines are functionally important in the maintenance of many types of behavior, including operant behavior. The fact that many drugs which exhibit drug-behavior interactions also produce characteristic effects on the metabolism of central nervous system catecholamines suggests that the performance of operant behavior per se modifies brain catecholamine metabolism and thereby the subsequent drug effect. Experiments measuring the depletion of catecholamines following synthesis inhibition with alphaMT, or changes in the specific activity of norepinephrine after tritium labeling, have shown that operant behavior alters the metabolism of catecholamines. Preliminary evidence  is also presented from experiments designed to determine variables associated with the performance-induced changes in catecholamine metabolism. These variables include: rate of responses; rate or density of reinforcement; and response-reinforcer contingencies. The results of these experiments suggest a neurochemical mechanism for the rate-dependent effects of amphetamine and alphaMT. A model is presented that may account for the general phenomenon of drug-behavior interactions in neurochemical terms.


Assessing the impact of low level chemicals on development: behavioral and latent effects. There is growing evidence that nervous tissue, especially the brain, is more sensitive to many foreign chemical substances than has previously been suspected, and that toxic effects may be manifested as subtle disturbances of behavior long before any classical symptoms of poisoning become apparent. Early detection of an insidious toxic process (behavioral toxicology) may enable the prevention or attenuation of harm to humans and other organisms. Adding to both the sensitivity and complexity of behavioral toxicologic testing is the increasing evidence that individuals are more vulnerable to adverse factors during the period of development (conception yields puberty) than at any other time in life. Subtle functional disturbances in organisms exposed while immature (behavioral teratology) may be one of the most sensitive indicators of chemical toxicity. Furthermore, defects in a developmental process may have only delayed effects. A morphological or biochemical lesion can be dormant and not manifest itself until later in life as a behavioral disorder, mental deficiency, or overt functional impairment. Longitudinal evaluation is required to detect long-term or delayed effects of a particular developmental influence on biological and behavioral functions. Examples from research on the subtle and latent consequences of prenatal and early postnatal exposure to methylmercury that illustrate the above principles are presented. It is concluded that behavioral and long-term evaluation of organisms exposed during development are essential for a thorough assessment of the impact of certain low level chemicals on human health.


The role of discriminative stimuli in modulating drug action. Behavior reinforced in the presence of a stimulus comes under the control of the stimulus. A drug can then modify that control and, therefore, modify the behavior itself. Studies over the past 2 decades have shown that the nature of the controlling (or discriminative) stimulus can govern the degree to which drugs change performance. These experiments usually have compared behavior on various schedules of reinforcement with and without added discriminative stimuli. For instance, pigeons that had been trained on a fixed-interval schedule showed great changes in response distribution after amphetamine and scopolamine. The same birds, when performing on a fixed-interval schedule to which time-correlated discriminative stimuli had been added, showed smaller changes in response distribution. Other pigeons were trained to make a minimum number of consecutive responses on one key before a peck on a second key would be reinforced; beta-amphetamine and scopolamine led to pronounced increases in premature switching. Adding a discriminative stimulus when the response requirement was fulfilled increased the likelihood that a switch would occur only after the appropriate number of pecks had been emitted. It also attenuated the effects of the drugs. The presence of discriminative stimuli did not make as large a difference in performance in either of these experiments when chlorpromazine and promazine were studied. In general, work with other schedules of reinforcement supports the conclusion that behavior under stron external stimulus control is less apt to be readily affected by many drugs. Addition of the discriminative stimulus can also "improve" the behavior of pigeons that have been given enough methylmercury to increase greatly the variability of their performance.


Inhibition of implantation in the golden hamster by zona-precipitating antibody. Antisera prepared against saline extracts of hamster ovary, and made specific to ovary by absorption with small intestine, precipitated the zona pellucida of provulatory hamster ova and all early embryonic stages examined, including the pronuclear, 2-, 4-, 8-, and 16-cell, morula, and blastocyst stages; this indicates that (1) the zona antigen is present during oocyte maturation and early embryonic development and (2) the antigen does not change its ability to react with zonaprecipitating antibody. Embryos in the morula and blastocyst stages, treated in vitro with zona-precipitating antibody, pre-immunization rabbit serum, or control media were transferred into synchronized pseudopregnant recipients. Precipitation of zonae by specific antibody inhibited implantation by blocking the process known as zona shedding, and thereby prevented the embryo from making contact with the uterus.


