Urethral pressure profile: current concepts. The urethral pressure profile is an artifactual assessment of urethral response to physiologic distension. It is a reproducible clinical tool used to evaluate numerous disease states. Examples of its usefulness are presented to illustrate the wide variety of clinical uses. The urethral pressure profile assists the clinician in the selection of the proper form of management in difficult cases of urinary incontinence or obstruction.


Clinical trial with glipizide in uncomplicated maturity onset diabetes mellitus. A clinical trial with a new hypoglycaemic drug glipizide was carried out for an average period of 7 months, on 51 non-insulin independent adult diabetics attending the out-patients clinic of the Diabetic Association of Pakistan, Karachi. Forty five patients were satisfactorily controlled on glipizide. No toxic side effects were observed and the drug was well tolerated.


Aspects of paediatric liver disease in Karachi. Seventy children with hepatomegaly, between the ages of 3 months and 13 years, were investigated including a liver biopsy in 60, to study the general pattern of liver disease in children. Thirty percent had acute viral hapatitis, 20 percent cirrhosis, 17.6 percent pulmonary tuberculosis, 18 percent hereditary diseases and 14 percent miscellaneous diseases involving the liver. None of the cases met the criteria for Indian childhood cirrhosis. It was concluded that in Karachi pulmonary tuberculosis was a common case of hepatosplenomegaly in children and that the aetiology of cirrhosis was probably multifactorial.


The role of drug information centres for improving patient care in Pakistan and other developing countries. Relevant and uptodate information about drugs in common use is either unavailable or scarce, in Pakistan and other developing countries. Developed countries inspite of all the facilities available for learning have recognised the limitation of human memory. Drug information centres have therefore been established for repeated reminder and continued education for the practicing doctors in prescribing drugs and early recognition of adverse reactions to them. The proposal for establishing such drug information centres in Pakistan and other developing countries for further improving the patient care and early reporting of adverse reaction to drugs in this paper is based on the encouraging response to and beneficial experience by such centres in the western world. There is every reason that it will succeed in improving the health of the people of Pakistan.


The relationship between the chemical structure of fatty acids and their mycobactericidal activity. The bactericidal activity of long-chain fatty acids on mycobacteria was examined by exposing the organisms to these acids at 0.04 mM in 0.05 M acetate buffer (pH 5.6). The lethal effect of saturated fatty acids was related to the chain-length of hydrocarbon, C14:0 being the strongest in the activity and longer and shorter fatty acids being less active. Unsaturation, isomerism and the presence of alpha-hydroxy group were found to be other factors governing the activity. The lethal effect was greater in the order of C18:3 greater than C18:2 greater than C18:1(cis) greater than C18:1(trans) greater than alpha-OH C18:0 greater than C18:0. C20:4 was placed between C18:3 and C18:2 in this respect. Esterification of C14:0,  C18:1 and C20:4 to methyl esters and cholesteryl esters abolished completely the bactericidal activity of these acids, suggesting the requirement of carboxyl group for the activity. The relationship between the fatty acid structure and the lethal effect was discussed in reference to these observations.


A new Paramyxovirus isolated from cynomolgus monkeys. A new virus was isolated from cynomolgus monkeys for laboratory use imported from Indonesia in July, 1973. The virus agglutinated erythrocytes of some avian and mammalian species and hemolyzed chick erythrocytes. The virus was eluted from the surface of chick red blood cells by its neuraminidase activity. The virus was inactivated by ether; its nucleic acid was RNA. On electron micrographs, the particles varied from 250 to 400 nm in diameter, being covered with envelopes in which the surface projections were embedded. The diameter of inner helical structure was about 18 nm. These observations indicate that the virus belongs to a group of paramyxoviruses. On the basis of serological examinations, this virus can be identified as a new virus having some relations with Yucaipa or Bangore viruses. This virus is designated as "Murayama virus" from the name of the place where it was isolated.


[Parathyroid function in patients on chronic intermittent hemodialysis (author's transl)]. In three groups of hemodialysis patients the effects of an acute elevation of the serum calcium concentration on the predialysis parathyroid hormone concentration was studied. In the first group (13 patients) the predialysis parathyroid hormone (PTH) concentrations were normal, in the second group (11 patients) slightly elevated, in the third group (5 patients) highly elevated. Calcium was determined by atomic absorption-spectrophotometry, PTH by radioimmunological methods. In hemodialysis patients with normal predialysis PTH concentrations a correlation between the serum calcium concentration and the serum PTH concentration could not be detected. In hemodialysis patients with slightly as well as with highly elevated predialysis PTH concentrations a significant, linear, negative correlation was found between the calcium and the PTH concentration. This correlation, however, was only strong within groups of similar parathyroid hyperfunction. If instead of the absolute PTH concentration calcium is correlated with the changes of the PTH concentration in per cent, a strong correlation between these two parameters can be detected, it is independent of the degree of parathyroid hyperfunction.


Breeding the owl monkey (Aotus trivirgatus) in a laboratory environment. A breeding colony of owl monkeys (Aotus trivirgatus) established in 1972 produced 35 live infants during the first 3 years from an average daily population of 30 monogamous pairs. Initial productivity was poor, but once the breeding pairs were set up by karyotypes, reproductive performance improved. No seasonal influence on births was observed and most births occurred during daylight hours. Uterine size during gestation ranged from about 1 cm in diameter at 30 days after conception to 7--8 cm (transverse diameter) x 18--20 cm (longitudinal diameter) at 115 days after conception. The fetal head was palpable at 85 days. A gestation period of 120-140 days was estimated from extrapolation of uterine palpation data and interbirth intervals. Vaginal swabs collected from six females during two separate 1-month periods did not consistently reveal estrous cycles. An analysis of owl monkey milk showed it to contain 88.2% water, 2.16% crude protein, 2.09% fat, 7.52% lactose, and 0.36% ash.


Behavioral research in breeding colonies of Old World monkeys. The existence of an active behavioral research program using animals in primate breeding colonies was considered to be not only a compatable multiple use of animals, but a way of materially improving the management and efficiency of the breeding colonies. In colonies of monkeys specifically established for behavioral research programs directed at the examination of social relationships, incidental breeding resulted in levels of reproductive success equivalent to or greater than that normally experienced in colonies devoted entirely to breeding. Behavioral research revealed patterns of seasonality, fostering, kidnapping, and infant care which would otherwise have escaped notice and which would significantly influence culling and management choices in a breeding colony. Many young males and certain low ranking adult males actively contributed to reproduction. Females born and reared in the colonies were the most productive, exceeding wild born or other introduced females in reproductive efficiency. Specific recommendations for establishing, expanding and culling of nonhuman primate breeding colonies were derived from the behavioral research.


Factors influencing aggressive behavior and risk of trauma in the pigtail macaque (Macaca nemestrina). Several experiments and surveys were conducted in a large colony of pigtail macaques (Macaca nemestrina) to determine some of the influences of spatial and social factors on aggressive behavior and risk of trauma. Female subjects exhibited more aggression when they had access to two-room suites than when they had access to single rooms. The frequency of aggressive interactions among females was positively related to the number of females per group. The presence of one or more males in groups inhibited aggressive interaction among females. Less aggression occurred among females in groups containing infants than in groups containing no infants. Provision of cover by introduction of concrete cylinders into rooms reduced aggression among members of stable groups. Subjects in newly-formed groups composed of unfamiliar animals sustained fewer injuries than did those in groups formed by merger of groups or subgroups of familiar animals.


Breeding and rearing squirrel monkeys (Saimiri sciureus) in captivity. A breeding colony of squirrel monkeys (Saimiri sciureus) was established to provide animals for behavioral research concerned with early development. The origin of the initial breeders was Peru, Colombia, and Bolivia. During the past 10 years, the colony has grown to 125 adult females, 20 adult males, and 120 immature animals of various ages. The annual conception rate for the last 5 years averaged 68%. This resulted in 84% viable births of which 82% survived past 6 months of age. The majority of the births (65%) occurred during June-August, and 87% during May-September. The most efficient and successful breeding strategy was to form mixed-sexed groups of 10--15 females and 2--3 males before the mating season began and to maintain the integrity of these groups with minimal interference. Progeny were reared apart from their natural mother without difficulty, and their growth and development were found to be similar to those of mother-reared monkeys.


Isolation and partial characterization of the heterophile antigen of infectious mononucleosis from bovine erythrocytes. The heterophile antigen (Paul-Bunnell antigen, PBA) of infectious mononucleosis was isolated by extraction of an aqueous suspension of bovine erythrocyte stromata with chloroform-methanol (2:1). The upper aqueous layer contained gangliosides, PBA, and a high-molecular-weight glycoprotein. PBA and gangliosides were separated from the high-molecular-weight glycoprotein by extraction of lyophilized upper layer with chloroform-methanol solvents. Separation of PBA from gangliosides was carried out by chromatography on DEAE-cellulose with chloroform-methanol solvents. PBA appeared to be a minor glycoprotein component of the erythrocyte membrane and had both hydrophobic and hydrophilic properties. It was soluble in either organic or aqueous solvents. On SDS-polyacrylamide gel electrophoresis, it migrated as a single component that stained for protein with Coomassie blue, for carbohydrate with periodic acid-Schiff reagent, and for lipid with oil red 0; it had an apparent molecular weight of 26,000. It was composed of 62% protein with major amino acids; glutamic acid, proline, glycine, isoleucine, leucine, and threonine (158, 116, 98, 90, 85, and 82 residues per 1,000 residues, respectively). Carbohydrate content was 9.2% with major sugar constituents: sialic acid, galactosamine, and galactose. Serologic activity of PBA was destroyed by pronase but not by trypsin.


Radiation induced carcinoma of the temporal bone. This report presents a case of squamous cell carcinoma of the temporal bone induced by high dose radiation therapy. Several important surgical techniques are stressed which serve to make this procedure far safer in the avoidance of catastrophic hemorrhage.


Antimicrobial lipids: natural and synthetic fatty acids and monoglycerides. Over 40 natural or synthetic lipophilic compounds were screened for antimicrobial activity. Gram (+) bacteria and yeasts but not Gram (-) bacteria were affected by these agents. Epimino and selena fatty acids are more active than their corresponding straight chain unsubstituted fatty acids. The position of selenium influenced the antimicrobial activity of the fatty acids. The presence and position of a double or triple bond, usually an important factor in long chain fatty acids (greater than C14) had little or no effect in C11 fatty acids. Optimum antimicrobial activity was found for fatty acids and their corresponding monoglycerides when the chain lenght was C12. The dilaurin derivative was not active.


