Energetics of galactose, proline, and glutamine transport in a cytochrome-deficient mutant of Salmonella typhimurium. The effect of inhibitors and uncouplers on the osmotic shock-sensitive transport systems for glutamine and galactose (by the beta-methyl galactoside permease) was compared to their effect on the osmotic shock-resistant proline and galactose permease systems in cytochrome-deficient cells of Salmonella typhimurium SASY28. Both osmotic shock-sensitive and -resistant systems were sensitive to uncouplers and to inhibitors of the membrane-bound Ca2+, Mg2+-activated adenosine triphosphatase. This suggests that uptake by both types of systems is energized in these cells by an electrochemical gradient of protons formed by ATP hydrolysis through the ATPase.


[Model of motion sickness in dogs for assessing the effectiveness of pharmacological substances]. The paper describes a model of motion sickness for dogs. The method is based on the simultaneous use of vertical and rotatory movement of the device with a continuously varying angular velocity of rotation to generate Coriolis acceleration. The exposure increases significantly the number of sick animals to be used in the selection of antimotion drugs. Diphenidol, marezine, tigane, bromotigane and metachloropromide were tested. Diphenidol and to a lesser extent marezine and metachloropromide proved effective. Tigane and bromotigane were ineffective against motion sickness.


[Hygienic evaluation of the water reclaimed from various moisture-containing wastes]. The paper reviews 5 experiments on 25 healthy male test subjects, aged 20-36. For drinking and cooking they used water reclaimed from various water-containing wastes (atmospheric condensate, urine, fluids used in engineering processes and biological wastes) by the oxidation-catalytic and sorption techniques. The resultant water was saturated with salts and decontaminated by ionic silver at a dose of 0.1 mg/l. The experimental data on the excretion of water and minerals allow the conclusion that reclaimed and conditioned water is physiologically adequate and that the human body reacts to its intake as it does to normal potable water.


Pilot open-label study of triazolam in the treatment of insomnia following alcohol withdrawal. Insomnia and anxiety decreased in 12 outpatients taking triazolam following alcohol withdrawal.


[Variants of the control over a gas-exchange closed ecosystem with a periodically operating autotrophic component]. The paper discusses the problem of how to control a gas exchange closed ecosystem that consists of autotrophic and heterotrophic components and operates periodically in the light or in the dark. The purpose of the control is to maintain the steady state of an ecosystem with a man-oriented atmosphere. This problem of control has different solutions each of which is characterized by a set of six dimensionless variables associated with three equations--steady-state conditions. The physical characteristics of the variables and conditions of similarity of ecosystems are described. The resultant methods of control are evaluated from the point of view of economic operation of the ecosystem and the level of stability of its amosphere. The class of ecosystems for which the results obtained are valid in the event of accidental perturbations is presented.


[Diagnosis and treatment of postoperative infections following hip injuries]. The authors studied the diagnosis and treatment of posttraumatic infections of the hip joint, based on their own material. In case of latent infection the increased sedimentation rate and taking of comparative X-ray films are held important, that shows a narrowing and disappearance of the sclerosed edge of the acetabulum. Following dislocation of the hip joint ankylosis may be attained, but after fractures of the proximal and of the femur the infection cannot be cured, unless the nail and the head of the femur are removed.


[Treatment of childhood humeral fractures by wire fixation]. Out of 526 upper limb fractures treated in the Pediatric Surgery Department of the Péterfy Sándor Hospital between 1970-1975, 63 patients were operated on. (11.9%). Fractures in childhood are generally treated by closed methods because healing of the growing bone is favourable. If it is reasonable, fractures of the forearm bones are successfully treated by means of intramedullary wire fixation, fractures of the elbow by means of transfixation. No septic complication occured following operation. Growth disturbancies were not observed in the affected bones after the operative intervention in the course of 1 to 5 years. On this ground the author recommends the adaptational "minimal" osteosynthesis in the treatment of fractures in infancy, if closed methods do not promise optimal results.


[The role of orthopedic surgery in the treatment of spastic patients]. The authors performed 958 operations on spastic patients. Based on this clinical material, they introduce the possibilities and principles of operative treatment. Position of joints in the lower limb, their synergism and compensatory changes in a closed kinetic chain are analysed in the article. These factors must be attended to carefully if one should decide the site and variety of operation to be performed. The authors suggest that patients should be operated on early, in certain cases even preventive operation is necessary. Results are better if children who already can stand and walk are operated on, but in many cases operation itself is needed to enable them to these activities. Results were good in 83,2%, no changes in 3,4%, worse in 4,2 out of the 716 operations evaluated. Operative treatment along with conductive pedagogy and other methods of physiotherapy help these patients to be able to take care of themselves and to become useful members of society.


[Possibilities of treatment of open fractures of the tibia]. Results of healing in 477 cases of open leg fractures treated in the Central Institut of Traumatology in Budapest are analysed in the article. 47,2% of cases were treated by closed methods. The authors are convinced that careful conservative management leads to good results, if the type of the fracture is suitable. Conditions of operative treatment are outlined. In favourable circumstances a stable internal fixation should be performed, otherwise inramedullary wiring and plaster may hold the fragments until healing occurs. Soft tissues should be handled carefully and placing sutures under tension must be avoided, by all means.


[Stable osteosynthesis on the hand].

[Stable osteosynthesis on the hand]. The authors write on the usefulness of the A.S.I.F. Small Fragment Instrumentary, its possible ways of application in the treatment of fractures of bones of the hand. The operative techniques is introduced, indication and contraindications based on the clinical material of the authors are discussed in the article. Limitations to the application of this method are also included.


[Syringomyelia with severe osteo-articular changes]. Attention was drawn to a patient after admission to the Central Institute of Oncology, and syringomyelia was diagnosed on the basis of X-ray films taken by the author. The deformations were symmetrical and they were localized in the area of innervation of the C VI, VII, D I segment. The radiological diagnosis was proved by the neurological examinations.


Evidence for inhibition of dopamine-beta-hydroxylase in vivo after sub-acute pyrazole treatment in rats. Pyrazole, a widely used inhibitor of alcohol dehydrogenase, has been shown to cause a decrease of brain and heart noradrenaline (NA). An attempt to explain the mechanism of this effect is now described. L-DOPA (50-200 mg/kg, s.c.) was unable to restore brain or heart noradrenaline levels in pyrazole pre-treated rats. After monoamine oxidase inhibition with tranylcypromine or pargyline there was a slight increase in brain NA in these rats but no further increase was observed in response to L-DOPA (30 mg/kg). Brain dopamine levels were relatively higher in pyrazole pre-treated rats. This difference was particularly clear in the hypothalamus but not present at all in striatum. It was impossible to duplicate the above results using nialamide as the monoamine oxidase inhibitor. After depletion of monoamine stores by reserpine (2 x 2 mg/kg) or oxypertine (75 mg/kg) and treatment with tranylcypromine and L-DOPA it is possible to get an indication of the maximal rate of synthesis of NA. In pyrazole treated rats synthesis of NA in brain was 70% reduced and about 50% reduced in heart. Synthesis of dopamine from L-DOPA was unimpaired. Dopamine-beta-hydroxylase activity in the hypothalamus of rats treated for four days with pyrazole (100 mg/kg i.p.) was more than 40% reduced. This inhibition could not be obtained by addition of pyrazole to samples of purified dopamine-beta-hydroxylase. The results strongly suggest that the reason for the decrease in brain and peripheral NA seen after pyrazole administration in rats is due to inhibition of dopamine-beta-hydroxylase.


Physicians, physicians' assistants, and the social characteristics of patients in southern Appalachia. A focus on health care delivery systems and the emergence of New Health Practitioners, particularly Physicians' Assistants (PAs), represents one of the more significant nonbiomedical developments in American medicine since World War II. Much discussion about PAs revolves around the kinds of illnesses they are qualified to treat which then permits physicians to concentrate on patients with other types of illnesses. Ignored in this focus on illness characteristics is the possibility that physicians and PAs may treat patients with different social characteristics. That issue is the topic of this paper. Differences between the status characteristics of physician and PA patients are reported for a rural community where PAs and physicians work side by side in the same offices. The relationships observed in this rural community suggest that the higher a patient's socioeconomic status, the more likely (s)he is to be treated by the physician.