Evaluation of human sera for antibodies against sperm by immunofluorescence. Newborn cord sera and sera from pregnant women and from couples with unexplained infertility were observed by indirect immunofluorescence for reactions against human sperm. The sera from the infertile couples had been tested for macro-agglutination and complement-dependent immobilizing antibodies as well. Nonspecific fluorescence was noted only on the quatorial segment. Acrosomes and tail end-pieces were strongly immunofluorescent (positive at a serum dilution of 1:16) with 60 to 70% and 30 to 50%, respectively, of the sera from each main group, with the exception of the nonreactive cord blood. End-piece fluorescence was primarily due to the IgM globulin fraction. It is suggested that cord serum anti-sperm antibodies, directed mainly against the tail main piece, are due to IgG passively acquired from the mother. There was no apparent difference in immunofluorescence between infertile patients and control groups (except for the acrosome and end-piece, with cord sera). However, when the sera from infertile patients were subdivided into groups containing only agglutinating antibody, only immobilizing antibody, and both types of antibody, a higher percentage of the sera from the group having only agglutinating antibody reacted with all sperm areas. This reaction seemed more uniform over the sperm and included the usually negative posnuclear cap and midpiece. The other subgroups showed no obvious trends.


Basement membranes: current concepts of structure and synthesis. Basement membranes are composed of dissimilar protein subunits. The procollagen-like subunit is associated with noncollagenous matrix glycoproteins. The proportion of the latter components varies among basement membranes. The various subunits interact via hydrogen bonds, disulfide bonds and aldehyde-derived cross-links. The extensive degree of cross-linking renders basement membranes highly insoluble. A procollagen-like molecule, extracted from calf anterior lens capsule, exhibits on electron microscopy a filamentous component with a globular portion attached at one end. Treatment of basement membranes with pepsin at low temperature digests the noncollagenous glycoprotein components and allows the collagenous component to come into solution. Purification of the pepsin-solubilized collagen from basement membranes reveals a molecule composed of three identical alpha-chains. Other unique features include 40-50 residues of hydroxylysine, 128-140 residues of 4-hydroxyproline, 12-15 residues of 3-hydroxyproline, 29 residues of arginine, 35 residues alanine, 2-4 residues of half-cystine, 38 residues of glucosyl-galactosyl-hydroxylysine, 3 residues of mannose, 2 residues of glucosamine, and 0.3 residues of fucose. Immunochemical studies indicate the presence of three distinct antigenic components and support the evidence that one is collagenous and the other two are noncollagenous glycoproteins. One of the latter corresponds to the non-helical extension of procollagen. The other is a large-molecular weight highly cross-linked matrix protein.


Changes of pituitary sensitivity to LH-RH during the rat estrous cycle. The plasma LH (luteinizing hormone) response to 200 ng of LH-RH (LH-releasing hormone) injected subcutaneously at different stages of the estrous cycle in normal rats under Surital anesthisia was maximal during the afternoon of proestrus and lowest on diestrus I. The area under the plasma LH curve measured at 13:00 on proestrus was approximately 7-fold higher than that obtained at 15:30 h on diestrus I. Intermediate responses were found on diestrus II, estrus and morning of proestrus. An approsimately 2.5-fold higher LH response was observed on proestrus than on diestrus I after injection of [D-Ala2, des Gly-NH2-10] LH-RH ethylamide at 15:00 h. That these marked changes of LH response are not secondary to interference by endogenous LH-RH, changes of the metabolism or transport of exogenous LH-RH or modification of plasma LH clearance is ascertanied by the finding of similar changes of pituitary sensitivity to LH-RH under in vitro conditions using pituitaries collected at the same stag-s of the estrous cycle. As measured both in vivo and in vitro, not only the amplitude but also the speed of LH response are maximal during the afternoon of proestrus and minimal on diestrus I.