[Effect of different carbon, nitrogen and phosphorus sources on the biosynthesis of proteases with coagulase activity by Bacillus subtilis var, amyloliquefaciens]. Proteolytic enzymes with coagulase activity were found in the cultural broth of Bacillus subtilis var. amyloliquefaciens 759 grown on chemically defined and natural media. The effect of various sources of carbon, nitrogen and phosphorus on biosynthesis of proteases with coagulase activity was studied; mineral and organic nitrogen sources were equally favourable for the growth and protease biosynthesis. The best sources of carbon for biosynthesis of the enzymes were glucose, sucrose, maltose, fructose, and sorbitol. Potassium salts of ortho-phosphoric acid were assimilated as a source of phosphorus.


[Hypophase carotenoids and the structure of epiphase carotenoids of Anabaena variabilis]. Four major and three minor carotenoids of the glucoside nature were isolated by column and thin-layer chromatography on cellulose from the hypophase fraction of the pigment extract of Anabaena variabilis growing for 8 days. One of these major pigment components was supposed to be myxoxanthophyll. The structure of some epiphase carotenoids of Anabaena variabilis was established. The following pigments were also found to be present in the cell: beta-carotene, echinenone, neoechinenone U, and 3'-hydroxyechinenone, cryptoxanthin, zeaxanthin.


[Relation of the growth of Anabaena variabilis cyanophages to photosynthesis and respiration]. Cyanophages A-1 (L) and A-4C (L) grow within the cells of Anabaena variabilis under aerobic conditions in the dark in the presence of endogenous or exogenous (surcose) sources of energy. DNP inhibits the growth of cyanophages in the light and almost completely supresses it in the dark, o-phenanthroline entirely supresses the growth in both cases. DCMU has almost no effect on the yield of the virus in the light. Virus particles can apparently be synthesized at the account of the energy of both oxidative and cyclic photophosphorylation.


[Effect of formaldehyde on a Pseudomonas fluorescens strain]. The strain of Pseudomonas fluorescens was isolated from active ooze and was capable of growth on a medium containing 100 mg/litre of formaldehyde. As a result of stepwise selection, a variant of Ps. fluorescens 27 oxidizing 250 mg/litre of formaldehyde was obtained. It differed from the parent strain in cultural, morphological, and biochemical properties.


[Transport and excretion of a fluorescent pigment by cells of a Pseudomonas fluorescens culture]. The transport and exretion  of a yellow-green pigment were studied with the culture of Pseudomonas fluorescens K-1. These processes were found to be accomplished by means of membranous formations having a lamellar structure.


Fast neutrons from a 25-MeV betatron.

Fast neutrons from a 25-MeV betatron. Since published results for the fast-neutron dose per x-ray rad from high-energy therapy installations have differed by as much as a factor of 300, we have measured the neutron production from our 25-MeV betatron. Fast-neutron activation of aluminum foils was the method used. The effect of photoneutron production in the detectors, which has affected some past work, has been eliminated. A major source of neutrons in the treatment field was the platinum target. The neutron spectra used in the calculations of fluence were obtained by interpolation between published energies and between neighboring elements. Fluences per rad of x rays without a phantom were largely independent of field size and energy in the range 18-23 MeV. At 100 cm SSD and 23 MeV a large beam flattener contributed 15% of the neutrons, the remainder coming equally from the target and background. A phantom increased the neutron fluence/rad of x rays by 0%-10% depending on the field size. At 23 MeV we estimated the neutron dose to a patient to be 2.2 X 10(-4) rad per rad of x rays inside the treatment field and 3 X 10(-5) at 20 cm outside the field. The uncertainty in these figures is believed to be +/- 50%. In the electron beam the neutron dose per rad was about 50 times smaller than in the x-ray beam. Estimates were made of neutron fluences at other energies and target thicknesses. We discuss our results in comparison with those of others.


Use of a dynamic rangeshifter for modifying the depth-dose distributions of negative pions. In order to use negative pions for the treatment of large deep-seated tumors in radiotherapy, it is necessary to produce depth-dose distributions tailored to specific shapes. We present here a method of beam shaping which utilizes a fluid-filled piston having a programmable, computer-controlled, time-dependent thickness. The fluid alters the residual range of the pions such that predetermined depth-dose distributions can be obtained. Changing from one distribution to another can be accomplished simply and rapidly without access to the treatment room. Depth-dose distributions which are flat over a range in depth up to 10 cm have been produced. Distributions tailored to produce flat "effective dose" versus depth have also been obtained.


Measurement of photon dose fraction in a neutron radiotherapy beam. Photon dose fractions (PDFs) have been measured in and around a neutron radiotherapy beam with a tissue-equivalent proportional counter (TEPC) and with paired ion chambers. The PDFs were found to increase linearly with increasing field size and width depth in phantom. PDFs were shown to decrease with decreasing phantom size and to be larger in the shielded region of the phantom than in the direct beam. Uncertainties in the PDF values were estimated to be 10%-15% for the TEPC measurements but about 50% for the measurement made with ion chambers.


Dosimetry of pion therapy beams.

Dosimetry of pion therapy beams. Cellular, animal, and human radiobiology studies are in progress at the Los Alamos Meson Physics Facility as part of a joint University of New Mexico and Los Alamos Scientific Laboratory pion therapy project. To support these activities, dosimetry has been performed on many different pion beam configurations. The effect of both static and dynamic momentum spreaders and of collimators on beam profiles, depth-dose distributions, and peak-to-plateau ratios have been studied. The absorbed dose is obtained by the application of Bragg-Gray cavity theory to ionization chamber measurements. Calculations have been made for the effective W values and average mass-stopping-power ratios needed for the Bragg-Gray equation. Kerma corrections are applied to transform the dose from the chamber wall to dose in muscle.


High-energy-photon dose measurements using exposure-calibrated ionization chambers. The current method for determining absorbed dose from high-energy photons is to use in water a Cobalt-60 exposure-calibrated ionization chamber and Clambda. Recently questions have arisen about the correctness of currently recommended Clambda values and whether or not the Cobalt-60 buildup cap should be used for in-water dose measurements. The effect of the buidup cap on Clambda was obtained by measuring Farmer chamber response in water with and without the buildup cap. Results show no measurable change at Cobalt-60 or 4 MV but an increase of 1%-2% above 20 MV. The effects of the wall materials and the displacement factors on Clambda are also considered. It is shown that at high energies errors of 3%-5% can be made in determining dose in water using commercially available Farmer or Farmer-like chambers and currently recommended Clambda. The exact size of the error depends upon the materials and thicknesses of the wall and cap, the chamber cavity volume, and whether or not the buildup cap is used.


Bacterial sensitivity to the aminoglycosides. From the reports of bacterial sensitivity testing reviewed here, it can be concluded that gentamicin has currently a very broad spectrum, with few resistant organisms. Gentamicin, amikacin, and tobramycin are the most effective of the aminoglycosides against Pseudomonas. They are also effective against Escherichia, salmonellae, staphylococci, pasteurellae, Klebsiella, and others; they are less effective against streptococci. Streptomycin is effective but bacterial resistance to it develops very rapidly and there are a large number of resistant strains involved in animal diseases. It is the least effective aminoglycoside that is commercially available. Neomycin is fairly effective against staphylococci, less effective against streptococci, and fairly effective against gram-negative intestinal organisms.


Tissue-maximum ratios for high-energy x rays. The tissue-maximum ratios for high-energy betatron x rays, measured at target-axis distances of 90, 110, and 130 cm, exhibit a strong dependence on the target-axis distance in the buildup region as well as a significant dependence in the exponential region. This dependence and the field-size dependence of the tissue-maximum ratios at a fixed target-axis distance are studied with the use of phantom and collimator scatter factors. The depth and field-size dependence of these scatter factors are determined experimentally. The measurements indicate that the collimator scatter factor is dependent on both the collimator opening and the targetaxis distance. These components are quantitated separately and are associated primarily with high-energy electron scatter from the collimating system. An equation involving these components of the collimator scatter factor is derived for the conversion of tissue-maximum ratios from one target-axis distance to another. With the use of this equation, the tissue-maximum ratios measured for one target-axis distance can be used to calculate within 1% those at other target-axis distances.


Characteristics of Clinac-18 wedged fields for 10-MV x rays. The characteristics of wedged fields which affect their clinical use have been examined for the 10-MV x-ray beam from the Clinac-18. The methods used for obtaining and analyzing the wedged-field data are discussed. These characteristics have been examined in terms of (a) the wedge angle, (b) the variation of the wedge angle with field size, (c) the variation in the angle through which isodose curves between the approximate depths of 5 and 15 cm are turned relative to the central axis as a function of depth, and (d) the variation of wedge central-axis transmission factor with field size. Analysis of the data pertinent to these categories is presented for the 15-, 30-, 45-, and 60-deg wedges. In addition, the effect of the 60-deg wedge upon the position of maximum dose on the central axis was determined.


Satellite digital display for the Clinac-18. A satellite digital display of the gantry and collimator positions has been mounted on the Clinac-18 console. This module provides simultaneous digital readout of the gantry angle, collimator rotation angle, upper-jaw position, and lower-jaw position. Continuous display of these parameters during the treatment is important in minimizing patient treatment errors.


Contributions from the animal laboratory-- drug and response inhibition. Recent developments in animal psychopharmacology were reviewed with special reference to our 10-year studies in confirming the disinhibitory theory of chlordiazepoxide in frustrative nonreward (rats), spontaneous alternation (rats), discrimination reversal (rats), successive discrimination (rats), go/no-go type descrimination (rats, monkeys), passive and shuttle avoidance (rats) and differential heart rate conditioning (rats). Although anticholinergics have a similar behavioral function, their sites of action seem to be different because of their effect on the hippocampal electrical activity is markedly distinct from that of chlordiazepoxide.


[The effect of primidone treatment of thyroid hormones in epileptic children and adolescents (author's transl)]. In primidon-treated patients there are significantly decreased serum concentrations of total and free thyroxin, protein bound iodine and base line serum TSH values. In primidon-treated children T3-resin test values, concentration of thyroxin-binding protein and total cholesterol are identical to those of the control group. Degree of diminution in serum concentration of protein bound iodine, total and free thyroxin and base line TSH was independant of the primidon dose per day. Probably the demonstrated alteration in the thyroid function tests studied, is mainly caused by phenobarbital, the major metabolite of primidon and not directly by unmetabolized primidon. It is suggested that the high protein-binding capacity of phenobarbital results in a competitive displacement of protein bound thyroxin comparable to that of DPH. Phenobarbital is know to be a stimulator of the drug metabolizing enzyme system in the liver. This effect may be the cause of an increased turnover of T4 which results in a decreased serum concentration of total and free T4 at last. It seems possible that there is a balance in serum concentration of thyroid hormones on a lower level. Normal euthyroid state may be presumed, if T4-secretion raises, but there is no clue for an increased pituarity response. In contrast to the normal group in primidon-treated children the base line serum TSH values are decreased. It is supposed that another effect of primidon is responsible for this fact. There may be an influence of primidon treatment on hypothalamic pituarity axis. Our findings do not indicate clearly a hypothyroid state in primidon-treated patients; further investigations should give an answer to the guestion, if side effects as tiredness, decreased impetus and constipation are not partly caused by alterations in thyroid hormone system.