The distribution of physician extenders. As part of the Medicare Physician Extender Reimbursement Study, a mail survey was conducted of 5,572 physician extenders (PEs) to identify potential study participants. Analysis of survey results indicates that PEs are distributed disproportionately more often than physicians to primary care practices and to rural low income areas. However, there are substantial differences among types of PEs with regard to practice location and practice arrangement. The relationship between these findings and the distribution of other medical manpower and innovations is then discussed.


Physician assistants: an overview of an emerging health profession. This article describes the background characteristics, work environments, and job characteristics of the physician assistant profession as they existed in late 1974 and early 1975. Of the 939 physician assistants participating in this study, three-fourths were working in primary care specialties and half were located in communities having fewer than 50,000 persons. Favorable levels of responsibility for patient care, supervisory support, and role acceptance were reported by respondents. The mean income was $14,285. Job opportunities appeared plentiful, but career opportunities were considered by most to be either limited or nonexistent. Physician assistants are providing important additional medical manpower in primary care fields and in smaller communities, but the preceived lack of opportunities for career advancement may prove to be a significant problem for this emerging health profession in the years ahead.


The effectiveness and cost of acute respiratory illness medical care provided by physicians and algorithm-assisted physicians' assistants. The medical management of patients with acute respiratory illnesses was analyzed at two different clinics during a 14- to 21-month period. Patients received care from either physicians or physician-supervised physician's assistants (PA). The PAs used respiratory illness clinical algorithms to guide their choice of diagnostic tests and treatment. Illness outcome, patient satisfaction, and medical care cost data were obtained for all patients approximately two weeks after the index illness. Despite significant differences in patient population characteristics, illness outcomes were similar, regardless of the provider's educational background. Medical care costs, however, were highest for the physician's patients. For all patients, diagnostic tests contributed about one-third of the total direct costs, mainly because of chest x-ray and throat culture use. Sixty to eighty per cent of medication costs were due to nonprescription drugs used principally for symptom relief. The data demonstrate that the medical care delivered by these physician's assistants was as effective and less costly than the care provided by physicians. Reducing chest x-ray and throat culture use would have a significant economic impact, without adversely affecting medical care effectiveness.


[Changes of serum and urinary uric-acid levels after portacaval anastomosis in the rat]. Significantly higher levels of uric acid in serum and urine together with increased urine volume and pH were observed in rats after portacaval end-to-side anastomosis in comparison to sham-operated and non-operated pair-fed controls. An increased supply of endogenous uric acid by reduced transformation of uric acid to allantoin and decreased uricase activity in the liver was assumed. Adaptation of enzyme activities of other metabolic pathways of the liver after PCA due to diminished blood and oxygen supply were described in previous experiments. This model seems suitable for other studies on hyperuricemia, hyperuricosuria and uric acid lithiasis.


The dietary regulation of stearyl coenzyme A desaturase activity and membrane fluidity in the rat aorta. Numerous studies have demonstrated that alterations in membrane composition or fluidity are often associated with alterations in the properties of membrane-bound enzymes. In order to obtain membranes of varying fluidity, rats were fed diets that were either fat-free or supplemented with 15% safflower oil, and two properties associated with aorta and liver microsomal membranes were selected for study: stearyl CoA desaturase activity, and fluidity as monitored by fatty acid composition and microviscosity (measured by fluorescence depolarization). If fluidity directly modulates desaturase activity, one would predict that a low fluidity would stimulate the desaturase activity. Ten times more desaturase activity is present in aorta microsomes from rats on a fat-free diet than in microsomes from rats on a safflower oil supplemented diet. However, on the fat-free diet, these aorta microsomes were more fluid than those of rats fed safflower oil supplemented diet. The fluidity of liver microsomal membranes was not altered in response to diet, despite significant changes in desaturase enzyme content. The contrasting evidence presented here suggests that no correlation exists between desaturase enzyme activity and membrane fluidity in the two tissues studies. We have demonstrated that the aorta has appreciable capacity to desaturate stearyl CoA and that dietary manipulation causes significant changes in aorta membrane fluidity that may be of sufficient magnitude to affect the overall metaboism of aorta cells.


Biochemical properties of a penicillinase from Escherichia coli carrying Rms 298. We obtained two R plasmids, i.e., Rms195 and Rms298, from a clinical isolate, E. coli GN5503. Penicillin beta-lactamase (PCase) was extracted from ML1410 Rms195+ and Rms298+, and was purified by chromatography. Rms195 PCase was identical to the type I PCase mediated by R-TEM, RI and Rms212. The isoelectric point of Rms298 PCase was 5.9 and its molecular weight was 21,000 +/- 1,000. The substrate profile and physiochemical properties indicate that Rms298 PCase belongs to the type IV PCase mediated by Rms139 isolated from Pseudomonas aeruginosa.


[Neurological complications following whooping-cough vaccination (author's transl)]. The clinical symptoms, frequency, etiology, pathogenesis and differential diagnosis of neurological complications following immunisation against pertussis are being discussed. Guide lines are presented for the evaluation of the causal connection between the observed complications and the vaccination.


Mutagenic and recombinogenic action of pesticides in Aspergillus nidulans. Thirteen pesticides, aminotriazole, benomyl, captafol, captan, dalapon-Na, dichlorvos, dinobuton, dodine, ioxynil, mecoprop, neburon, picloram and tordon were tested for ability to induce (1) point mutations to 8-azaguanine resistance, (2) mitotic crossing-over, and (3) mitotic non-disjunction and haploidization in Aspergillus nidulans. Tests were performed at three different pHs, i.e. 4.5, 7, 8.2. Three of the pesticides, captan , captafol and dichlorvos induced point mutations; dichlorvos also induced a high frequency of mitotic crossing-over and non-disjunction; benomyl induced a very high frequency of non-disjunction whereas aminotriazole induced weakly both types of somatic segregation.


Differentiation of cardiac chronotropic and inotropic effects of beta-adrenoceptor agonists. The relative inotropic and chronotropic activity of beta-adrenoceptor agonists was studied in the noradrenaline-depleted, anaesthetized cat. Terbutaline, a selective beta2-adrenoceptor agonist, gave at a certain dose a more pronounced chronotropic than inotropic response, while a new beta1-selective adrenoceptor agonist (-)-H 80/62 produced the same degree of chronotropic and inotropic stimulation. The results indicate that there is some difference between the beta-adrenoceptors in the sinus node mediating chronotropic stimulation and beta-adrenoceptors in the ventricular myocardium mediating stimulation of the contractile force. It has been shown that there are both beta1- and beta2-adrenoceptors in the heart (Carlsson et al., 1972). In the light of this finding it is hypothetized that there are differences in the relative distribution of beta1- and beta2-adrenoceptors in the sinus node and in the myocardium. Athough beta1 is the predominant type of beta-adrenoceptor in both regions, the beta1:beta2 concentration ratio seems to be higher in the myocardium, than in the sinus node.


Regulation of nerve growth factor content in C6 glioma cells by beta-adrenergic receptor stimulation. The C6 glioma cell line contains nerve growth factor (NGF) which can be released into the medium. Treatment of the cells with beta-adrenoceptor agonists resulted in increased content of NGF in both the cells and the medium within a few hours, whereas alpha-adrenoceptor agonists were ineffective. The response was blocked by beta- but not alpha-adrenoceptor antagonists. The increase of the NGF content of glioma cells appeared to be mediated by an elevation of cyclic AMP or GMP. The addition to the cell cultures of other putative neurotransmitters failed to change the content of either NGF or cyclic AMP. These results are discussed with respect to a model for adrenergic neuron-glial interactions.