In vitro pituitary responsiveness to gonadotropin-releasing hormone (LH-RH) in intact and castrated male and female rats. The in vitro response of pituitaries isolated from both normal and 18-21 day post-castration male and female intact rats to incremental doses of synthetic gonadotropin-releasing hormone (LH-RH) has been investigated. Intact male pituitaries released luteinizing hormone (LH) maximally at the smallest dose of LH-RH (0.1 ng/ml) whereas intact female pituitaries released LH in a dose-response fashion. FSH release from intact male pituitaries was considerably greater than that from intact female pituitaries. As with LH, intact male pituitaries appeared maximally stimulated at 0.1 ng/ml of LH-RH. Intact female pituitaries did not release FSH until a 10 ng/ml dose of LH-RH was used. Male and female castrate pituitaries were more susceptible to LH-RH-induced LH and FSH release than were their intact counterparts, although this was more pronounced with regard to LH release. In addition castrate male pituitaries were more sensitive to lower doses of LH-RH than were castrate female pituitaries, this being most pronounced regarding LH release. Castrate female pituitaries released less FSH at the 100 ng/ml dose than at the 10 ng/ml dose, possibly indicating inhibition at these higher doses. In addition, pituitary extraction and serum from normal and castrate male and female rats were examined for LH and FSH content. LH content of castrated rat pituitaries of both sexes was considerably greater than that of their intact counterparts, as expected. However, castrate male pituitaries contained significantly less FSH than intact male pituitaries, whereas the opposite was true for the female groups. Serum LH and FSH levels were increased in the castrate groups with no difference between sexes. Serum from intact males contained considerably more FSH than did the serum from intact females.


RAST studies : IgE antibodies to Dermatogoides pteronyssinus (house dust mite), Aspergillus fumigatus and beta-lactoglobulin in sudden death in infancy syndrome (SDIS). The incidence of 2.5 SDIS cases per 1,000 live births found in Western Australia is in agreement with figures reported for other centres. While the age range of SDIS victims extended from two weeks to 15 months, 57 per cent of deaths occurred in children of two to four months of age. Boys outnumbered girls 1.6:1. Environmental factors are implicated in that the majority of deaths occurred in a biphasic distribution - autumn and late winter months. No significant differences were observed in total IgE levels in serum from SDIS victims, post mortem children who died in trauma of known aetiology and live control children of the same age range. Serum IgE antibodies to D.pteronyssinus were found in 37% of SDIS victims compared with 7% of matched controls (post mortem plus live groups). IgE antibodies to beta-lactoglobulin, the major allergen of cow's milk, appeared with twice the frequency in SDIS vs. control group but both groups showed a similar incidence of antibodies to the allergens of Aspergillus fumigatus. The prevalence of IgE antibodies to D.pteronyssinus in SDIS victims who died in the late winter -- early spring period was double that found in the group who died in the autumn period. Sixtyfour percent of the SDIS victims had antibodies to two or more of the three allergens tested while the control sera were positive to only one allergen. These results support the hypothesis that anaphylaxis induced by immediate hypersensitivity to D.pteronyssinus in particular may be one of the causative factors in SDIS in Western Australia.


Multiple mycobacterial antigens in diagnostic tuberculins. Guinea-pig antisera containing IgG1 antibodies have been prepared either with killed mycobacterial in paraffin oil or living BCG or intradermal injections of fractions of unheated culture filtrate. Sera, found to contain antibodies specific for different mycobacterial antigens are used in passive cutaneous anaphylaxis (PCA) in 12 times the dilution-to-extinction titer. Animals prepared with sera respond in all sites when unheated culture filtrate, strain H37Rv, is injected intravenously (i.v.) at 17-20 hours. Injection of diagnostic tuberculins i.v. into parallel recipients, in selected amounts, reveals, through reacting sites, the presence of the corresponding antigens and some information on relative amounts. Tuberculins of PPD type are precipitated from heated culture filtrate by ammonium sulfate or trichloroacetic acid (TCA) or benzoic acid. Old Tuberculins are made classically by long heating and evaporation. In all products heat-labile antigens are absent or present in small amount; yet, PPD-S was found to possess five antigens. In all PPD products, there was one dominant antigen, absent from Old Tuberculins. The dominant antigen of OT's was excluded from the TCA-PPD's but was present in most ammonium sulfate-type PPD's. It can be concluded that diagnostic testing made with OT detects a particular delayed-type sensitivity that is different in specificity from that which reacts to TCA-PPD's. Many but not all of the ammonium sulfate PPD's test for both specificities. Several different delayed-type sensitivities are acquired during infection. Supported by Grant AI 01258 of the National Institute of Health.