[Rational diagnosis of malignant systemic hematological diseases (author's transl)]. The present discussion on the cost explosion in the health system compels all concerned to act according to the basic principles of economy. Efficiency in diagnosis, therapy and the supervision of the patient during treatment must not suffer, however, from a wrong idea of economy. Discussion of the diagnostic and differential diagnostic measures for the detection of acute leukemias, of myeloproliferative and lymphoreticular diseases and of monoclonal gammopathies takes place principally from the point of view of clinical relevance. In particular it ought to be stated which laboratory investigations are indispensable for an exact diagnosis.


[Hemorrhage in portal hypertension (author's transl)]. The increasing number of toxic cirrhoses of the liver and their concomitant diseases demands differentiation in the choice of surgical technique in acute hemorrhage. The characteristics of the habitually orthostatic human circulation give some indications on the formation of varices. Experience offers new approaches to the prevention of reflux in the esophagus. Diagnostic and therapeutic procedures in the different types of bleeding in the acute hemorrhage of portal hypertension and intrahepatic block are discussed.


[Symptom changes and rational therapy of vitamin B12 absorption disturbances (author's transl)]. Longterm parenteral therapy with the physiological depot form of vitamin B12 (aquocobalamin) is now the treatment of choice for pernicious anemia and funicular myelopathy. An optimal dosage scheme is given. High-dose oral and intrathecal applications of viatamin B12 are also possible in the individual case. If symptoms of neurological deficiency are already present in funicular myelopathy, additional physiotherapeutic measures, supervision of bladder function, prophylaxis of decubitus ulcers and contractures are necessary.


[Echography of knee joint cysts (author's transl)]. Because of a palpable swelling, 57 popliteal fossae were examined echographically. In 24 cases, the echography revealed a probable Baker's cyst. This diagnosis was confirmed by arthrography or at operation in 21 of the 24 cases. Two of the three findings which did not correspond were due to over-interpretation of the echographic picture and can be avoided in future by giving particular intention to the sound intensity. The causes of the discrepancy in the third case are still undetermined. These results show that echography is suitable for the discovery and assessment of Baker's cysts and should be used first as a non-invasive, painless, rapidly reproducible method.


[Recurrent retroperitoneal giant lipoma (author's transl)]. A giant lipoma weighing 9.1 kg situated retroperitoneally which was removed by operation from a 74-year-old woman is reported. The diagnosis of tumors is discussed. The characteristics of this primary benign tumor such as the rapid growth, tendency to malignant degeneration and recurrence make radical surgical removal necessary.


[Whole body computer tomography: principle-purpose - requirements (author's transl)]. After explaining the principle of whole body computer tomography the field of indication is outlined with reference to some of our own experiences. Up to now, it has proved its value in the following indications: preoperative diagnosis, supplementing pulmonary radiodiagnosis, substitution of invasive diagnostic procedures in mediastinal diseases, clarification of diseases of the abdominal cavity, of space-occupying processes in the kidney, in the true pelvis, and detection of retroperitoneal processes. The financial expenditure for this novel method of investigation is described according to a formula. The cost of given or estimated numerical values show the importance of adequate usage. The added costs for a second personnel shift for an examination rate of more than 7 patients a day are trivial because of the high basic expenditure.


[The oral antidiabetics (author's transl)]. Oral antidiabetics are given for preference to adult diabetics who do not need insulin. Biguanides are particularly indicated for adipose diabetics, sulphonamides for those of normal weight. Phenformin must not be used in the presence of renal insufficiency and severe liver diseases because of the high risk of lactacidosis. Oral antidiabetics should not to be given during pregnancy. With oral treatment of diabetics under the age of 30, proteinuria, peripheral vascular diseases and disturbances of fat metabolism occure more frequently while retinopathies, coronary diseases, peripheral neuropathies or infections of the urinary tract cannot be influenced orally, nor by insulin nor by a combination of the two. The i. v. lipid tolerance test is always pathological even in apparently well-adjusted orally treated diabetics. On the other hand it is normal even in less well adjusted insulin therapy. More epidemiological investigations should be carried out in order to be able to assess clearly the longterm effects of oral antidiabetics.


[Etiology of diabetes (author's transl)]. Numerous factors are involved in the genesis of diabetes. Consequently it is difficult to summarize the different theories and ideas in a uniform hypothesis. The principal factor is the failure of the beta-cells. Genetic factors, auto-immune reactions, virus infections, all may play a role. Age, sex, menopause, pregnancy and adiposity may be important for triggering a diabetes, quite apart from diseases of the pancreas, endocrine disturbances and possible effects of medicaments. And this is not the end of the list of potential factors either.


[Monocomponent insulins (author's transl)]. "Monocomponent" insulins (M. C. insulins) are characterized by a high degree of purity. They do not stimulate the production of antibodies at all or only very slightly, reduce insulin resistance and allergic reactions, cause lipodystrophies to disappear and lower the insulin requirement. The author was able to confirm this from his own experience. With the exception of one Australian team, other authors also judge M. C. insulins favorably. Whether these insulins can also reduce vascular complications cannot yet be finally decided.


[Insulin receptors (author's transl)].

[Insulin receptors (author's transl)]. The saturable insulin binding is linked to insulin degradation in two important target cells: The hepatocyte and the adipocyte. One of the consequences is that the changes in binding which are observed under various conditions cannot a priori be regarded as caused by either increased number of receptors or increased affinity of the binding site. This observation raises new questions. For instance, could the effect of insulin be mediated by a fragment of the molecule? No evidence which is available for the moment seems to rule out this hypothesis. The findings with insulin analogues, the kinetics of insulin binding and activation and the effect of mild trypsin treatment, would equally well support the hypothesis that the binding itself causes activation of hexose transport and that degradation secondary to binding mediates the activation.


Laboratory-acquired Rocky Mountain spotted fever. The hazard of aerosol transmission. Nine patients with laboratory-acquired Rocky Mountain spotted fever were seen during the period 1971 to 1976. Investigation of each case revealed either definite or probable exposure to an aerosol containing infectious rickettsiae; in no case was there evidence of parenteral exposure either by accidental self-inoculation or by tick bite. These illnesses are believed to represent infection acquired via the respiratory route. This report emphasizes the aerosol hazard of Rickettsia rickettsii in the laboratory and discusses the possibility of respiratory transmission of Rocky Mountain spotted fever in nature. The illness occurred only in personnel who had received either no vaccination or the primary series of the commercial (Lederie) vaccine against this infection. Other personnel who had received the primary series with multiple booster vaccinations demonstrated increased immunity as measured by humoral antibody titers and rickettsial antigen-induced lymphocyte transformation; no cases of clinical disease developed in these multiply-vaccinated personnel.


Prostaglandin-producing suppressor cells in Hodgkin's disease. We examined the role of a prostaglandin-producing suppressor cell in the hyporesponsiveness to phytohemagglutinin seen in Hodgkin's disease. Addition of indomethacin to phytohemagglutinin cultures of lymphocytes from six patients with Hodgkin's disease resulted in an increase of 182 +/- 60 per cent in 3H-thymidine incorporation versus a 44 +/- 18% increase in 29 controls (mean +/- S.D., P less than 0.001). Without indomethacin the mean response of the lymphocytes in Hodgkin's disease was 48% of that of control. With indomethacin it was 94% of the control value. Phytohemagglutinin cultures of Hodgkin-disease lymphocytes produced approximately fourfold more prostaglandin E2 after 48 hours than did normal lymphocytes (P less than 0.02). Removal of glass-adherent cells markedly decreased the enhancement seen with indomethacin; it reduced prostaglandin E2 production by more than 80% and eliminated the differences in response to phytohemagglutinin between Hodgkin-disease and normal lymphocytes. Thus, a glass-adherent, prostaglandin-producing suppressor cell is responsible for the hyporesponsiveness to phytohemagglutinin seen with Hodgkin-disease lymphocytes.


Human mammary gland associated antigens. Lack of D-type retravirus-induced antigens. Antisera against tumor-associated and organ-specific antigens of human mammary glands, as well as mammary carcinoma patient sera were used in cross-reactions with the test-system for a nucleoid antigen of Hep-2 retravirus. None of the antigens, revealed in mammary carcinomas and human milk seems to be either viral structural, or virus-induced cellular antigen. No cross-reactivity was revealed between preparations, containing A-type particles, isolated from Hep-2 cells and human milk and mammary carcinomas. Cell surface antigen, nonidentical to viral structural antigens, was detected in Hep-2 cells. It proved to be shared by E16b and some other stable cell lines, however it cannot be detected in mammary fibroadenomas, positive for the D-type nucleoid antigen, and in mammary carcinomas. Only gastric carcinoma homogenates exhibited reaction of identity with the cell surface antigen, shared by Hep-2 and E16b cells. It suggests that some common stem cells might be involved in its synthesis, rather than D-type retravirus genome. This question is worth a special investigation. The findings obtained show the genome of D-type retravirus is repressed in mammary carcinomas in contrast with fibroadenomas, when synthesis of nucleoid antigens was revealed by ILYIN [7].


[Enterohepatic circulation of bile acids and biliary lipid secretion]. The enterohepatic circulation of bile acids in man is reviewed. The chemistry of biliary bile acids is summarized and related to the formation of primary bile acids in the liver and secondary bile acids in the intestinal lumen. New findings showing that lithocholic acid is absorbed in man are presented, and the recent experiments showing that lithocholic acid is extensively sulfated are reviewed. The consistent hepatotoxicity of chenodeoxycholic acid in the rhesus monkey, which contrasts with its non-toxicity in man, is explained by the inability of the rhesus monkey to sulfate abosrbed lithocholic acid; this accumulates in the enterohepatic circulation of the monkey causing liver damage. In man, absorbed lithocholic acid is rapidly sulfated, and the sulfated conjugates are excreted fecally without enterohepatic cycling. The physical chemistry of bile is highlighted, and it is shown that the saturation of bile with cholesterol depends on the amount of bile acids passing through the liver: at low bile acid flow rates, such as occurs during overnight fasting, bile is supersaturated in both gallstone and healthy persons. Chenodeoxycholic acid decreases cholesterol secretion into bile, renders bile unsaturated during most of the day and night, and thus induces gallstone dissolution.