Effects of medium pH on p-aminohippurate transport in rat kidney fragments. Addition of many oxidizable substrates to medium often enhances p-aminohippurate (PAH) transport by incubating renal tissue. Since the oxidation of various substrates by rat kidney tissue may change medium pH and this pH change has not been considered by many in conclusions, we followed the effects of medium pH on the magnitude and kinetics of in vitro PAH transport. Two previous studies employing rat kidney slices reported different optimal medium pH for PAH accumulation, i.e. pH 6.5 and pH 8.0. By repeating these studies over a wide range of medium pH, we confirmed the presence of enhanced steady state accumulation relative to pH 7.4 at two separate pH ranges, one at pH 6.7--6.9 (+ 15%), and the other at pH 7.7--7.9 (+ 22%). PAH influx, as measured by early tissue accumulation, was not different at pH 7.4 and 7.8; while at pH 6.8, it actually decreased. It was only later in the incubation that accumulation was greater at pH 6.8 and 7.8. Probably due to the small stimulation in steady state accumulation at either pH, we could not discern, by the methodology currently available, if this was secondary to augmented influx, decreased efflux, or a combination of both in the latter part of incubation. We conclude that the contribution secondary to medium pH changes must be considered when evaluating the effects of various substrates on PAH accumulation by kidney slices.


Further evidence on the role of the hypothalamic afferents on the estrogen-induced prolactin release. Serum prolactin (Prl) concentrations in ovariectomized rats were low without significant differences between morning and afternoon values. These levels were not affected by either frontal or caudal hypothalamic deafferentation. However, they increased after lesioning the hypothalamic median eminence (ME). Three days after the injection of 20 microgram estradiol benzoate (EB) into ovariectomized non-lesioned rats, a rise in serum Prl occurred in the afternoon but not in the morning. In animals with ME lesions estrogen enhanced both morning and afternoon values. The animals with caudal hypothalamic deafferentation and those which had undergone sham operation showed the same pattern as the normal animals. On the contrary, after estrogen treatment of rats with frontal hypothalamic deafferentation high serum Prl concentration during the morning and low levels in the afternoon were observed. It is concluded that estrogen effects on Prl secretion are in part mediated by frontal neural afferents to the hypothalamus. They would facilitate Prl inhibiting factor (PIF) secretion in the morning and inhibit PIF secretion in the afternoon.


Thphenidate.

Thphenidate. Plasma cyclic-AMP responses to adrenergic agonists are due to stimulation of the peripheral beta-adrenergic receptor. Mood responses to stimulants are thought to be due to actions leading to stimulation of central catecholamine receptors. To determine if a peripheral measure of receptor sensitivity could predict central mood effects of stimulants, the plasma cyclic-AMP response and the mood response to intravenous methylphenidate were determined simultaneously in 13 subjects. No correlation between the two responses was found.


Ultrasonographic study of the effect of different miotics on the eye components. The effect of topical instillations of carbachol 3%, pilocarpine 2%, aceclidine 2%, aceclidine 2%-adrenaline 1%, and of the Ocusert delivery system was determined and compared in 151 eyes. The depth of the anterior chamber, the thickness and the position of the lens, the length of the vitreous and the refraction were studied. Aceclidine has negligible side effects on the ocular components (maximal change of the anterior chamber 0.20 mm; maximal change of the lens thickness 0.14 mm; maximal myopisation: -1.5 delta. Carbachol has the strongest side effects (maximal change of the anterior chamber 0.80 mm; maximal change of the lens thickness 0.80 mm; maximal myopisation -11.50 delta). Carbachol and pilocarpine may cause an important forward displacement of the lens with the risk of an angle-closure glaucoma in an eye with shallow anterior chamber.


Phosphorylation of human erythrocyte membrane protein. Differences according to the assay procedure. Phosphorylation of the human erythrocyte membrane proteins by gamma (32P) ATP was studied at pH 6 and pH 7.4, at 30 degrees C, with incubation times varying from 5 to 90 minutes, and with or without cyclic AMP. Incorporated radioactivity was much higher at pH 7.4 because of the prevalent activity of cAMP independent protein-kinase. Maximum incorporation was obtained in both pH after 30-45 minutes incubation, thereafter incorporated radioactivity was either stable or decreased. The part of the radioactivity due to cAMP stimulation was low and seems constant with the incubation time. Analysis of the substrates showed the predominant cAMP independent protein kinase activity in the phosphorylation of the spectrin second component and component III and that of cAMP dependent activity in the phosphorylation of component II4, IV5 and other minor bands.


Electrolyte pH changes in Human Milk.

Electrolyte pH changes in Human Milk. Milk samples from 100 lactating mothers in the 10 days following delivery have been analyzed for pH, sodium, and potassium. The sodium concentration was high in the first 5 days, mean 21 +/- 5 mmol/liter, but fell to a mean 15 mmol/liter by the end of the first week and 12 mmol/liter by the 10th day. A similar downward trend was shown for potassium with an initial mean concentration of 18.5 mmol/liter falling to 15 mmol/liter by the 10th day. The pH fluctuated widely from day to day through a range of 6.75-7.42 with a mean pH 7.09. Considerable variations were shown in individuals from day to day, and from the beginning to the end of feeds (Table 1). The relatively high sodium concentration in the first few days may be an important defense mechanism against dehydration and hyponatremia during a period of relative thirst and starvation. The variation in the pH and electrolyte content of human milk may be expected to have some influence on the acid-base and electrolyte status of the infant.


Effect of H+ on spontaneous neuronal activity in the surface layer of the rat medulla oblongata in vitro. The effect of changing extracellular pH (pHe) on the spontaneous activity of neurons in brain slices taken from the ventral layer of the rat medulla oblongata was compared to the response of neurons in dorsal slices. In the ventral medulla, more than 50% of the neurons were excited by H+. These neurons were found just lateral to the pyramidal tract between the root of the hypoglossal nerve and the trapezoid body. In the dorsal medulla, low pHe caused an inhibition of activity in most neurons, although a few were excited. The fact that H+ elicted excitation predominantly in the ventral medullary substrate to respond to pHe changes. Depression of synaptic transmission within the neuronal network in the slice by reducing the [Ca2+]e and increasing the [Mg2+]e altered the nature of responses of neurons to H+: In the ventral medulla, the majority of neurons were inhibited by H+, whereas in the dorsal medulla more than 50% of neurons were excited. Therefore, "specificity" of the ventral medullary neurons seemed to be dependent upon intact synaptic connections. A possible role of acetylcholine-acetylcholinesterase system in the response of ventral medullary neurons to H+ is discussed.


The use of microelectrodes for measurement of local H+ activity in the cortical subarachnoidal space of cats. pH microelectrodes with pointed tip (Hinke-type) were constructed for the continuous measurement of the local pH in the perivascular space of pial arteries in the feline cerebral cortex. The sensitive tip had a length of 20-60 mu and a base diameter of 10-25 mu. As reference electrode, a micropipette (tip diameter 2 mu), filled with 150 mM KCl was used. Calibration curves were linear and showed a sensitivity of 54.5-57.5 mV/pH unit at 38 degrees C. Advantages of such electrodes are the easy penetration of the subarachnoid membrane, the long life span, the quick response, and a minimal drift. The electrodes were tested in vivo during hyper- and hypoventilation and during local perivascular injection of mock spinal fluid at varying pH. A close correlation was observed between the change in perivascular pH and the corresponding change in pial arterial diameter.


On the secretagogue effect of dibutyryl cyclic AMP in the rat exocrine pancreas. DbcAMP greater than or equal to 0.1 mM induces the discharge of exportable enzymes from rat pancreas fragments incubated in vitro. This effect is qualitatively similar to the action of physiological secretagogues acting via hormone receptors: 1) it is accompanied by the appearance of exocytotic images at the acinar cell apex; 2) it is energy dependent but energy supply is low while that required for the carbamylcholine or caerulein response is high and can only be afforded by oxidative phosphorylation; 3) it is calcium dependent, but no alteration of inward or outward calcium movement can be observed; 4) it is altered by agents known to disrupt the microfilamentous microtubular system [41]. However, the secretory response to DbcAMP is quantitatively less than that obtained with hormonal stimuli. A damaging effect of DbcAMP on pancreatic acinar cells is ruled out on histological and biochemical grounds: there is no significant leakage of LDH; protein synthesis, 2-deoxy-D-glucose and L-leucine uptake are unaltered. The secretagogue effect of DbcAMP is reversible, dose-related and specific. It is not mediated by neurotransmitter release or by interaction with their receptors. The evidence presented points to a direct interaction of DbcAMP on the pancreatic acinar cell and suggests the last step of the secretory cycle as the most probable site of action of the nucleotide derivative.