Physical-chemical properties of precipitated and fractionated allergens from Mycobacterium bovis. Seven allergens were prepared from cultures of Mycobacterium bovis. The culture filtrates were divided in half and each aliquot precipitated with either ammonium sulfate or trichloroacetic acid to prepare purified protein derivatives (PPD). These samples of PPD-bovis were analyzed for nitrogen, carbohydrate, RNA and DNA. Physical tests, such as: cellulose acetate electrophoresis, disc gel electrophoresis, ultracentrifugation, isoelectricfocusing and gel filtration were also performed. Precipitation with ammonium sulfate provided PPD's with less impurities than those precipitated with trichloroacetic acid although there was little difference in the allergenic activity of the products precipitated by either method. Several lots of PPD-bovis were fractionated by means of ultrafiltration and the fractions analyzed by many of the above chemical and physical tests as well as tests for amino acid composition and allergenic activity. The greatest amount of protein was found in the fractions with an apparent molecular weight in excess of 300,000. The carbohydrate was usually distributed in proportion to the amount of protein in each fraction while the nucleic acids were predominately found in the higher molecular weight fractions. The amino acid analysis and allergenic activity of the various molecular weight fractions provided data that would support the theory that the various fractions are polymers of a small molecular weight sub-unit. The number of amino acid residues were calculated and the minimum molecular weight of the tubercular protein estimated to be 8700. The estimated molecular weights of the fractions and the amino acid data concur with those previously reported for proteins from other mycobacteria.


Adipose tissue cellularity in relation to metabolism in juvenile onset diabetes mellitus. Adipose tissue cellularity was determined by a microscopic method in 18 men suffering from insulin dependent, juvenile diabetes mellitus for several years. These results were set in relation to the degree of clinical control estimated from the average urinary glucose output or fasting blood glucose during the year preceding the investigation. Furthermore, the results were compared with controls of comparable age and of the same sex. Both young and middleaged diabetic men had smaller fat cells than non-diabetic men. Fat cell size was correlated to the degree of clinical control, small fat cells indicating a poor control. It was suggested that fat cell size might be included as a measure of the long-term metabolic control in patients with insulin dependent diabetes mellitus.


In vitro cellular responses to autologous tumor extract detected by inhibition of macrophage migration. Indirect macrophage migration technique was employed to study in vitro cellular immune response to autologous tumor extract in man. Cellular hypersensitivity to autologous tumor extract was detected in 21 (26%) of 80 patients with various carcinomas preoperatively by means of the in vitro production of macrophage migration inhibitory factor (MIF). The relative frequency of MIF production in these patients varied inversely with progress of the diseases. The follow-up studies reveal postoperative decline of the cellular hypersensitivity after curative operation. These findings indicate that this assay can be applied for detecting cellular hypersensitivity to autologous tumor extracts in clinical situation.


Pancreatic cholera. Sudies on tumoral secretions and pathophysiology of diarrhea. Tumoral secretions and pathophysiology of diarrhea were studied in 1 patient with pancreatic cholera. High concentrations of vasoactive intestinal peptide were found in both systemic blood and tumoral extracts, together with increased plasma levels of calcitonin and protaglandins E and Falpha. Gastric inhibitory peptide and gastrointestinal and pancreatic hormones were absent from the tumor, except for small amounts of glucagon, and their blood levels were normal. Decreased basal but normal pentagastrin-stimulated gastric acid secretion, normal basal and secretin-stimulated pancreatic secretion, increased volume of gallbladder bile with high bicarbonate, and low bile salt concentrations were observed, but the electrolyte content and flow rate of fluid passing the duodenojejunal junction were within normal limits. Small intestine was found to be the origin of the water and electrolyte fasting losses. Jejunum was the site of bicarbonate secretion. Jejunal glucose and leucine-stimulated water and sodium transports were also strikingly decreased, whereas the absorption rates of the sugar and amino acid were normal. Colon reabsorbed high amounts of water and sodium but increased potassium losses. Biological effects of vasoactive intestinal peptide may explain most of the patient's upper digestive secretion abnormalities and small intestinal function impairments, whereas secondary aldosteronism might explain the modified colonic function.