A fever index evaluation of chloramphenicol or clindamycin in patients with serious pelvic infections. The fever index measured the responses of 102 women with serious pelvic infections who had received either chloramphenicol or clindamycin, in combination with other antibiotics. There was no statistical difference in the number of degree hours in the two populations. Patients with salpingo-oophoritis had significantly more fever than those with a septic abortion. Bacteremia did not delineate a group of women with a markedly elevated febrile response. Within the populaton with salpingo-oophoritis, neither black women nor women with an intrauterine device in place had significantly more fever, but patients requiring operation had more fever while those with an endocervical culture positive for the gonococcus at the time of admission had the most favorable clinical response. The significance of these findings is discussed.


Aortic compression and uterine blood flow during pregnancy. To understand the effects of uterine compression on the abdominal aorta in pregnant women, the abdominal aorta in pregnant animals was experimentally constricted. This procedure produced symptoms identical to toxemia in humans. A physical model simulating the human aorta with blood flowing under physiologic pressure, and a "term uterus" pressing on it showed that blood flow reduction thus produced easily could be within the range observed in the toxemic human. Experimental constriction or compression of the abdominal aorta in pregnant animals produced a parallel drop in the femoral artery pulse pressure and uterine artery blood flow. This observation is applicable to pregnant women in the supine position. When the pregnant uterus presses on the abdominal aorta, reduced uterine artery blood flow was noted by following femoral or popliteal artery pulse pressure reduction. In 379 pregnant patients studied, 40% showed a drop in popliteal artery pulse pressure during uterine contraction and 11% during uterine relaxation. During relaxation, this was observed in 16% of primiparous patients and in 6% of multiparious patients.


The effect of angiotensin II and indomethacin on uterine artery blood flow in pregnant monkeys. In experiments performed in anesthetized monkeys in the third trimester of pregnancy, mean maternal arterial blood pressure was continuously monitored, the uterine artery blood flow was measured with an electromagnetic flow probe, and prostaglandin levels were assayed in the uterine venous effluent. After inhibition of prostaglandin systhesis with indomethacin, the mean arterial blood pressure in response to angiotensin II was greater than the response prior to indomethacin treatment, and an increase in uterine artery blood flow was prevented. These findings are consistent with the suggestion that prostaglandins mediate the uterine artery blood flow response to angiotensin II, as well as modifying the maternal systemic blood pressure response.


[Time of gene activity during drosophila ontogenesis. III. Temperature-sensitive period of the homeotic mutation nasobemia]. The temperature-sensitive period (TSP) was determined for the homoeotic mutation Nasobemia which causes the antenna to leg transformation in D. melanogaster. The rate of homoetic transformation was measured in the adult flies which emerged after the temperature shift from 29 to 17 degrees and vice versa applied at different larval stages. The TSP begins at 29 degrees at 63 hrs and ends at 39 hrs prior to the pupation, while at 17 degrees it begins at 216 hrs and ends at 132 hrs prior to the pupation. This means that the end of the 1 st larval instar and practically all the 2nd instar are temperature sensitive. A suggestion is put forward to the effect that the TSP corresponds to the period during which the process of abnormal determination of the imaginal disc cells takes place.


[Changes in glycogen metabolism in chick embryo liver in relation to the formation of glycosomes]. In the chick embryo liver the portion of granular glycogen increases from 15 to 90% of the total content during the period from the 8th till the 14th days of developments. The activity of glycogen synthetase (KF 2.4.1.11) localized in the fraction of granular glycogen increases from 40 to 90% of the total activity in the 18 days old embryo. The activity of phosphorylase (KF 2.4.1.1) is detected in the granular glycogen of the liver only on the 12th day of development (10% of the total activity) and increase up to 80% on the 19th day of development. The maximal activation of glycogen synthetase and phosphorylase is noted after the glycosomes of formation in the developing embryoliver. A suggestion is put forward to the effect that the process of glycosome formation is a factor of the control of glycogen synthetase and phosphorylase activity.


Effects of the water-soluble carcinogen 4-nitroquinoline N-oxide on hamster lingual mucosa. The water-soluble carcinogen 4-nitroquinoline N-oxide (4NQO) was painted onto hamster ventral lingual mucosa twice weekly for up to 20 weeks. No neoplasms developed during this period. The promoting agent croton oil was applied to the treated areas in an attempt to determine whether initiation had occurred. During the following 6 months, one animal developed a papilloma and three animals showed areas of epithelial atypia in the treated mucosa. No malignant neoplasms were seen. Despite its efficiency in producing intraoral neoplasms in the rat, 4NQO would appear to be a poor choice in the hamster.


The effect of topical antihistamine on the initial pulpal inflammatory response of monkey teeth. Cavity preparations were made in sixty sound teeth of healthy monkeys. Thermal trauma was delivered to the pulps of all teeth through application of a heated soldering iron to the floor of a cavity preparation. Fifteen teeth were randomly designated as controls and were restored immediately with zinc oxide and eugenol. Forty-five teeth were designated as test teeth. These were treated topically with a 4 per cent antihistamine solution and restored with zinc oxide and eugenol. Histologic sections were prepared to show the effect of the antihistamine on the thermally initiated inflammatory response during the postoperative period. No significant difference was observed in the inflammatory reactions of treated or untreated pulps. A 4 per cent aqueous solution of topically applied antihistamine did not appear to be of any significant value in obviating pulpal inflammation.


Effect of otolith end organ ablation on horizontal optokinetic nystagmus, and optokinetic afternystagmus in the squirrel monkey. Horizontal optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN) (stimulus speed 0-200 degrees/sec with 1 degree/sec constant angular acceleration) were examined before and after utriculo-sacculectomy (bilateral, two-stage) in squirrel monkeys. OKN exhibited a slight decline only after bilateral otolith and organ ablations. OKAN showed a minimal decline after unilateral operation but no change after bilateral operations. Severe OKN reduction and disappearance of OKAN after bilateral labyrinthectomy in primates should basically reflect the elimination of inputs from the cristae ampullares, and not from the maculae.


[Treatment of severe Rhesus erythroblastosis]. Report about the management of cases of severe Rhesus erythroblastosis. One case is specially discussed because of it's actuality. This was a patient with severe Rh-sensitization (OOD at 450 mm from the beginning of the 30th week of gestation in zone III according to Liley). Because of the haemolytic disease and the chronic fetal distress the Caesarean section was already performed in the 32nd week of gestation after Betamethason treatment of the mother. The Lecithin-Sphingomyelin (L/S) ratio in the amniotic fluid as a criterium of fetal lung maturity raised almost twicefold (from 0.9 to 1.6) after Cortison treatment. The intensive care (assisted ventilation with PEEP, correction of the acidosis and transfusion of packed red cells) of the severely anaemic (Hb 3.5 g%, Hk 15 vol.%) and hydropic newborn was already started in the delivery room. The newborn developed no RDS and was discharged healthy. With reference to this and other cases the management of severe Rh-sensitization before the 34th week of gestation is discussed. Premature infants are mainly susceptable to the development of a Respiratory Distress syndrome (RDS). After antepartum Cortison treatment for prevention of an RDS the date of confinement should be arranged earlier. The value of an early Caesarian section after antepartum Glucocorticoid treatment as compared to the application of intrauterine transfusions in cases of severe erythroblastosis is discussed. It is also reported about recent methods of treatment of severe conditions of hydrops fetalis.


[Complement levels in children with idiophatic nephrotic syndrome (author's transl)]. C3, C4 and C3-activator were found in normal plasma-concentrations in 12 children with INS, compared to 26 healthy children. We could not find an activation of the complement-system by classical or alternate way in this disease. These results can be used for an additional possibility of differential diagnosis of glomerulopathies.


Quality control in the microbiological serum folate assay. Low values obtained in the microbiological assay of serum folate are often due to the presence of antibiotics in the test serum. The assay has been modified to permit consistent recognition of the presence and extent of such contamination. Other assay variables have been investigated and a quality control system devised which rapidly identifies the presence of inconsistencies in any one assay batch. The system further allows for the reporting of some clinically useful results from an imperfect assay batch thus reducing the necessity for reassay of some test sera.


Red blood cell carbonic anhydrase activity in children with distal renal tubular acidosis. Red blood cell carbonic anhydrase activity was studied in three children with distal renal tubular acidosis, the parents of one of the patients, and in control subjects. Although each patient had distal renal tubular acidosis as defined by an inappropriately high urine pH in the face of a systemic metabolic acidosis, hyperchloremia and a low (U-B)pCO2, they differed in that two had deafness. The deafness was inherited as an autosomal recessive mode in one and by an autosomal dominant gene in the other. Red blood cell carbonic anhydrase activity was determined in hemoglobin-free hemolysate by the esterolytic action of the enzyme on the substrate p-nitrophenyl acetate. The two isoenzymes, B and C, of carbonic anhydrase were identified using polyacrylamide disc gel electrophoresis. The red blood cell carbonic anhydrase activity of nine control children aged 2-10 years was 3.8 (3.2-5.0) units/g Hb. The values obtained from the three patients were 3.0, 3.7, and 4.36 units/g Hb. These did not differ from those of the control subjects. No abnormalities were found in the ratios of the B and C peaks or in their electrophoretic mobility.


[Toxoplasmids, their life cycle and systematic position]. Recent evidence on the life cycles of the toxoplasmids (Toxoplasma, Besnoitia, Sarcocystis, Hammondia, Frenkelia) has been analysed. The availability of the complex life cycles, including the alternation of sexual and asexual reproduction, in addition to gametogenesis involving the independent development of gametes that produce unequal numbers of gametes, makes it possible to include the toxoplasmids into the family Eimeriidae within the order Coccidiida. A detailed evidence recently provided for Isospora has suggested a kinship of this typical coccidian genus with toxoplasmids. At the same time much similarity is obvious between Isospora and Eimeria in the general pattern of their life cycles. Hence, the family Eimeriidae is suggested to be divided into two subfamilies: Eimeriinae Wenyon, 1926 with Eimeria as the type genus and Isosporinae Wenyon, 1926 with Isospora, Toxoplasma, Besnoitia, Sarcocystis, Frenkelia and Hammondia. The main features of the former subfamily are: various oocyst structures, the lack of the extra-intestinal development, obligatory monoxeny. The main characters of the latter subfamily: oocysts of the same pattern, the involvement of extra-intestinal development, shifts from facultative to obligatory heteroxeny.