The influence of the pH of feed on the acid-base balance of mink. The acid-base balance in small carnivores (mink, Mustela vison) was examined during 6 feeding periods, when the same animals were given different feeds during a prolonged time. The feeds consisted of normal farm feed to which different amounts of sulphuric acid-preserved feed and feed silaged with organic acids were added (Tables I--II). When the pH of the feed was decreased to below 5.5, the acid-base balance of the animals was changed and metabolic acidosis occurred (Tables III--V, Fig. 1). On neutralization of the acid-preserved feed a normal acid-base balance could be maintained. However, the growth of the animals was reduced after prolonged feeding with silage as they lost weight during the following periods (Table vii).


[Piribedil, dopaminergic agonist. Prolonged clinical and electrophysiological study in 60 parkinsonian patients (author's transl)]. Sixty cases of Parkinson's disease were treated with piribedil alone (dose : 274 mg/day, duration : 20,4 months). The overall clinical improvement, confirmed by recordings of tremor and EMG, was 34%, tremor being improved of 59%. Before treatment, an intravenous test does of piribedil with recording made it possible to predict the effectiveness of oral treatment. Side-effects (vasomotor, digestive, psychiatric) were moderate. Orthostatic hypotension, dyskinesia and fluctuations were exceptional. The basic indication for piribedil lies in forms of recent onset in which tremor predominates, patients in whom L-dopa is contraindicated and a certain number in whom the latter has failed (tremor, fluctuating action).


[Blood gas study in "small airway disease"]. A study of blood gasometry at rest and after exercise was carried out on 98 subjects: 49 healthy, 31 cases with "small airway disease" and 18 cases of clinically nondecompensated obstructive lung disease. The most interesting results arose from the study of PaO2. Its mean value increased after exercise in all groups, but in a manner less obvious as the bronchial obstruction appeared and increased. This increase was almost imperceptible in obstructive patients. The whole of gasometric behaviour ranged the subjects with "small airway disease" in an intermediate position between the normal controls and the obstructive patients. This finding leads the authors to suppose that the "small airway disease" implies the existence of disorders of intrapulmonary gas exchanges which foreshadow the obstructive disease.


Kinetics and mechanism of degradation of some 2-sulfanilamidopyrimidine derivatives: part IV. Mechanism and kinetics of specific acid-catalyzed hydrolysis of sulfadimidine. The following products of acid hydrolysis of sulfadimidine (SDMP) were isolated and identified: sulfanilic acid (Sac), sulfanilamide (SA), 2-amino-4, 6-dimethylprimidine (ADMP) and 2-hydroxy-4, 6-dimethylpyrimidine (HDMP). The apparent first-order rate constants (k1, k2 and k3) were determined for the reaction: (formula: see text). The catalytic rate constants kH+ = ki/[H+] and the thermodynamic parameters delta Ha, delta H not equal to, deltaS not equal to, deltaG not equal to and log A were also determined for that reaction.


The effects of lesion of mesolimbic dopamine neurons on pain threshold and morphine analgesia in rats. Lesions of ventral tegmental area, localised in the region of A 10 group of dopaminergic mesolimbic neurons decreased the pain threshold in rats. The absolute threshold values in morphine treated animals with the above lesion were lower than in sham-operated controls, however, the thresholds expressed as percentage of predrug threshold values did not differ in both lesioned and sham-operated animals. It is thought, that lesions of ventral tegmental dopamine neurons decrease the pain threshold due to the increase of general excitability of animals, and that there is no direct involvement of the lesioned structure in the primary mechanism of morphine analgesia.


Interaction between phenylephrine hydrochloride and polyethylene glycol 400. Evidence of complexing tendency of the water-soluble polymer polyethylene glycol 400 (PEG 400) and phenylephrine hydrochloride was supported by the equilibrium dialysis method. The influence of polymer concentration, ionic concentration, and hydrogen ion concentration of the systems on the interaction was investigated. Attempts to separate the complex by using paper chromatographic techniques have also been made.


Effect of anti-parkinsonism drugs on gastric emptying and intestinal transit in the rat. The effect of atropine sulfate, trihexyphenidyl HCl, benztropine mesylate, diphenhydramine HCl and ethopropazine HCl on gastric emptying and intestinal transit of a phenol red solution in the rat was examined. Intraperitoneal administration of 0.3 mg/kg atropine, 1.2 mg/kg benztropine and trihexyphenidyl results in a marked decrease in gastric emptying and intestinal transit rate when compared to controls. Oral administration of these agents produced variable and unpredictable results. Single and multiple oral dose (0.6--3 mg/kg) studies with trihexyphenidyl failed to produce any significant decreases in gastric emptying rates. A single oral dose of benztropine (0.6--3 mg/kg) failed to reduce the gastric emptying rate, but multiple dose studies produced a significant decrease in the gastric emptying rate. Effects on gastric emptying and intestinal transit were seen after single and multiple oral doses of diphenhydramine and ethopropazine.


Cytological effects of phenothiazine tranquilizing agents on barley meristems. A growth reduction of 30--40% was noted in barley plants grown in two phenothiazine tranquilizers. Similar reductions were noted in the number of mid-anaphase cells, indicating the reduced growth could have been the result of a reduced mitotic rate. Also observed were several types of chromosomal aberrations. Electron microscopy revealed less endoplasmic reticulum and cytoplasmic organelles in the treated cells than in untreated cells. Various sized discontinuities in the nuclear membrane was the most frequent abnormality observed in the electron micrographs. The abnormal nuclear membrane was possibly a result of enzyme degradation.


[Pharmacologic effect of protracted neuroleptics, fluphenazine oenanthate and oxyprothepine oenanthate (VUFB 9447)]. Two neuroleptica with protracted effect, i.e. Fluphenazin-Oenanthat and Oxyprothepin-Oenanthat, were tested on rats, dogs and rabbits. It was found that both drugs, after intramuscular injection in doses between 5--30 mg/kg, produced a long-lasting neuroleptic effect, in particular the inhibition of conditioned reflexes in rats, the antagonistic effect against apomorphine vomiting in dogs and the EEG-brain activity specific for neuroleptica. Hardly any differences were found between the effects of the two drugs. Both neuroleptica caused interesting spike activity in the EEG-registration particularly in the limbic structures which have hitherto not been described in the literature.


[Tests on the vegetative dynamics of depression under thymoleptic treatment]. 40 patients with endogenic depression, who exhibited an inhibited-mel ancholic symptomatology received Dibenzepin (30 patients) and Imipramin (10 patients) as a mood-elucidating and activating anti-depressant. Exact determinations of blood pressure, pulse rate, the orthostatic-reaction, Schellong's test and the cold-pressure test were carried out on these patients. The results were tabulated. They show fundamentally that (1) the thymoleptic circulatory reaction as a sign of the influence of the vegetative functions makes possible in many cases a prognosis of the secondary effects of treatment and (2) a strong acceleration in the rate of pulse, and a rise in the systolic blood pressure at rest as well as the normalization of the orthostatic-test chiefly indicate an improvement or remission of depression.


Does dopamine play a role in schizophrenia? Inhibition of central dopamine functions appears to be a common basic property of antipsychotic drugs. The mesolimbic and nigrostriatal portions of the dopaminergic system are probably the main targets of these drugs for the mental and the extrapyramidal actions respectively. Dopaminergic hyperfunction, induced by amphetamines or dopa, may lead to a disturbance mimicking paranoid schizophrenia, lending further support for a key role of dopamine in mental functions. While a primary disturbance in dopamine function in schizophrenia cannot be ruled out, the intimate relationship between dopaminergic and other neuronal systems must be emphasized. The possible involvement of other amine, aminoacid or peptide transmitters in schizophrenia cannot be disregarded.