Synthesis and secretion of protein and pepsinogen by rabbit gastric mucosa in organ culture. When maintained in organ culture, rabbit gastric mucosal biopsies incorporated [14tc]leucine into tissue protein and secreted labeled protein into culture medium steadily for 24 hr. Incorporation of radioactivity was abolished by cycloheximide. When examined by sodium dodecyl sulfate gel electrophoresis, dextran gel filtration, and ion exchange chromatography, 65 to 90% of macromolecular radioactivity secreted into culture medium migrated coincidentally with enzymatically assayed pepsinogen. Pepsin activity in cultured biopsies did not decrease during 24 hr of organ culture. Nevertheless, pepsin activity increased linearly in culture medium during this period. Acetylcholine markedly stimulated secretion of labeled protein and pepsinogen by cultured biopsies. In the presence of a subthreshold concentration (10(-10) M) of acetylcholine, pentagastrin, secretin, and the octapeptide of cholecystokinin, all stimulated protein secretion. Over-all incorporation of [14C]leucine into protein by cultured biopsies was stimulated by 10(-9) M pentagastrin. These results directly demonstrate: (1) synthesis and secretion of protein and pepsinogen by isolated gastric mucosa, (2) stimulation of gastric secretion of protein by acetylcholine and polypeptide hormones, and (3) stimulation of gastric synthesis of protein by pentagastrin.


Metabolism of lithocholate in healthy man. II. Enterohepatic circulation. Studies were carried out in healthy subjects to characterize the enterohepatic circulation of lithocholate and its metabolites. When mixed with bile and infused into the jejunum, radiolabeled lithocholylglycine was absorbed more rapidly and more efficiently than sulfolithocholylglycine, based on recovery from bile. When these metabolites were administered at 1800 hr in a liquid test meal containing radiolabeled taurocholate as an absorbable marker, 60% of lithocholylglycine was conserved, based on recovery of radioactivity in fasting bile the following morning, but only 20% of sulfolithocholylglycine was conserved. Iotope dilution studies in 4 subjects showed that daily input of lithocholate into the bile acid pool averaged 100 mg per day, about one-third to one-half of the chenodeoxycholic acid synthesis, but the t 1/2 was extremely short (0.74 day). The small lithocholate pool (about 100 mg) could be explained by rapid fecal excretion caused by sulfation which decreases passive absorption in the jejunum and active absorption in the ileum. Experiments with [35S]sulfo- [3H]lithocholylglycine indicated little desulfation during enterohepatic cycling but rapid desulfation in the distal intestine, with absorption of 35S (presumably as sulfate) followed by urinary excretion. A decreasing 35S:3H ratio in bile indicated that some steroid moiety was conserved to be resulfated. These studies indicate that considerable lithocholate is absorbed from the distal intestine in healthy subjects but efficient sulfation results in rapid fecal excretion, so that the total lithocholate pool remains small. A multicompartment model, previously used to describe the metabolism of the steroid and amino acid moieties of the major conjugated biliary bile acids, was extended to encompass lithocholyl conjugates and their sulfates.


A controlled trial of azathioprine in the management of chronic ulcerative colitis. To determine the efficacy of azathioprine in the treatment of ulcerative colitis, a 6-month double blind trial was carried out. Thirty patients with chronic ulcerative colitis who required the equivalent of at least 10 mg of prednisone per day over the 3 months prior to entering the study were randomized into placebo and azathioprine (1.5 mg per kg) treatment groups. Reduction of steriods was a major objective of the trial. Age and sex distribution, number of bowel movements, sense of well being, steroid dosage, and findings on proctoscopy, rectal biopsy, and colon X-ray initially were similar in the two groups. No side effects were associated with azathioprine. Although steroid dose was lower (p less than 0.05) in the azathioprine group at the termination of the study, no difference between the two groups could be detected in the number of bowel movements, sense of well being, and findings on proctoscopy during the first 3 weeks compared with the last 3 and during the first 3 months compared with the last 3. Although azathioprine does not confer dramatic benefit upon patients with chronic ulcerative colitis who require steroids, it does permit reduction of steroid dosage without apparent worsening of the disease. Its major value in ulcerative colitis may be in facilitating significant decreases or complete discontinuance of steroids.


Complications of endoscopic retrograde cholangiopancreatography. Analysis of 300 consecutive cases. A retrospective analysis of complications arising from 300 consecutive attempts at endoscopic retrograde cholangiopancreatography (ERCP) in 278 patients was undetaken to determine the rate and severity of complications. An over-all complication rate of 5% (15 cases) was documented. Complications were categorized in terms of those arising from endoscopy itself or from the administration of pharmacological agents (7 cases), and those observed after the injection of radioopaque contrast into the biliary tree or pancreas (8 cases). Complications which might be considered coincidental to a patient's underlying illness were not excluded. Complications were significantly more frequent after injection of diseased duct systems. Brief, self-limited pancreatitis after retrograde pancreatography occurred in 5 of 90 patients with pancreatic disease. No cases of pancreatitis were observed after retrograde pancreatography in 102 patients without pancreatic disease X2 = 5.82, P less than 0.025). Sepsis occurred after retrograde cholangiography in 3 of 56 patients with extrahepatic biliary obstruction. In the absence of extrahepatic obstruction, cholangiography was performed without complication in 85 cases (X2 = 3.62, P less than 0.1), although 25 of these had intense cholestasis due to hepatic parenchymal disease. This analysis provides the basis for modifications of ERCP technique and management that may reduce the future incidence of complications. This study suggests that the incidence and severity of complications that arise from ERCP compare favorably with procedures of equivalent diagnostic yield.