Regional services for children and youth with diabetes. A regional diabetes program for children and youth comprising outreach clinics, frequent routine and emergency telephone contact, and a camping program was developed within the State Children's Medical Services (Crippled Children's) Program. The pediatric nurse specialist in diabetes served as the pivotal professional in the education and supervision of patients. Cost benefit was calculated from estimated hospital days prevented based on average length of admissions at diagnosis (14 days) and hospital days in the year prior to referral of those with established diabetes. During the first year 369 hospital days were prevented, for an estimated savings of $65,000; the second year 547 hospital days were avoided, a value of $96,000. Total annual program costs to the state and private patients (including camp fees) were $36,000. Although hospital costs are an apparent and useful reference to justify funding, the main value of the program must be in the prevention of secondary physical and emotional disability. This requires continuous commitment and availability of persons who know the patient and family, who can interpret information related to metabolic control of diabetes, and who are able to influence the family and community to respond appropriately to the youngster's needs.


Protein deprivation in primates: XII. food preferences of juvenile rhesus monkeys. 21 male and 18 female juvenile rhesus monkeys whose mothers' prenatal diets varied according to protein content (either 1-, 2-, or 4-gm protein/kg body weight/day) were given a food-preference task. 20 monkeys were between 3 and 4 yr. old; 19 were between 1 1/2 and 2 1/2 yr. old. For each trial small pieces of the same type food were placed in 8 equally spaced wells about the circumference of a circular tray held outside each monkey's cage. Responsiveness to the 21 natural foods (assorted cheeses, meats, vegetables, nuts, cereals, fruits, and candies) offered 3 times on 3 different occasions was measured by recording number of pieces taken, number eaten, and elapsed time for taking all 8 pieces. All 3 measures were highly correlated. All diet groups exhibited the same general order of preference, males taking and eating more food pieces faster than females. Order of preference was significantly different for old versus young juveniles, with older juveniles' preferences more similar to those of adult female monkeys given the same task. The most notable differences in eating behavior were that younger juveniles played with their food and were less finicky about what they ate. Results suggest that food preferences of juvenile monkeys are not altered as a consequence of their mothers' prenatal protein deprivation.


[Simple propositions in the treatment of acute lymphoblastic leukaemia (author's transl)]. Acute lymphoblastic leukaemias which are, at the present time, curable are those which go 01.cfhçinto remission following treatment with the combination prednisone-vincristine, in which lymphoblastic meningitis does not occur after preventive treatment of the central nervous system and which show no recurrence during maintenance chemotherapy. In order that the largest possible number of these potentially curable patients may be transformed into truly cured cases, we propose here a simple outline of treatment: induction of remission by one month of treatment with prednisone 40 mg/m2/day and vincristine 1.5 mg/m2/week, immediately followed by treatment of the central nervous system: 2 400 rads to the brain down to C2 in two weeks and an half and 6 injection (2 per week) of intrathecal methotrexate 5 mg/m2/injection and maintenance chemotherapy for two years with 6 MP, 25 to 50 mg/m2/day and parenteral methotrexate, 10 to 15 mg/m2/week, then immunotherapy with BCG, for a minimum of three years and a maximum of five.


A rapid cytosine-specific modification of E. coli tRNA Leu 1 by semicarbazide-bisulfite, a probe for polynucleotide conformations. Cytosine residues in 32P-labeled E. coli tRNA Leu 1 were modified by treatment of the tRNA with the semicarbazide-bisulfite reagents [Hayatsu, H. (1976) Biochemistry 15, 2677-2682]. Analysis of the modification sites showed that only four cytidine residues, i.e. C35, C53, C85 and C86, reacted. They were identical with the cytidines of this tRNA accessible to methoxyamine [Chang, S. E. and Ish-Horowicz, D. (1974) J. Mol. Biol. 84, 375-388] and the accessibility was consistent with the conformational features recognized for tRNA in general. The rapidity and the simple nature of this modification demonstrate that the semicarbazide-bisulfite reaction is a useful tool in studying conformations of polynucleotides.


Nucleotide sequence relationships between vertebrate 5.8 S ribosomal RNAs. Nucleotide sequences of the 5.8 S ribosomal RNAs from HeLa cells, Xenopus laevis and chick embryo fibroblasts were compared. Xenopus laevis 5.8 S RNA differs from that of HeLa cells in four internal positions and at the 3' end of the molecule. Chick 5.8 S RNA differs from that of HeLa cells in two positions. Six out of the seven interspecies differences are due to base substitutions. The other difference is due to the presence of an extra nucleotide, internally located, within the Xenopus 5.8 S sequence.


Mapping adenines, guanines, and pyrimidines in RNA. The positions of adenines, guanines, and pyrimidines can be determined by partial nuclease digestion of a terminally labeles RNA molecule. In urea, at elevated temperatures, RNase T1 generates a pattern reflecting cleavage at guanines while RNase U2 cleaves only at adenine. A limited alkaline hydrolysis provides a continuum of fragments derived from breaks at every phosphodiester bond. The reaction products are electrophoretically fractionated by size in adjacent lanes of a polyacrylamide gel. An autoradiograph of the gel displays the sequence up to 100 nucleotides from the end of the molecule, although uracil cannot as yet be distinguished from cytosine. These techniques form the basis of an RNA sequencing method and are demonstrated on yeast 5.8S ribosomal RNA.


Action of pancreatic DNase: requirements for activation of DNA as a template-primer for DNA polymerase. Pancreatic DNase requires both Ca2+ and Mg2+ for its activity as measured by formation of an activated DNA template for in vitro DNA polymerase alpha assay and by the hyperchromic shift. Mn2+ can partially satisfy the Mg2+ requirement of the DNase for activation of DNA but the resulting template is only 50% as active in the DNA polymerase assay. When precautions are taken to avoid divalent ion contamination, pancreatic DNase is not active in the presence of Ca2+ or Mg2+ alone. analysis of the DNA by sucrose gradient centrifugation shows that only in the presence of Ca2+ plus Mg2+ or Mn2+ does pancreatic DNase produce extensive strand breaks in the DNA. The activated DNA template that yields maximal DNA polymerase activity is low molecular weight material of 30,000 to 50,000 daltons.


Search for revertants of the glutamine mischarging mutans of Escherichia coli su+3 tyrosine suppressor tRNA that are able to insert tyrosine at the site of amber mutation. We have isolated a bacterial amber mutation (nadam) that is suppressed by the tyrosine inserting suppressor su+3 but not by the glutamine (su+2, su+3 A1, su+3 G82 and su+3 A1G82), serine (su+1) and leucine (su+6) inserting suppressors. The su+7 suppressor which inserts glutamine and tryptophan also suppresses this mutation indicating that tryptophan, in addition to tyrosine, is accepted at the site of amber mutation. We have used this amber mutation to search for revertants of the su+3 glutamine mischarging mutants su+3 A1, su+3 G82 and su+3 A1G82 that are able to insert tyrosine at the site of amber mutation. Two types of revertants were found in the case of su+3 A1. One type corresponding to the true revertant A1 leads to G, and the other to the second site revertants C81 leads to U (A1U81). The A1U81 revertant has been shown to insert both glutamine and tyrosine at the site of amber mutation. Only true revertants (G82 leads to A) were obtained when su+3 G82 was analyzed. No revertants were obtained in the case of the su+3 A1G82. These results are discussed in relation to aminoacyl-tRNA recognition.


The nucleotide sequence of phenylalanine tRNA from Bacillus subtilis. The nucleotide sequence of tRNA(Phe) from Bacillussubtilis W 23 has been determined using (32)P labeled tRNA. This is the second B. subtilis tRNA so far reported. The nucleotide sequence was found to be pG-G-C-U-C-G-G-U-A-G-C-U-C-A-G-U-D-G-G-D-A-G-A-G-C-A-A-C-G-G-A-C-U-Gm-A-A- ms(2)i(6)A-A-psi-C-C-G-U-G-U-m(7)G-U-C-G-G-C-G-G-T-psi- C-G-A-U-U-C-C-G-U-C-C-C-G-A-G-C-C-A-C-C-A(OH).Images


Oligonucleotide mapping of non-radioactive virus and messenger RNAs. A modification of the known method for obtaining radioactive fingerprints from non-radioactive nucleic acids by labelling a digest with 5'-hydroxyl polynucleotide kinase and [gamma-32P]-ATP has been applied to RNase T1 digests from various high molecular weight virus RNAs and to ovalbumin mRNA. Fractionation of the resultant [32P]-labelled T1 RNase digests by two-dimensional polyacrylamide electrophoresis demonstrates that in the case of virus RNAs, the fingerprints thus obtained are very similar to those derived from uniformly labelled RNAs. The value of this technique is that it requires only 1-5 microgram of purified virus RNA and at least three orders of magnitude less radioactivity than is routinely employed in preparing uniformly labelled RNA.


Antibodies specific to a deoxyribodinucleotide sequence. Antibodies were raised in rabbits against the bovine serum albumin conjugate of dpApT. Analysis by double diffusion in agar gel and quantitative precipitation test showed the presence of antibodies specific to the hapten in the antisera. Quantitative data on the specificity of the antibodies were obtained by studying the inhibition of the binding of 3H-dpApT to the antisera by various nonradioactive mono- and oligonucleotides, using a nitrocellulose membrane binding assay. The antibodies were found to be highly specific for the dinucleotide sequence dpApT. The antibodies were able to bind to synthetic oligonucleotides containing the sequence dpApT and to denatured calf thymus DNA.


Changes in chromatin structure induced by EDTA treatment and partial removal of histone H1. Electron microscopy shows that EDTA treatment or partial removal of histone HI converts 200-250 A chromatin fibres characteristic for native chromatin, isolated in low ionic strength conditions into fibres consisting of nucleosomes connected by segments of DNA. This structural transition is accompanied by an increase in the amplitude of positive band of CD spectra at 280 nm. Comparison of electron microscopic, thermal denaturation and electrophoretic data suggests that multiphasic character of melting curves, observed for chromatin, lacking histone HI is due to the removal of histone HI and destabilisation of the DNA segments, connecting nucleosomes. It is also shown that bivalent cations play an important part both in the stabilisation of 200 A globules and of nucleosomes.


Use of aurintricarboxylic acid as an inhibitor of nucleases during nucleic acid isolation. Aurintricarboxylic acid (ATA) is a general inhibitor of nucleases. ATA has been shown to inhibit the following enzymes in vitro: DNAse I, RNAse A, S1 nuclease, exonuclease III, and restriction endonucleases Sal I, Bam HI, Pst I and Sma I. The observed inhibition is consistent with the proposal by Blumenthal and Landers (BBRC 55, 680, 1973) that most nucleic acid binding proteins will be sensitive to ATA. The action of ATA as a nuclease inhibitor can be used to advantage in the isolation of cellular nucleic acids.