[Behavior of some liver enzyme activities in newborn infants with jaundice treated with phototherapy]. The recent hypothesis that phototherapy is capable of altering the liver cell, enough to allow passive diffusion of free bilirubin from the blood to the bile, and the discovery of substantial differences between the breakdown products of bilirubin obtained in vivo and in vitro, has prompted the AA. to investigate the enzymatic values in newborn infants with jaundice undergoing phototherapy. A study was made of the variations of cytolithic enzymes (GPT-GOT-GLDH-SDH) and secretions enzymes (FA-LAP-gammaGT-CHE) before and after phototherapy among different sized groups of infants with jaundice, between the 36th and 40th week of the gestational age, and with body weight varying from 1940 to 4150 g. No significant alteration of the cytolithic enzymes were recorded and among the secretion enzymes only the gammaGT was seen to increase. According to the AA., phototherapy does not alter the presence of a possible transitory cholestasis in newborn infants with physiological jaundice and causes no significant damage to the liver cells.


Slow-drip dibenzepine infusion in depression. Proof of rapid efficacy by quantitative EEG and affect-polarity profile studies. The efficacy of a new intensive antidepressive treatment procedure--48 h slow drip infusion with 1,440 mg dibenzepine2 and subsequent oral treatment--was investigated in endomorphous (endogenous) depressed patients. In addition to evaluations of alterations in psychopathology by clinicians, time of onset and the extent of the therapeutic effect was determined by the patients themselves using the affect-polarity profile, and by EEG power-spectral density analysis. Clinical improvement started as early as in the 3rd hour of the dibenzepine infusion and was predominantly due to an anxiolytic/sedative drug effect. The thymoleptic effect started at the end of the infusion and increased with progressing oral treatment up to the 3rd week. Neurophysiological changes were ahead of the psychopathological ones, since a statistical decrease in dominant frequency of the EEG occurred 1 h after the start of dibenzepine infusion.


Separation and characterization of peptides of delta chain from haemoglobin A2 by fingerprint at pH 3.5. Peptide mapping or fingerprint of delta chain of haemoglobin A2 at pH 3.5 in comparison at pH 6.4 was investigated. The peptides which are in the neutral zone at pH 6.4 can be separated with efficiency at pH 3.5 and this method makes the interpretation and extraction of several peptides easy.


Calcium transport and release by the sarcoplasmic reticulum. The slow rate of calcium transport by cardiac sarcoplasmic reticulum vesicles, compared to those prepared from skeletal muscle, is due mainly to a lesser density of transport sites and a lower Ca2+ affinity. Because the turnover rate of the cardiac sarcoplasmic reticulum calcium pump is similar to that of comparable skeletal muscle preparations, the cardiac sarcoplasmic reticulum seems able to effect the slower relaxation of the heart. Calcium permeability of skeletal sarcoplasmic reticulum vesicles is increased when the Ca2+ concentration outside the vesicles is increased, or when that inside the vesicle is decreased.


Isolation and enzymatic characterization of guinea pig cardiac sarcolemma. Sarcolemma was isolated by fractionation of salt-extracted particles on two consecutive sucrose density gradients. Salt extraction of homogenates, rather than of washed particles, was found to preserve the activities of adenylate cyclase and ouabain-sensitive (Na+,-K+)-ATPase in the isolated sarcolemmal membranes. Purified sarcolemma contained substantial adenylate cyclase and guanylate cyclase activities that were stimulable by beta-adrenergic and muscarinic agonists, respectively. Significant ouabain-sensitive (Na+, K+)-ATPase activity as well as putative digitalis receptor activity was also present in sarcolemma. Cyclic nucleotide phosphodiesterases of sarcolemma, both cAMP- and cGMP-dependent, displayed positive cooperativity of substrate interactions; Ca2+ ions were found to increase the activity of the GMP-dependent enzyme.


Properties of membrane-bound and soluble guanylate cyclase of cardiac and skeletal muscle. Kinetic properties of guanylate cyclase present in the washed particles, plasma membranes, and the soluble cytoplasm of heart and skeletal muscle are described; properties of the enzyme solubilized by Triton X-100 treatment of the particles or membrane fractions are also reported. It is apparent from the data that the membrane-bound guanylate cyclase in the cell may be regulated by acetylcholine, may exist as a metallo-protein with bound Mn2+ (essential for activity), and that Mg2+ regulates, whereas Ca2+ and nucleotides (especially ATP) modulate, guanylate cyclase activity. The findings also suggest that guanylate cyclase, similar to adenylate cyclase and (Na+, K+)-ATPase, is mainly located in the plasma membranes of heart and skeletal muscle.


Metabolic effect of pH on myocardium of heart-lung preparation. Cardiac performance and metabolism of heart-lung preparation of rat were studied with acid, normal, and alkali perfusions. Cardiac output, glucose uptake, and myocardial content of lactate, malate, glycerophosphate, and CP were increased in alkali and decreased in acid perfusion of 20 min. On the other hand, when pH of the perfusate was abruptly changed, CP and ATP were decreased independent of the performance. FDP was high and PEP was low in acute acidifying experiments. From these findings it is concluded that cardiac performance and carbohydrate metabolism are accelerated in alkali and depressed in acid perfusion, and that myocardial metabolism could be affected by pH not only secondary to the change of performance but also by itself.


Dose-dependent depression of cardiac function and metabolism by inhalation anesthetics in chronically instrumented dogs. Halothane, methoxyflurane, and enflurane produce dose-dependent depression in ventricular function in the dog. Myocardial blood flow and oxygen consumption are decreased accordingly without evidence of myocardial tissue hypoxia. Low-dose fluoxene does not depress the heart, while there is less depression with high-dose fluroxene than with the other anesthetics. In spite of this depression, myocardial blood flow was unchanged, and the decreased oxygen consumption during high-dose fluroxene was a result of decreased oxygen extraction by the heart. Sympathetic nervous system stimulation produced by fluroxene anesthesia is probably responsible for these effects, but further work is necessary for confirmation of this hypothesis.


Control of energy production in cardiac muscle: effects of ischemia in acidosis. Evidence is summarized indicating that mitochondrial respiration and citric acid cycle activity in the intact heart are controlled by the cytosolic phosphate potential and mitochondrial NAD oxidation-reduction state. Data are presented showing that the effect of respiratory acidosis is greater than that of metabolic acidosis in inhibiting left ventricular pressure development in the perfused rat heart, because of a greater fall of intracellular pH under the former conditions. Respiratory acidosis is shown to be readily associated with tissue hypoxia as a result of an increased vascular resistance and diminished flow rate through the coronary circulation. In nonischemic respiratory acidosis, the rate of ATP production is well balanced by the rate of ATP utilization, and tissue ATP and creatine-P levels remain approximately normal. Partially ischemic respiratory acidosis was associated with low tissue levels of ATP and creatine-P and high tissue levels of lactate and NADH. Ischemic areas with sharp border zones were visualized during and after an abrupt decrease of perfusion fluid pH by directly photographing NADH fluorescence from the surface of perfused hearts. Reversal of the hypodynamic state with partially ischemic respiratory acidosis could not be achieved by augmenting the coronary flow by means of an external pump. The demonstration of the existence of sharp zones of high pyridine nucleotide fluorescence adjacent to normal zones indicates a great heterogeneity of coronary perfusion and the existence of steep oxygen gradients in the intact heart.


Calcium ion in cardiac contractility.

Calcium ion in cardiac contractility. Under physiological conditions where the intracellular Ca ion concentration does not exceed 3 X 10(-6) M, the sarcoplasmic reticulum plays a major role in the relaxation process of cardiac muscle; mitochondria do not take up a significant amount of Ca ion during this process. If cardiac muscle undergoes maximum contraction, in which the intracellular Ca ion concentration should reach 10(-4) M, the role of mitochondria in reducing intracellular Ca ion becomes appreciable. The relationship of the tension developed by cardiac glycerinated muscle fibers to the Ca ion concentration resembles the relationship of the amount of bound Ca of cardiac troponin to the Ca ion concentrations, being less steep in its slope compared with those of fast and slow skeletal muscles. This gentle slope seems to reflect the great diversity of affinities for Ca ion of the two Ca-binding sites of cardiac troponin, one being about 100 times that of the other.