Bacterial studies of Clindamycin-associated colitis. A preliminary report. The cause of pseudomembraneous colitis is not known but has been attributed to an alteration in the microbial flora of the colon. To test this hypothesis, a blind, prospective study was undertaken in which fecal samples were cultured quantitatively for aerobic and anaerobic organisms. The patients from which these samples were taken were all receiving clindamycin and had diarrhea secondary to the use of the drug. We were able to show definite differences in the colonic microflora which correlated with the presence of pseudomembranes on biopsy. Those patients who had diarrhea and pseudomembranous colitis showed a striking decrease, both quantitatively and qualitatively, in the number of anaerobes present. Those patients who had diarrhea but no pseudomembranes had large numbers of anaerobes which qualitatively approximated normal fecal cultures but quantitatively were fewer in number. A third group of patients, which had resolving pseudomembranous colitis, and were no longer symptomatic, had large numbers of anaerobic organisms which approximated those found in normal fecal cultures. There were no differences among the three groups with regard to facultative anaerobic microflora. Thus, the presence of pseudomembranous colitis correlated directly with a striking quantitative and qualitative decrease in the anaerobic microflora of the colon. The symptom of diarrhea alone appeared to have no meaning with regard to changes in the bacterial flora. Resolution of pseudomembranous colitis was associated with a return of the anaerobic microflora.


Inhibition of gastric acid secretion in man by the transcranial application of lwo intensity pulsed current. This study was conducted to determine the effectiveness of transcranial electrotherapy (TCE) in reducing gastric secretion in man. TCE has been proposed as a therapeutic modality which induces a relaxed psychological state by the application of low intensity diffuse electrical current and has been purported by Soviet investigators to be beneficial in the treatment of peptic ulcers. Secretion rates were monitored in adult male volunteers by a method of intragastric titration utilizing a pH-sensitive telemetry capsule. In one study 5 subjects had their basal secretion rates monitored before, during, and after the application of TCE at graduated current intensities. A threshold of inhibition was observed for currents of 0.9 ma and greater. In a second study, 12 subjects had histamine-stimulated maximum acid output determined for control and during TCE application. Gastric acid secretion was reduced by an average of 30% when 1-ma TCE was applied, with individual reductions ranging from 5.7% to 53.2%. Since the application of relatively high TCE currents may produce discomfort in some subjects, a third study was conducted to determine whether the inhibition might not merely be the result of nonspecific noxious stimuli. For this study the electrical connections to the TCE electrodes were altered so that the same uncomfortable sensation was produced on the forehead, but no current was actually applied transcranially. This "placebo" TCE produced no reduction in the maximal acid output of 6 volunteers, but when the currents were applied transcranially, the gastric acid secretion was reduced by an average of 27% below control values.