The nucleotide sequence surrounding the origin of DNA replication of Col E1. The DNA of Col E1 replicates from a unique origin located at a distance of 17-19% of the genome length from the single Eco RI clevage site. The nucleotide sequence about this site has been determined by a combination of RNA and DNA sequencing techniques. The principal features of the sequence are two palindromes, one of which resembles a palindrome located in the intercistronic region of 0X174. The sequence also contains stretches of purine and pyrimidine clusters of the following compositions: pAT5G, pC2T5G, pGT5G. The origin sequence demonstrates that initiation of DNA replication takes place in an intercistronic region of Col E1DNA, although the possibility that this region makes small polypeptides 30-40 residues long cannot be strictly eliminated at this time.


Primary structure of baker's yeast tRNAVal 2b. The minor form of valine tRNA from baker's yeast-tRNAVal 2b--purified by column chromatography was completely digested with guanylo-RNase and pancreatic RNase. The products of these digestions were separated by a combination of thin-layer chromatography on cellulose and high voltage electrophoresis on DEAE-paper and then identified. The halves of tRNA Val 2b were prepared by partial digestion with pancreatic RNase, and their complete guanylo-RNase and pancreatic RNase digests were analysed. Basing on the obtained data the primary structure of baker's yeast tRNA Val 2b was reconstructed.


The attempts of retarding the release of nitroglycerin from granules. The effect of Eudragit S, RL, or RS and ethylcellulose on the rate of release of nitroglycerin from granules has been studied. It was shown that Eudragits (acryl resins) and ethylcellulose decrease the rate of release of nitroglycerin from granules. The retarding effect depends on the amount and the kind of a retarding agent. Eudragit RS was the most effective one.


[Rhesus factor distribution in the families of hypophyseal nanism patients]. The author examined 211 members of 57 families with a genetic (familial) and idiopathic (sporadic) hypophysial nanism of obscure genesis. Rh-negative blood or weakened varieties of the Rh-antigen were revealed in 71 of 211 persons (33.1%), in 44 of 57 families (77.2%). Heterozygotic character of the majority of the positive parents of the sick children, by the Rh-factor, is undoubtful. Analysis of the Rh-factor distribution and of the antigens of the ABO system in the families suffering from hypophysial nanism permitted to exclude the significance of the hematological conflict by these antigens between the mother and the fetus, as a determining factor. It is supposed that there is a possible pathogenetic association between the hypophysial nanism and the absence of the Rh-antigen which is inherited also as an autosomic-recessive sign.


Independent expression of the gene coding for the constant domain of immunoglobulin light chain: evidence from sequence analyses of the precursor of the constant region polypeptide. The mRNA coding for the kappa-type constant region (C(kappa)) was purified from two clones derived from the MPC-11 mouse myeloma. This mRNA directs the cell-free synthesis of a C(kappa) precursor (molecular weight, about 15,000) in which an extra piece, 17 residues long, precedes the NH(2)-terminal residue (Ala(109)) of the C(kappa) region. The partial sequence of the extra piece is: Met-X-Thr-Asp-Thr-Leu-Leu-Leu-Trp-Val-Leu-Leu-Leu-Trp-Val-Pro-X- (X is unknown). Met(1) was shown to be the initiator methionine. The sequence of the C(kappa) extra piece is completely different from any known sequence preceding residue Ala(109) in whole light (L) chains, thus establishing that the C(kappa)-region mRNA could not have originated from mRNA coding for the whole L chain. The structural features of the C(kappa) extra piece (marked hydrophobicity, size, and a methionine at the NH(2)-terminus) are identical to those characteristic of the NH(2)-terminal extra piece linked to the variable (V) region of whole L-chain precursors. In addition, the C(kappa) extra piece and the extra piece linked to the V region of MOPC-321 L chain have 70% sequence homology. These findings can be explained by the two genes-one Ig chain hypothesis, if we assume that the DNA coding for the extra piece (xp-DNA) is a constitutive part of the V gene. According to this model, the C(kappa)-region mRNA could have originated from: (i) translocation of this V gene to the C gene, deletion of the entire mature V gene, and "end-to-end" repair of the remaining xp-DNA to the C gene; (ii) translocation to the C gene only of the xp-DNA portion of the V gene. Alternatively, we may assume that the xp-DNA is not covalently linked to the mature V gene at all times, as might be the case for the DNA of hypervariable regions presumed to be in episomes. This raises the intriguing speculation that the xp-DNA represents a third distinct gene, designated xp-gene. The presumed xp-gene may be involved in the regulation of gene transcription: when linked to the mature V gene it initiates a chain of events leading to whole L-chain mRNA formation; when attached to the C gene it leads to its transcription to provide the C-region mRNA.


Presence of a putative 15S precursor to beta-globin mRNA but not to alpha-globin mRNA in Friend cells. Dimethyl sulfoxide-induced Friend cells were labeled for periods of 5-60 min. The denatured RNA was fractionated by sucrose gradient centrifugation and the distribution of alpha- and beta-globin-specific [(3)H]RNA was determined by hybridization to hybrid plasmids containing mouse alpha- and beta-globin DNA, respectively. After 5 min of labeling, a 15S peak of beta-globin-specific (but not alpha-globin-specific) [(3)H]RNA was detected, next to an equal amount of 10S beta-globin [(3)H]RNA. With increasing periods of labeling, the amount of 15S beta-globin [(3)H]RNA remained constant but the amount 10S beta-globin [(3)H]RNA increased steadily. alpha-Globin-specific [(3)H]RNA sedimented at 11 S after 5 min of labeling and at 9.5 S after longer labeling periods. Analysis of 15S globin-specific [(3)H]RNA purified by the poly(dC)-cDNA method [Curtis, P. J. & Weissmann, C. (1976) J. Mol. Biol. 106, 1061-1075] showed oligonucleotides characteristic of beta-globin mRNA but not of alpha-globin mRNA, as well as about 20 new oligonucleotides. Our results suggest that 10S beta-globin mRNA arises via a 15S precursor that has a half-life of 5 min or less; 9.5S alpha-globin mRNA may be derived from an 11S precursor.


DNA-directed synthesis in vitro of beta-galactosidase: requirement for a ribosome release factor. The DNA-directed synthesis of beta-galactosidase in Escherichia coli extracts has been investigated in a partially fractionated system. A dependency was obtained for 3',5'-cyclic AMP receptor protein and also for a factor, from the salt wash of ribosomes, that has been purified to near homogeneity. This factor has been identified with a ribosome release factor previously purified from the supernatant fraction by A. Hirashima and A. Kaji [(1972) Biochemistry 11,4037-4044]. In the coupled transcription-translation system this factor stimulates beta-galactosidase synthesis and total protein synthesis 2- to 4-fold. It is thus clear that the ribosome release factor has a physiological function in translation. It may also affect transcription, because it stimulated total RNA synthesis up to 50% in this in vitro system.


Isolation of an iron-molybdenum cofactor from nitrogenase. A method for the isolation of an iron-molybdenum cofactor (FeMoCo) from component I of nitrogenase is described. This method is used to isolate FeMoCo from aerobic, anaerobic, facultative, and photosynthetic nitrogen-fixing organisms. The Fe/Mo ratio in the FeMoCo from Azotobacter vinelandii and Clostridium pasteurianum is 8:1. The FeMoCo contains six atoms of acid-labile sulfide per eight Fe atoms. Crystalline component I from A. vinelandii contains 2 Mo, 33 Fe, and 27 acid-labile sulfide atoms per molecular weight of 250,000. The specific activity of FeMoCo is 425 nmol of C(2)H(4) formed/min per nmol of Mo. There is better than 98% reconstitution between FeMoCo and inactive component I in A. vinelandii mutant strain UW45. The FeMoCo yield from component I is about 90%. FeMoCo from nitrogenase component I of C. pasteurianum, Klebsiella pneumoniae, Bacillus polymyxa, and Rhodospirillum rubrum activates inactive component I in an extract from mutant strain UW45 and follows saturation kinetics. The FeMoCo in various nitrogen-fixing organisms seems to be very similar. Wild-type A. vinelandii derepressed for nitrogenase synthesis in tungsten-containing medium and K. pneumoniae mutant strain UN109 are also activated in vitro by FeMoCo. The FeMoCo is very sensitive to oxygen, but is stable even at room temperature as long as it is kept anaerobic and in N-methylformamide, the solvent used for its isolation. FeMoCo is unstable in an aqueous environment, even though it is kept strictly anaerobic. Knowledge of the structure of this cofactor should be useful for understanding the role of molybdenum at the active site of nitrogenase, role of ligands close to molybdenum in electron and proton transfer, and the catalytic mechanism of nitrogen fixation. The FeMoCo might be used as a model for synthesizing catalysts for chemical nitrogen fixation.


Murine leukemia virus morphogenesis: cleavage of P70 in vitro can be accompanied by a shift from a concentrically coiled internal strand ("immature") to a collapsed ("mature") form of the virus core. Disruption of Rauscher leukemia virus (RLV) with low levels of Nonidet P-40 yielded "immature" cores. These cores have a diameter of about 920 A, as opposed to the 1300-A diameter of RLV, possess knob-like protuberances, and contain a concentrically coiled internal strand apposed to the core shell. The two major polypeptide components of immature cores are (i) p30, the 30,000-dalton group-specific antigen, and (ii) a polypeptide that has the size and antigenic characteristics of P70, the 70,000-dalton precursor protein of the group-specific antigens of murine leukemia virus. Disruption of RLV at high ratios of Nonidet P-40 to virus yielded "mature" cores. These cores have an average diameter of 850 A, a smooth proteinaceous perimeter, and a collapsed internal strand, and they contain predominantly p30. Treatment of RLV with low levels of Nonidet P-40 for 16 hr at 22 degrees yielded cores that showed (I) a 70% decrease in the number of immature forms and concomitant increase in the number of mature forms, (II) a 60-90% decrease of P70, and (iii) a 30% increase in a 40,000- to 42,000-dalton protein. These results suggest that maturation of RLV cores is accomplished by cleavage of P70.