Myocardial metabolism during prolonged selectived hypothermic coronary perfusion. In the study discussed below, we assessed the myocardial protection provided by our method of selective hypothermic coronary perfusion. Using arterial and coronary venous blood samples, the following biochemical aspects of myocardial metabolism were calculated: 1) coronary arteriovenous (A-V) pH difference, 2) O2 difference, 3) CO2 difference, 4) respiratory quotient, 5) coronary A-V pyruvate difference, 6) lactate difference, 7) cardiac excess lactate, and 8) redox potential difference. Results indicate that, during coronary perfusion performed according to out method, metabolic changes are minimal and easily reversible shortly after coronary perfusion is terminated.


Enamel microhardness and fluoride uptake underneath fermenting and non-fermenting artificial plaque. Washed cells of Streptococcus sanguis were used to form artificial plaque on the surface of bovine enamel and incubated underneath buffer solutions, initial pH 6, for 36 h at 37 degrees C. The decrease in the microhardness of the enamel surface under fermenting "plaque" could be prevented with fluoride. Enamel under a fermenting "plaque" took up significantly more (P less than 0.0u) fluoride than enamel under a non-fermenting "plaque" (initial F- in buffer: 10 parts/10(6)). The artificial plaque did not accumulate fluoride. Within fermenting "plaques/, the pH decreased significantly more without flouride (P less than 0.01) than with fluoride. Fluoride combined with sucrose more than negated the softening of the enamel caused by sucrose fermentation, i.e. it increased the hardness above the original values. The diffusion of fluoride through the fermenting artificial plaque was more rapid than through a non-fermenting plaque. These findings suggest that caries-conducive circumstances may promote fluoride uptake by enamel compared with non-caries-conducive circumstances.


PH and the effect of fluoride and zinc on protein and collagen biosynthesis in rabbit dental pulp in vitro. The effect of pH in the range 6.6-8.2 on the incorporation of 14C-proline into the rabbit dental pulp incubated in vitro has been studied. The amount of label in the cold TCA-soluble pool, total protein, and hydroxyproline (i.e. collagen) of the pulp tissue increased linearly with pH in all three fractions. A similar increase was found in the amount of labeled total protein and collagen recovered from the incubation medium. The results indicated that the uptake of 14C-proline into the TCA-soluble pool was the pH-sensitive step, whereas the incorporation into protein, formation of hydroxyproline, and the release of labeled macromolecules into the medium were not affected to any measurable degree by the ambient pH. In this system, zinc (60 micrometer) had less effect on the incorporation of 14C-proline into the different fractions of the pulp tissue at pH 6.6 as compared with pH 7.4, whereas with fluoride (1.3 mM) an increased inhibition of the uptake of 14C-proline into the TCA-soluble pool and the incorporation into total protein was found upon lowering the pH to 6.8. The inhibitory effect of zinc and fluoride on the release of labeled total protein and collagen into the incubation medium was not affected when the pH was lowered.


Toxicity of some dental cements in a cell culture system. A cell culture method has been used to study the effect of zinc phosphate cement (De Trey's Zinc Zement Improved), zinc silicophosphate cement (Fluoro-Thin) and polycarboxylate cement (Durelon) on animal cells. Disks (20 x 1 mm) of the materials were placed in the center of plastic Petri dishes and subsequently incubated with human epithelial cells. Cell multiplication, medium pH and the release of cement constituents were measured. All three cements exhibited a cytotoxic effect, which was most pronounced in the cultures with zinc silicophosphate cement and polycarboxylate cement. The results also indicated that cell growth on the surface of the disks is a more sensitive indicator of cytotoxicity than cell growth around the disks. pH of the medium was only slightly affected in cultures with polycarboxylate cement, whereas a decrease was found in cultures with zinc phosphate cement and especially with zinc silicophosphate cement. A rapid release of phosphate was found in cultures with zinc silicophosphate cement. Zinc was released into the medium from disks of zinc phosphate cement, zinc silicophosphate cement and polycarboxylate cement--exceeding the toxicity level for the present cell line after 24 h. In cultures with zinc silicophosphate cement and polycarboxylate cement the release of fluoride reached toxic levels within the same time interval.


Effect of "APUD"-type hormones on osteolysis in vitro. Besides their well-known actions, glucagon, ACTH, pentagastrin and insulin from the APUD series exert a direct action on the bone calcium content. Incubation with these substances of rat calvaria in vitro yields an evident stimulation of osteolysis with ACTH. Pentagastrin inhibits osteolysis. Glucagon and insulin inhibit parathormone-stimulated osteolysis, with no influence on the spontaneous one. Glucagon, resembling calcitonin, stimulates the 45Ca uptake from the incubation medium. The action of these substances completes the series of hormones influencing bone calcium metabolism, underlining possible interference actions of APUD-type hormones.


Characterization of the beta-adrenergic receptors in the lower urinary tract of the cat. The corpus-fundus and the outlet region of the urinary bladder of the cat was studied in vitro to characterize the beta-adrenergic receptors. In the corpus-fundus only beta1-receptors were found in contrast to the outlet region where the beta-receptors had both beta1-and beta2-characteristics.


Polyarteritis nodosa of the penis.

Polyarteritis nodosa of the penis. The course of polyarteritis nodosa in a patient showing an isolated nodule localized to the glans penis is described. The underlying disease was not recognised and the patient was wrongly thought to have a penile cancer. Treatment with radiotherapy and Bleomycin had no effect and he subsequently died in uraemia. Postmortem examination revealed polyarteritis nodosa involving the kidneys and also causing localized changes to the glans penis.


Phosphorylated proteins as physiological effectors. A variety of neurotransmitters, hormones, and other regulatory agents affect the phosphorylation of specific proteins in their target tissues. The types of stimuli that share this common effect on protein phosphorylation include numerous substances that do not act through cyclic AMP. These and other observations suggest that many different classes of regulatory substances achieve certain of their biological effects by altering the phosphorylation of specific proteins.


Dopaminergic inhibition of adrenergic neurotransmission as a model for studies on dopamine receptor mechanisms. Dopamine and apomorphine produced concentration-dependent inhibition of adrenergic neurotransmission in the isolated, perfused, rabbit ear artery. The inhibitory action of both dopamine and apomorphine was competitively antagonized by haloperidol and several other antipsychotic drugs. The calculated affinities of these drugs for the dopaminergic receptor correlate closely with both the pharmacological potencies of these drugs in vivo and their reported potencies as inhibitors of [3H]haloperidol binding to "dopamine receptors" in brain homogenates.


Recent advances in alcohol withdrawal states. Recent advances in alcohol withdrawal states are described. New concepts of classification, the development of the syndrome and its management are outlined. In the light of recent research, more optimistic results for this much maligned but common condition may be achieved.


Chronotropism and blood flow patterns following teratogenic doses of catecholamines in 5-day-old chick embryos. In vivo heart rates of 5-day-old chick embryos were recorded from electrodes placed in close proximity to the heart. L-epinephrine (4X10(-10) mole), 1-norepinephrine (1X10(-9)mole) and 1-isoproterenol (1.6X10(-10)mole) in 5 microliter of isotonic saline transiently accerlerated the mean heart rate by almost 9 percent. L-phenylephrine (2X10(-9)mole/5microliter) and the experimental procedure produced no appreciable effect. The positive chronotropic effect of the catecholamines was found to be highly significant (P less than 0.0005) as computed by Student's t test. However, no direct relationship could be established between the chronotropic response and the aortic arch anomalies produced. A prolonged reduction of blood flow in the primitive heart tube and the sixth aortic arch after administration of epinephrine and isoproterenol is apparently related to the induction of hypoplastic right pulmonary artery with absent or hypoplastic right ductus arteriosus.


5alpha-Pregna-1,20-dien-3-one and related compounds from a soft coral. Four unusual pregnane derivatives, 5alpha-pregna-1,20-dien-3-one (1), 1,4,20-pregnatrien-3-one (3), 5alpha-pregn-20-en-3alpha-o1 o-acetate (4), and 5alpha-pregn-20-en-1alpha,3alpha-diol 3-acetate (6) have been isolated from an unidentified soft coral from Canton Island.