Effect of prolonged administration of homologous and heterologous intrinsic factor antibodies on the parietal and peptic cell masses and the secretory function of the rat gastric mucosa. In order to determine the possible effects of the circulating intrinsic factor antibodies (IFA) on gastric morphology and secretory function, four groups of 12 rats each received intravenous injection daily for 8 to 12 weeks of immunoglobulin G (IgG) fractions separated on DEAE-cellulose columns from various sources: (1) sera of patients with pernicious anemia, containing both IFA and parietal cell antibodies (PCA), (2) sera from patients with atrophic gastritis, containing parietal cell antibody only, and (3) and (4) sera of rabbits immunized with semipurified human or rat intrinsic factor (IF). In addition three control groups of 12 rats each received intravenous injections daily for 8 to 12 weeks of either (5) saline or (6) and (7) IgG processed from human or rabbit normal sera. Still another group of 12 rats (8) did not receive any injections whatsoever for the same duration of time. One-third of the rats were intubated biweekly after histamine stimulation and the hourly outputs of CHl pepsin, and IF were determined. At conclusion of the experiments, rats were killed, the mucosal surface and thickness of the mucosa were measured, and parietal cell and peptic cell masses were counted. The control groups showed either progressive growth of the cellular mass in gastric mucosa and increase of the HCl, pepsin, and IF outputs, or no significant changes. In contrast, rats injected with IgG containing IFA to human or rat IF showed a statistically significant thinning of the gastric mucosa, reduction of peptic cells, which are known to secret IF in this species, and corresponding decreases in the ouputs of pepsin and IF. These became reduced by about 50% from initial values, and by 62 or 75%, respectively, when compared to rats injected with normal human or rabbit IgG's. In rats injected with IgG's from pernicious anemia sera, which contained both IFA and PCA, the outputs of IF, pepsin, and HCl decreased signigicantly, as well as the peptic and parietal cell masses. The rats injected with PCA only demonstrated thinning of the gastric mucosa, reduction of parietal cell mass, and a significant decrease of the HCl output. These findings imply an active role of the circulating gastric.


[The risk of yeast infection, of the newborn during and after delivery (author's transl)]. The importance of yeast infections in obstetrics was investigated in 200 pregnant women and their newborns. In the maternity patients the vagina was tested shortly before the delivery and the mouth of the neonates was tested 1 day prior to the discharge from the hospital. In 22% of the pregnant women and in 8,4% of the newborns, yeast (predominantly candida albicans) was found in the culture. Infants of mothers with positive cultures for yeast showed yeast more frequently (13,2%) themselves as infants of mothers with negative cultures for yeast (7,2%). Only 1 infant had clinical trush. Only 1/7 of the women who had positive cultures for yeast at delivery also had positive cultures for yeast 5--8 weeks following delivery although they were not treated. Second to the maternal vagina, the mouth of the mothers and the nursing personnel are the most important sources for yeast infections of the newborn infant. The demand to make the birth canal free of yeast at the end of the pregnancy does not appear to be justified for all obstetric units according to the results of our investigations. The incidence of a clinical yeast infection in the mature and healthy newborn infant was between 0,5 and 0,9% during the past 2 1/2 years at the Obstetric Department of the University of Erlangen, Germany. Prophylactic medication against yeast is important for all high risk neonates such as premature infants, infants with asphyxia and infants under antibiotic treatment.


Elevated mutability of polA derivatives of Escherichia coli B/r at sublethal doses of ultraviolet light: evidence for an inducible error-prone repair system ("SOS repair") and its anomalous expression in these strains. The SOS repair hypothesis proposes that UV-induced mutations in E. coli are caused by an inducible error-prone repair system (SOS repair) which is normally induced coordinately with such other recApluslexplus-dependent functions as filamentous growth, prophage induction and W-reactivation-2 in response to UV or other inhibitors of DNA synthesis. Since polA-l strains induce these functions at unusually low doses of UV, the SOS hypothesis predicts elevated UV mutability for such strains at these low doses (50 ergs per mm2 and below) Strain WP6, a polA-1 derivative of B/r, exhibits the predicted high UV mutability in this dose range, producing ten times as many Trp+ mutations as its polA+ counterpart, strain WP1, at a dose of 12.5 ergs per mm-2. The UV sensitivity of a lex polA double mutant, in which the lex and polA mutations fail to exert their individual effects on UV sensitivity additively, also confirms a prediction generated by the SOS hypothesis.--The uvrA polA-1 strain WP67 also shows elevated UV mutability at very low UV doses (5 ergs per mm-2 and below), producing about ten times as many Trp+ mutations at a dose of 0.6 ergs per mm-2 as its uvrA polA+ parent strain WP2s. It is proposed that the double mutant induces the SOS repair system (and probably other "reclex" inducible functions) at unusually low doses of UV as a consequence of its relatively inefficient repair of DNA damage when plated on broth-supplemented media.