Cloning of an immunoglobulin variable region gene from mouse embryo. A 4.8-kilobase DNA fragment carrying an immunoglobulin gene coding for a mouse lambda chain variable region (Vlambda gene) was enriched about 350-fold from a total endonuclease  EcoRI digest of embryonic DNA by a combination of preparative agarose gel electrophoresis of double-stranded DNA and CsCl density gradient centrifugation of R-loops formed with a purified lambda chain mRNA. DNA fragments thus enriched for the immunoglobulin gene were inserted in vitro in the middle of the genome of the vector phage lambdagt Wam  403, Eam 100, Sam 100 by use of the EcoRI cohesive ends. Transfection of CaCl2-treated Escherichia coli 803 [rk-, mk- (lacking restriction and modification systems for K-12)] with such hybrid DNA and subsequent screening of about 4000 plaques by in situ hybridization with purified 125I-labeled lambda chain mRNA led to isolation of a clone that carries a Vlambda gene (lambdagtWES-Ig 13). Electron microscopy of R-loops confirmed the presence of sequences homologous to part of the lambda chain mRNA in its 5'-end.


Secretion of mediators following T lymphocyte-macrophage interaction is regulated by the major histocompatibility complex. In this study we show that T cells from mice infected with Listeria monocytogenes can interact in vitro with normal macrophages to produce a number of soluble mediators, including lymphostimulatory molecules. One of these molecules was a 15,000-dalton protein mitogenic for thymocytes. Generation of mitogenic activity was essentially completed by the first 24 hr of culture and did not require the addition of Listeria antigens. Production of mitogenic protein required contact between the lymphocytes and macrophages, because it did not occur when the two cells were separated by a cell-impermeable membrane. Optimal production of mitogenic protein occurred only when the lymphocytes and macrophages shared homologous I-A regions of the major histocompatibility complex. Once generated, the mitogenic protein did not display histocompatibility restriction and could stimulate allogeneic as well as syngeneic thymocytes. Strains of mice with the C57 background responded poorly to mitogenic protein even though those strains were capable of producing it. We conclude that an early stage in T cell immunity to Listeria involves an intimate association with macrophages regulated by the H-2 complex.


Formation of lung surfactant films from intact lamellar bodies. Lamellar bodies, an intracellular source of lung alveolar surfactant, were isolated from rat lung homogenates and studied in the Langmuir-Adams surface balance. By layering intact lamellar bodies on the surface of a more dense sucrose subphase, we studied the factors affecting film formation from surface tension-vs-time data and determined surface tension-surface area isotherms by compression and expansion of the resulting films. We found that films with properties representative of the alveolar surfactant are formed in the presence of Ca2+ or Mg2+ alone, or either plus Na+; that film formation is incomplete with Na+ alone or on ion-free subphases; and that Ca2+-induced film formation is blocked by chelation with EGTA but is unaffected by diisopropylfluorophosphate. The results suggest that divalent cations induce film formation by interactions at sites within the lamellar bodies and may be responsible for the binding of membrane lipids to membrane proteins in lung surfactant.


Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets. Thromboxane synthase was localized to the microsomes of human platelets. The enzyme was insensitive to sulfhydryl reagents and thiols but was inhibited by 12L-hydroperoxy-5, 8, 10, 14-eicosatetraenoic acid (concentration for 50% inhibition = 0.1 mM). Treatment of microsomes with Triton X-100 solubilized the enzymes that catalyze the conversion of arachidonic acid to thromboxane B2. The solubilized material was resolved by DEAE-cellulose chromatography into two components, one converting arachidonic acid to prostaglandins G2 and H2 and the other converting prostaglandin H2 to thromboxane B2.


Secondary structure of heterogeneous nuclear RNA: two classes of double-stranded RNA in native ribonucleoprotein. Heterogeneous nuclear RNA (hnRNA) from HeLa cells contains intramolecular duplexes. Since hnRNA is associated with protein in vivo, it is possible that the double-stranded regions observed in deproteinized hnRNA form spontaneously upon the release of protein from single-stranded but potentially complementary sequences. We show here that this is not the case for a class of double-stranded sequences that is defined by resistance to RNases A + T(1) at high ionic strength. Exposure of HeLa hnRNA.ribonucleoprotein (hnRNP) particles to Escherichia coli RNase III, a double-strand-specific endoribonuclease, destroys most of the sequences resistant to RNases A + T(1). This effect is completely blocked when hnRNP is exposed to RNase III in the presence of an excess of purified double-stranded RNA. In addition, we show that there exist two classes of double-stranded RNA in hnRNP at a salt concentration of 0.13 M. These are distinguished by their relative resistance to RNases A + T(1). The more stable double-stranded sequences, which are resistant to RNases A + T(1) at 0.13 M, comprise 1.0-1.1% of the nucleotides in hnRNP. The less stable double-stranded sequences comprise an additional 1.5-2.0% of the nucleotides in hnRNP. These are sensitive to RNase III at 0.13 M, but are not resistant to RNases A + T(1) unless the salt concentration is raised to 0.63 M. The demonstration that double-stranded sequences resistant to RNases A + T(1) exist in native ribonucleoprotein and are not artifacts of deproteinization now makes it appropriate to seriously consider their possible functional role in hnRNA metabolism, perhaps as binding sites for regulatory proteins involved in mRNA processing.


New detection of brain dopamine receptors with (3H)dihydroergocryptine. Because dihydroergocryptine (DHE) and closely related ergots are dopamine-mimetic agonists, we tested [3H]DHE as a possible ligand for [3H]dopamine receptors in the calf caudate. In order to avoid [3H]DHE from tagging alpha-adrenergic receptors, an excess of 500 nM phentolamine was used to block these sites, permitting the dopamine receptors to be measured separately. Specific binding of [3H]DHE was defined as total binding minus that occurring in the presence of 1 muM (+)-butaclamol. Excess phentolamine reduced the specific binding of [3H]DHE from 328 down to 138 fmol/mg, the difference presumably representing alpha-receptors. The KD for [3H]DHE was 0.55 nM (with or without phentolamine), and this high affinity site was blocked (in the presence of phentolamine) by 250nM apomorphine, 650 nM dopamine, and 1200 mM (minus)-norepinephrine, indicating that[3H]DHE was binding to dopamine receptors. All neuroleptics blocked specific [3H]DHE binding in direct relation to the clinical potency of the neuroleptic. The displacement of specific [3H]DHE binding by dopamine or by norepinephrine (in the presence of phentolamine) revealed two subsets of dopamine receptors.


Occurrence of a major protein associated with fruiting body development in Neurospora and related Ascomycetes. Electrophoretic and immunological analysis of fruiting body (perithecial) extracts demonstrates the occurrence of a major phase-specific perithecial protein in all Neurospora species and in the closely related Gelasinospora cerealis and Sordariafimicola. The perithecial proteins from these different species fall into a number of groups with different electrophoretic mobilities. They appear to be immunologically closely related but not identical to one another even within the same genus, with only partial identity exhibited between the heterothallic and pseudohomothallic Neurospora on the one hand and the homothallic Neurospora on the other hand. In immunological analysis of fruiting body extracts of the other Ascomycetes, Podospora anserina, Cochliobolus maydis, and Aspergillus nidulans, and of ascus extracts of Saccharomyces cerevisiae, no crossreaction with the Neurospora perithecial protein was found.


Induction of spectrin in erythroleukemic cells transformed by Friend virus. The presence and accumulation in murine erythroleukemic cells transformed by Friend virus of the erythrocyte membrane-associated protein spectrin has been investigated. Spectrin was present in the uninduced cells and was induced 10- to 20-fold in dimethyl sulfoxide-treated differentiating cells. The intracellular concentration of spectrin reached a peak on the third day of dimethyl sulfoxide treatment, after which it fell to levels found in mouse erythrocytes. We also found that the small subunit of spectrin was phosphorylated in the cells.


Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex. Mice were immunized intravenously with suboptimal numbers (3.5-5 X 10(5)) of sheep erythrocytes together with various anti-Ia antisera or with sheep erythrocytes alone, and the primary IgM and IgG plaque-forming cell responses were assayed 6 days later9 A/J (H-2a) mice given 5 X 10(5) sheep erythrocytes together with as little as 0.4 mul of a (129 X A.TH)F1 anti-A.TL (anti-Iak) antiserum developed 2-3 times as many IgM and IGG plaque-forming cells as mice injected with antigen alone or together with various antisera not containing anti-Ia antibodies. Similar results were obtained with BALB/c (H-2d) mice and a (C3H X LG/Ckc)F1 anti-C3H. OH (anti-Iad) antiserum plus sheep erythrocytes. In the case of the anti-Iad antiserum, the potentiating activity could be absorbed with C3H. OH (Id) but not C3H(Ik) spleen cells, demonstrating that the active antibodies were specific for the Id region. Antiserum to I-Jk subregion-coded determinants was tested in A/J (I-Jk) mice and found to also potentiate 2- to 3-fold the plaque-forming cell response to suboptimal erythrocyte immunization. This antiserum [(BIO.A(3R) X DBA/2)F1 anti-B10.(5R)] failed to potentiate responses in BALB/c (I-Jd) mice, as expected on a genetic basis. The potentiating antibodies could be removed by absorption with B10.BR (I-Jk) but not B10 (I-Jb) spleen cells, also confirming the I-J specificity of the activity. The interference of anti-I-J antibodies with T lymphocyte suppressor mechanisms is prposed as a possible explanation for this phenomenon.


Further structural studies of the heavy chain of HLA antigens and its similarity to immunoglobulins. The papain-solubilized fragment of the heavy chain of HLA-B7, which is the NH2-terminal part of the whole polypeptide chain, can be divided into three regions by mild acid and cyanogen bromide cleavages. The first 100 amino acids terminating in a methionine residue contain the carbohydrate moiety; this segment is followed by two others of molecular weights 9,999 and 13,000, each containing an intrachain disulfide bridge. The two intrachain disulfide bridges are separated by a stretch of amino acids containing an acid-labile aspartyl-prolHLA-2, A28, and AW25 contain this acid-labile peptide bond in their larger subunit. Sequencing from the acid cleavage site of HLA-7 through the third half-cystine revealed consideralbe homology with amino acid sequences around a half-cystine in immunoglobulin variable regions.


Histopathogenesis of 7,12-diemthylbenz(a)anthracene-induced rat mammary tumors. The histopathogenesis and growth behavior of mammary tumors and dysplasias induced by a single intragastric dose of 7,12-dimethylbenz[a]anthracene in 50-day-old virgin female Lewis rats were examined both in situ and after transplantation into gland-free mammary fat pads of syngeneic hosts. Terminal mammary ductules are indicated as a site of origin of both ovarian hormone-dependent mammary tumors and spontaneously gegressing mammary tumors, and terminal ductule hyperplasia appears to be an early stage in mammary tumor formation. The precancerous nature of hyperplastic alveolar nodules induced by dimethylbenzanthracene in rats has been further examined, and our studies indicate that these nodules are not significantly preneoplastic.