Culture of malaria parasites.

Culture of malaria parasites. A human malaria vaccine that will protect against the blood stages of Plasmodium falciparum is dependent upon the continuous cultre of the parasite. Scientists have demonstrated that it is now possible to achieve this on a small scale. Present expertise needs to be expanded to produce larger quantities of material for antigenic studies and potential vaccine production.


Marrow grafts between DLA-identical and homozygous unrelated dogs: evidence for an additional locus involved in graft-versus-host disease. Marrow transplants were carried out between unrelated donor-recipient pairs of dogs that were homozygous and identical for DLA-A, B, C, and D, i.e., mutually nonreactive in mixed leukocyte culture. Recipients were conditioned for transplantation by 1,200 R of total body irradiation and then treated with intermittent methotrexate for 102 days in order to prevent or delay graft-versus-host disease (GVHD). Of 13 dogs that received transplants, 4 are surviving with good grafts and no GVHD for more than 12 to 20 minutes. Nine died, 6 with GVHD between days 26 and 141, 1 with wasting on day 65, 1 with interstitial pneumonia on day 83, and 1 with graft rejection on day 23. In comparison, the survival of 17 DLA-identical littermates treated in the same manner was significantly better with 16 surviving without GVHD (P less than 0.01), while the survival of 54 DLA-nonidentical littermates was significantly worse with only two surviving without GVHD (P less than 0.025). These results are incompatible with the concept that solely the loci detected by mixed leukocyte culture and serotyping are responsible for GVHD. One or more additional loci appear to be involved. Knowledg e of this locus (loci) is important if marrow grafting between unrelated individuals is to be successful. However, results also indicate that an unrelated "compatible" marrow graft is more likely to succeed than a graft from an incompatible littermate.


Analysis of the major histocompatibility complex in Syrian hamsters. I. Skin graft rejection, graft-versus-host reactions, mixed lymphocyte reactions, and immune response genes in inbred strains. Five inbred strains of Syrian hamsters (Mesocricetus auratus) were examined for the presence of disparity at a genetic region similar to the major histocompatibility complex in other species. Vigorous reciprocal alloreactions developed in several strain combinations, which resulted in acute skin graft rejection, strong mixed lymphocyte reactions, and potent graft-versus-host reactions. In addition, we found evidence for an immune response gene which controls the antibody response to bovine serum albumin. Patterns of alloreactivity observed for skin graft rejection, graft-versus-host reactivity, and mixed lymphocyte reactivity are compatible with the hypothesis that hamsters possess a major histocompatibility complex, but the absence of discernable disparity at a serologically defined locus makes a definitive statement premature.


Analysis of the major histocompatibility complex in Syrian hamsters. II. Linkage studies. The genetic control of the histocompatibility antigens that induce strong alloreactions in Syrian hamsters was examined. Genetic studies revealed that the alloantigens involved in skin graft rejection, graft-versus-host reactions, and mixed lymphocyte reactions are under dominant single gene control and that these genetic loci are closely linked. These data suggest that this strong histocompatibility locus (i) may represent the major histocompatibility complex equivalent in this species, and this locus or group of loci has been called Hm-1. In addition, studies concerning the genetic control of the immune response to bovine serum albumin suggest that the high response is under dominant, single gene control; however, this gene is not linked to Hm-1.


Secretion of various antimicrobial substances in dogs with experimental bacterial prostatitis. Bacterial prostatitis in dogs was induced by injection of an E. coli 06 suspension into a branch of the prostatic artery. Three to six days later, secretion from the inflamed glands was obtained by pilocarpine stimulation and the concentrations of trimethoprim, sulphamethoxazole, erythromycin, doxycycline and ampicillin were measured during constant infusion of these drugs. In the prostatic secretion, only the concentrations of the lipid soluble substances trimethoprim and erythromycin exceeded the corresponding plasma levels. These two substances may therefore be of value in the treatment of bacterial prostatitis.


[The passage of nitrogenous compounds through the wall of perfused sheep rumen (author's transl)]. Experiments were performed by the method of the extracorporeal perfusion of sheep rumen lasting 150 minutes. After 60 minutes of perfusion, 20 g of enzymatic casein hydrolyzate were applied to the rumen. Ammonia, urea, and total nitrogen were determined in the samples of perfusate, and ammonia and pH were determined in the rumen content. Considerable amounts of ammonia accumulated in the perfusate in the course of the experiment. At the end of perfusion, the concentration of NH3-N reached an average value of up to 12 mg per 100 ml. The level of urea in the perfusate decreased only in the first phase of perfusion (before the application of casein hydrolyzate to the rumen) and remained unchanged in the subsequent phase. It is assumed that part of urea-N from the perfusate after urea hydrolysis, taking place already in the rumen wall, returned to the perfusate in the form of ammonia. In the first phase of perfusion the passage of nitrogen from the blood into the rumen took place, in the second phase its absorption from the rumen into the blood was observed. The urea-N ratio from the passage of total nitrogen into the rumen ranged between 4.63% and 13.84%, but the concentration of total nitrogen in the perfusate decreased by 7-15% and that of urea nitrogen by 37-42%. It follows from the results that a major part of endogenous nitrogen passing from perfusate to the rumen was represented by proteins and/or their peptidic splits.


[HCO3-stimulated adenosine triphosphatase in rat ovarian tumor cells]. Dependence of the HCO--3-stimulated ATPase activity from nuclei and mitochondria of rat ovary ascites tumor cells on pH and concentration of bicarbonate ions was studied. PCMB, NaN3, NaCNS, NaClO4 and NaF inhibited the HCO--3-stimulated ATPase activity. The properties of HCO--3-sensitive ATPase from rat ovary ascites tumor cells were similar to that of HCO--3-ATPases from other tissues.


[Role of adrenoreceptors in regulating aspartate aminotransferase isoenzyme activity in albino rat hearts]. Cytoplasmic (c) and mitochondrial (m) isoenzymes of aspartate aminotransferase (AAT, EC 2.6.1.1.) were isolated from rat heart extracts by electrophoresis in agar gel. Their pH optima and Km values were estimated; optimal conditions for estimation of the enzymatic activities are reported. Isadrine activated and adrenaline inhibited the cAAT activity. Noradrenaline did not affect the activity of both isoenzymes. Phentolamine, as contrary to obsidane which decreased the activity of both isoenzyme, activated the isoenzymes; the effect was partially decreased by obsidane. Phentolamine did not alter the noradrenaline effect on either mAAT or cAAT; it decreased significantly the free form of the mAAT activity only. Results of the experiments with administration of adrenomimetic drugs suggested that adrenaline and noradrenaline-isadrine had different sites of attachment through which they mediated their action on aspartate aminotransferase in rat heart mitochondria.


[Anion-sensitive nuclear ATPase of the rat heart]. Properties of HCO--3-stimulated ATPase from rat heart muscle nuclei were studied. The maximal activity of HCO--3-ATPase was observed at concentration of bicarbonate 25 mM. The enzyme had a pH optimum at pH 8.0-8.5. Bicarbonate stimulated the ATPase activity only in presence of Mg2+, Mn2+ and Zn2+, Co2+, Cd2+ and Ca2+ were ineffective. NaCO3 and Na2SO3 at concentration 30 mM stimulated the nuclear ATPase activity by 20% and 81%, respectively. Anions N3--, scn--, clO--4, and I-- inhibited both Mg2+-ATPase and HCO--3-ATPase. HSO--3 and SO2--4 ions did not affect the nuclear ATPase activity.