[Mechanisms of release of leucocytic pyrogen]. Mechanisms of the production and release of leucocytic pyrogen (LP) from peritoneal polymorphonuclear leucocytes (PMN) from rabbits were studied in vitro. The following results were obtained. 1) The fever curves of the microsomal and the lysosomal fractions had a later onset and were longer lasting than those from the extracellular fluid. The fever curves of the supernatant of 105,000 g showed the typical response of endogenous pyrogen characterized by a rapid onset and short lasting fever, as shown by the extracellular fluid. 2) The pyrogenicity of LP was the most potent at 60 min while the 105,000 g supernatant was most potent at 30 min after PMN incubation at 37 degrees C. 3) The extracellular protein attained the maximum level at 30 min after incubation of PMN, while the protein content in the supernatant of 105,000 g of PMN decreased gradually to the constant level at 30 min. 4) It was observed that the lysosomal degradation was stimulated with bacterial pyrogen (LPS) at 37 degrees C but LPS did not directly affect the lysosomal fraction of PMN.


Glucagon biosynthesis in human pancreatic islets: preliminary evidence for a biosynthetic intermediate. Viable pancreatic islets were isolated from the pancreas of humans using modifications of the collagenase digestion and Ficoll gradient techniques. Gel filtration of tissue extracts following islet incubation in the presence of 3H- tryptophan indicated that radioactivity becomes incorporated into at least two islet proteins. The larger of the two (LGI) has the approximate molecular size of proinsuiln and the smaller coelutes with glucagon as determined by column standardization. Radioimmunoassay of the gel filtration eluate for glucagon revealed that both molecules have glucagon immunoreactivity. Gel filtration in the presence of 8M urea did not alter the elution pattern of the LGI molecule. Polyacrylamide gel electrophoresis was performed on these glucagon immunoreactive molecules. The 3H radioactivity and the glucagon immunoreactivity of the smaller molecule were found to co-migrate electrophoretically with crystalline porcine glucagon and monodesamidoglucagon. With electrophoresis at high pH the electrophoretic mobility of the LGI molecule proved to be lower than that of glucagon. Partial tryptic degradation of the human LGI molecule yields 3H-tryptophan labeled products having charge and immunologic characteristics indistinguishable from porcine glucagon and monodesamidoglucagon. Although further investigation is indicatend may thus serve as a precursor or an intermediate in human glucagon biosynthesis.


Synthesis of a chemically reactive analog of the initiation codon: its reaction with ribosomes of Escherichia coli. Nitrophenylated 5'-adenylic acid could be employed as primer in a polyribonucleotide nucleotidyltransferase (Micrococcus luteus) reaction to yield 5'-nitrophenylated pA-U-G. After reduction and subsequent bromoacetylation, an A-U-G analog was obtained, which could be used as an affinity label for the ribosomal A-U-G-binding site(s). After incubating the A-U-G affinity label with 70S ribosomes, 30S subunits programmed for initiation-factor-dependent fMet-tRNAMetf binding were obtained. Hence, the A-U-G analog had irreversibly reacted at the ribosomal decoding site. Initiation complexes which were formed with the labeled 30S subunits were puromycin-resistant. Furthermore, GTP hydrolysis, necessary for proper accommodation of initiator tRNA at the ribosomal donorsite, did not function in these complexes. These data indicate that immobilization of A-U-G at the decoding site of the ribosome allows factor-dependent initiator tRNA binding, but impairs accommodation at the donor site. The ribosomal protein(s) to which A-U-G was covalently bound at the decoding site were identified by polyacrylamide gel electrophoresis in the presence of urea or sarkosyl. The predominant affinity-labeled protein was found to be protein S18. Variation of the incubation conditions of the affinity-labeling reaction leads to attachment of A-U-G label to another ribosomal protein, S4, the ram gene product.


PSRO's and peer review: problems and opportunities. Legislation passed in 1972 mandated the establisment of Professional Standards Review Organizationa to review the quality of medical services to beneficiaries of the Medicare, Medicaid, and the Maternal and Child Health programs. Physicians in all 203 designated PSRO areas must show a viable organization by January 1976, or a nonphysician group may be designated as a PSRO. The author discusses the provisions of the law, reactions of physicians and others, the law's alleged shortcomings, and the questions that arise as a result of its passage. He cites some preliminary studies in the psychiatric literature that report positive effects of reviews of patient care.


A psychiatric POMR for use by a multidisciplinary team. A psychiatric problem-oriented medical record designed for use by multidisciplinary teams was introduced at Fairfield Hills Hospital in Newtown, Connecticut, in 1972. The need for revision in the hospital's medical record system had been pointed up by the development of the teams, which shared more equally in responsibility for patient care, and by problems in meeting Medicare standards. The authors describe the various forms that make up the POMR. Most of the forms are completed by the teams in regularly scheduled conferences.