Action potentials occur in cells of the normal anterior pituitary gland and are stimulated by the hypophysiotropic peptide thyrotropin-releasing hormone. Electrical activity in the form of action potentials (spikes) was discovered in normal anterior pituitary cells obtained from rats by tissue dissociation and maintained in culture. Passage of outward current through the microsuction electrodes used for recording often increased spike frequency in spontaneously active cells or initiated spikes in cells previously electrically silent. Spiking persisted in the presence of tetrodotoxin and in the absence of sodium, but was inhibited by the calcium blockers D600 and lanthanum. Such spikes appear, therefore, to be calcium spikes, but contributions to spiking by other ions are not excluded. The stimulant hypophysiotropic peptide thyrotropin-releasing hormone elicited spiking in about ten percent of the cells on which it was tested. These cells are possibly thyrotrophs and mammotrophs, the physiological target cells for this hormone. These results, considered along with existing evidence that adenohypophyseal secretion requires calcium and is elicited by calcium ionophores, prompt the conclusion that action potentials involving calcium influx participate in stimulus-secretion coupling in the anterior pituitary. It may be by stimulating or modulating such electrical activity (with hypophysiotropic hormones) that the brain regulates anterior pituitary secretion.


Effects of amphetamine and methylphenidate on fixed-interval responding in the squirrel monkey. The effects of oral doses of d-amphetamine and methylphenidate on a fixed-interval operant response were studied in four young male squirrel monkeys. A fixed-interval of 80 sec with a limited hold of 20 sec was used. Methylphenidate produced no observable changes in behavior, while d-amphetamine produced dose related changes in both the rate of responding and the temporal patterning of responses. Since dose levels used included, and exceeded, human clinical dosages, the present findings may have implications for future research involving the clinical use of these drugs.


Hydroxylation of tyrosine by plant peroxidase and mushroom tyrosinase, with and without hydrazine, to retard the oxidation of dopa. Tyrosine was oxidized to dopa by horseradish peroxidase and mushroom tyrosinase. The first step of hydroxylation of tyrosine in the synthesis of melanin was demonstrated by isolation of dopa from the reaction mixture using hydrazine as a selective retardant.


[Some little-known conservative methods of treatment of Raynaud's syndrome]. In 20 patients with Raynaud's phenomenon affecting the upper or lower limbs (1974-1976), 4 methods of conservative therapy were used, in combinations according to the case: 1) Intraarterial injections of xylocaine-priscol-pronestyl. 2) Nitroglycerine ointment. 3) More rarely, paraphalangeal injections of 1% quinine-urea. 4) The hypertensive regime of Lassen and Larsen (mineralocorticoids by mouth). The age was in general between 45 and 75 years, and a vascular context, either arterial or venous, was frequent. Signs of scleroderma were absent. Disc disorders with radicular signs were not rare (6 cases). The most frequent combination, intraarterial injections and nitroglycerine ointment, generally had a remarkable effect. On only 3 occasions was recourse had to other methods. No patient had to undergo sympathectomy.


Pharmacological characterization of tardive dyskinesia. Tardive dyskinesia (TD) may be a clinical manifestation of a relative imbalance between the inversely related dopaminergic (DA) and acetylcholinergic (ACh) influences in the central nervous system (CNS). Six patients were evaluated with single challenge doses of a DA agonist, levodopa, and antagonist, droperidol, as well as with an ACh agonist, physostigmine, an antagonist, benztropine, and a placebo. A single blind trial with deanol and placebo followed. Responses, measured by an electrophysiological technique, formed two subgroups. The patients who improved with a DA antagonist or an ACh agonist improved while taking deanol. Another group of patients were made worse with a DA antagonist or ACh agonist and were worsened or had no response while taking deanol. While the results add support to the concept of counterbalancing DA-ACh influences in TD, further investigation of TD subtypes and predictors of drug response is warranted.


Reduced renal calcium excretion during lithium therapy. The renal excretion of calcium was determined in ten subjects before and at intervals during 3 months of lithium treatment. The calcium excretion fell by more than 40% within the first week of treatment and remained low throughout the treatment period. The reduction in urinary calcium excretion could be accounted for by an increase in fractional tubular reabsorption of calcium. There were no changes in serum calcium or inorganic phosphate, nor in urinary inorganic phosphate. The results indicate that lithium interferes with the regulation of calcium metabolism.


Head-shake distributions during self-maintained dependence on morphine, methadone, and l-alpha-acetylmethadol (LAAM) in the rat. Adult female Sprague-Dawley rats were prepared with chronic cortical and muscle electrodes and i.v. cannulas, made tolerant to and physically dependent on morphine, and trained to level press for i.v. morphine self-injections to maintain dependence. Methadone or l-alpha-acetylmethadol (LAAM) was then substituted for morphine in some of these rats. During self-maintained dependence on either morphine or methadone, head shakes appeared and increased in frequency before lever pressing for self-injections. In contrast, there were fewer head shakes during LAAM dependence, which were evenly distributed over the entire duration of the interinjection interval. These findings suggest a relationship between head-shake distributions, drug-seeking behavior and the pharmacodynamics of these three narcotics.


Effects on retention of posttraining amphetamine injections in mice: interaction with pretraining experience. These experiments examined the effects of d-amphethamine on retention of one-trial inhibitory (passive) avoidance training in mice. Water-deprived mice were pretrained to lick from a water spout at the end of a darkened compartment. Footshock was administered during licking after 4, 6, or 7 days of pretraining. Retention performance (latency to lick) was measured 24 h after training. The effects on memory of posttraining amphetamine varied not only with amphetamine dose but also with the amount of pretraining. In animals pretraining for 7 days, 0.3 and 1.0 mg/kg but not 0.03, 0.1, or 3.0 mg/kg posttraining amphetamine significantly enhanced later retention performance. In mice pretrained for 6 days, 1 mg/kg amphetamine also enhanced retention performance. However, in mice pretrained for only 4 days, 1 mg/kg amphetamine impaired later retention erd for only 4 days, 1 mg/kg amphetamine impaired later retention performance. These results are consistent with the view that posttraining treatment may affect memory storage processes by interacting with training-related arousal levels.


Differential attenuation by atropine and d-amphetamine on hyperactivity: possible clinical implications. Intraperitoneal administration of physostigmine (0.025 to 0.18 mg/kg) to rats resulted in significant increases in motor activity as measured with jiggle platforms. Doses of physostigmine 0.2 mg/kg or more decreased motor activity. The physostigmine-induced hyperactivity was attenuated by atropine (5 mg/kg) given before or after physostigmine (0.05 mg/kg). On the contrary, d-amphetamine (2 mg/kg), given before or after, significantly potentiated the physostigmine-induced increase in motor activity. The relevance of the cholinergic system in mediating hyperactive behaviour in children is discussed.


Naloxone (Narcan) treatment in depression: clinical observations and effects on CSF endorphins and monoamine metabolites. Various dysphoric states are seen both in mood depression and on taking opiates. On the hypothesis that opiate antagonists would alter mood level, naloxone (Narcan), 0.4--0.8 mg t.i.d., was given to five depressed patients in six trials for a duration of 6--12 days. The CSF endorphin and monoamine metabolite content was analyzed before and after naloxone treatment. We observed no positive effect on mood level. However, an abrupt worsening of symptoms was noted in two cases on discontinuation of treatment. Decreasing values of endorphin Fraction I as a result of treatment was noted as a general trend. Fraction II, although elevated, showed no distinct trend. 5HIAA increased in four of the six trials. The results suggest that naloxone treatment changes endorphin and serotonin activity, though not to a clinically observable extent.


The effects of methaqualone on the seizure susceptibility of mice. Methaqualone produces dose- and time-dependent decreases in susceptibility to electrically, chemically, and sound-induced seizures. The antagonism of methaqualone to electroconvulsive shock can be dissociated from its effects on temperature regulation and plasma corticosterone. Studies with SKF525A, a drug known to block enzymes in the liver that metabolize drugs, suggest that methaqualone, rather than a metabolite produced in the liver, is responsible for its anticonvulsant effects. Tolerance to the anticonvulsant effects of methaqualone is also demonstrated.


The effects of methaqualone on pituitary-adrenocortical activity in mice. Methaqualone produces a dose- and time-dependent increase in plasma corticosterone concentration in mice. Acute studies showed that this effect is largely independent of methaqualone-induced hypothermia but can be blocked by pretreatment with dexamethasone, thus demonstrating that the adrenal cortex is not being directly stimulated. It is not clear whether the pituitary-adrenal activation is primarily caused by methaqualone itself or by a hepatic metabolite(s) since pretreatment with SKF 525-A failed either to potentiate or block the effect. Studies employing chronic methaqualone administration provided evidence for a rapid development of tolerance to the pituitary-adrenal effect of the drug. Dose- and time-response studies demonstrated a parallel between plasma concentrations of methaqualone and the stimulation of pituitary-adrenal activity. Furthermore, drug concentrations 1 h following methaqualone administration were diminished in chronically pretreated animals was compared to those previously untreated, suggesting that an altered metabolism of methaqualone may be responsible for the development of tolerance.


Noradrenaline, depressive illness, and the action of amitriptyline. The tyramine-dose/pressor response test was carried out on a series of patients suffering from primary depressive illness before and during treatment with amitriptyline. The severity of their depression was assessed during the study of the Hamilton Rating Scale (HRS). The decreased tyramine sensitivity induced by the drug, which is related to the inhibition of NA reuptake, correlated significantly with the plasma concentration of nortriptyline. However, contrary to the expectation of the noradrenaline hypothesis of depression, the decreased tyramine sensitivity, i.e., the degree of NA-reuptake blockade, did not show any correlation with clinical improvement following 6 weeks' treatment with amitriptyline.


Narcotic blockade, length of addiction, and persistence of intravenous morphine self-administration in rats. Four groups of rats differing in the number of periods of prior exposure to morphine sulphate in the i.v. self-administration paradigm were studied under conditions of narcotic blockade. Three groups of subjects also differing in the amount of prior exposure to morphine sulphate were studied under saline conditions. At effective blocking doses of naloxone, opioid-seeking behavior was eliminated in relatively drug naive animals, whereas the persistence of secondary reinforcers in rats with longer addiction histories served to maintain opioid consumption in the presence of adequate pharmacological blockade. Data from saline-treated animals were very similar to data obtained in naloxone-treated animals. The authors conclude that at adequate blocking doses of narcotic antagonist the length of addiction appears to be the best predictor of opioid consumption.