[Long-term treatment with the new antiarrhythmic drug propafenone in correlation to plasma levels (author's transl)]. The results of long term oral therapy of cardiac arrhythmias in 43 patients successfully treated with propafenone are reported. The patients were treated for periods ranging between 1 month and 34 months with a mean of 13.4 months. The administered dose varied between 150 mg tds and 300 mg qds with an average daily dose of between 600 and 750 mg. The doses were decided on a body-weight basis with range of 6 to 17 mg/kg and an average of 12 mg/kg. Altogether 30 patients were successfully treated over a long period, sometimes in combination with other antiarrhythmic agents, particularly beta-blockers. 2 patients did not appear after some first controls. In 7 patients the drug was not effective, even when used in combination with others. 4 patients stopped the treatment due to side-effects. Further 18 patients complained temporarily of gastrointestinal and cerebral side-effects. Some Ecg changes were noted, particularly A-V conduction delays and spreading of the QRS-complex. We suggest that the clinically most important parameters for monitoring an antiarrhythmic regimen of propafenone are the patients's own history and Ecg-examination noting the PQ interval and particularly the width of the QRS-complex and long-term monitoring.


[Depression of rat liver acetyl-CoA-carboxylase activity by salicylate and other compounds]. Two intraperitoneal injections of salicylate at a dose of 250 mg/kg of body weight led to decrease in the acetyl-CoA-carboxylase activity in liver soluble fraction (140000xg) more than by 60%. Salicylate in concentrations 10(-4) and 10(-2) M inhibited the enzyme from rat liver soluble fraction by 25% and 80%, respectively, in vitro: it was found to be as effective inhibitor as kynurenate and clofibrate. Derivatives of salicylate -- acetyl salicylate and salicyl amide also showed this inhibitory effect, but their action was less disinct as compared with salicylate. 2-phenyl-3-methyl-hydroxypentanic and 2,3-diphenyl-3-hydroxypentanic acids (derivatives of deoxymevalonic acid) demonstrated the strong inhibitory effect on acetyl-CoA-carboxylase, comparable to the action of salicylate. The effect of salicylate on the reaction of carboxylation was not related to competition for acetyl-CoA (formation of acetyl salicylate), to interaction with biotin and to allosteric reaction with acetyl-CoA-carboxylase. Possible mechanisms of the salicylate effect on the enzyme activity are discussed.


[Tyrosine-alpha-ketoglutarate transaminase activity in the rat liver after partial hepatectomy and CCl4 poisoning]. Acitivity of tyrosine-alpha-ketoglutarate transaminase and induction of the enzyme by hydro cortisone were studied in rat liver tissue after partial hepatectomy and intoxication with CCl4 Administration of the hormone increased the enzymatic activity within 72 hrs after treatment with CCl4 but did not affect its value within 8 and 24 hrs. Activation of the enzyme by hydrocortisone correlated with the increased enzymatic activity observed within 20 hrs after partial hepatectomy. Possible mechanisms for activation of the enzyme, caused by endo- and exogenous factors, are discussed.


Chemical stimulation of Schistosoma mansoni miracidial activity. The movements of S. mansoni miracidia immersed in various solutions of organic chemicals were recorded by dark ground photography. Reduction of miracidial speed was recorded for miracidia in solutions of fatty acids and ammonia. The speed reduction was concentration dependant and pH dependant, indicating in both cases that the un-ionized molecule was responsible. Ammonia at concentrations between 0.4 mM and 0.8 mM elicited an increased "rate of change of direction" by miracidia. No changes in miracidial movements were recorded for miracidia immersed in aqueous solutions of amino acids, sugars or of molluscan nitrogenous excretion products other than ammonia. A possible role for chemo-klinokinetic behaviour patterns in miracidial host location was formulated.


[Thermostable basic proteinase inhibitors from potatoes. Isolation and characterization (author's transl)]. Four basic proteinase inhibitors were isolated from potato tubers (var. Maritta) by ammonium sulfate precipitation, heat treatment, chromatography on CM-cellulose and preparative polyacrylamide gel electrophoresis. Their isoelectric points are in the pH range 9.2--9.8. The molecular weights, as estimated by Sephadex gel filtration, were 8500 for inhibitor K 1 and 22000 for the inhibitors K3, K4, and K6. Differences in inhibitors regarding amino acid composition and specific activity against six different proteinases are discussed. Comparisons with previously described inhibitors are given. A correlation between high cystine content and thermostability of the inhibitor proteins is indicated.


[Aqueous chloride and bromine solutions as disinfectants: composition, redox potential, differences of reactivity (author's transl)]. A method is given to calculate the equilibrium concentrations of the molecules and ions emerging from the hydrolysis and dissociation of chlorine and bromine in aqueous soltuion. The differing influence the pH value and the initial (total) halogene concentration exerts to the HOX- and X2-equilibrium concentration is discussed. From the calculated equilibrium concentrations and tabulated standard reduction potentials the redox potentials of chlorine and bromine solutions at various pH values are calculated. No correlation between the reactivity and the redox potential of the two halogens was observed. Two possible explanations for the differing reactivity of chlorine and bromine against proteins are presented.


Some properties of the lipoxygenase from rabbit reticulocytes. A lipoxygenase was enriched from the stoma-free supernatant of rabbit reticulocytes. The enzyme causes drastic deterioration of mitochondrial membranes. The release of matrix enzymes is paralleled by formation of products of lipid peroxidation. The enzyme reacts with isolated phospholipds and free cis-unsaturated fatty acids. Some properties were determined: molecular weight, isoelectric point, temperature and pH-dependence and Km value for linoleic acid. The enzyme is inhibited by reaction products and a variety of inhibitors, especially antioxidants and chelating agents.


Thermodynamics of red cell glycolysis.

Thermodynamics of red cell glycolysis. 1. Changes of Gibbs energy, enthalpy and entropy in red cells during steady-state glycolysis were discussed. 2. The heat production of red cells at various metabolic conditions was measured on a flow microcalorimeter with simultaneous analyses of lactate and other metabolites. The results were discussed in relation to enthalpy changes of the different metabolic steps in the glycolytic pathway.


pH-dependent changes of 2,3-bisphosphoglycerate. A systematic study of the pH dependent changes in the range 6.6--7.4 of 2,3 bisphosphoglycerate (2,3-DPG) was performed in the presence and absence of glucose during transitional and steady states. The results indicate that 2,3-DPGase breaks down 2,3-DPG nealy independent of pH at a rate of 480 mu moles 2,3-DPG/1 cells.h. The 2,3-DPG mutase is practically completely inhibited below pH 6.9. The 2,3-DPG level in the presence of glucose reaches a pH dependent steady state after about 18 h. The share of the 2,3-DPG bypass in the steady state decreases from 24% at pH 7.4 to 12% at pH 7.0. The formation of pyruvate corresponds to the beadkdown of 2,3-DPG after consumption of an unknown reducing substance.


[Influence of bicarbonate on the content of 2,3-DPG (bisdihydroglycerophosphate) in preserved erythrocytes]. Both whole blood in ACD-adenine-guanosine solution (PCV about 36%) and resuspensions of erythrocytes from EDTA-blood (PCV about 80%) were stored at 4 degrees C with an admixture of sodium bicarbonate. To the resuspensions simultaneously were added xylitol and inorganic phosphate. The erythrocyte concentration of 2,3-disphosphoglycerate in whole blood will be preserved the longer the more bicarbonate is added. Compared with whole blood in resuspensions of erythrocytes the preservation of 2,3-DPG is significantly prolonged, probably because xylitol was added. From these results and from literature data it is concluded that bicarbonate is fixed to metabolites of the pentose metabolism. The products of the fixation of bicarbonate may influence the 2,3-DPG metabolism of the erythrocytes.


Experimental liver failure. A comparison between hepatectomy and hepatic devascularization in the pig. Difficulties in the treatment of acute hepatic failure due to insufficient knowledge of the pathogenesis and the impredectability of the course has made an experimental model desirable. A number of such models have been proposed, among these hepatectomy and total hepatic devascularization. In the present study hepatectomy and total hepatic devascularization have been compared, as it has been doubted if hepatectomy, not including necrotic liver tissue, is a valid model of human hepatic failure. No significant difference was found in the survival time which was 16 h 2 min +/- 57 min in the anhepatic and 18 h 33 min +/- 1 h 5 min in the devascularized preparation. The blood pressure of the anhepatic preparation decreased gradually, in contrast that of the devascularized preparation remained stable during most of the experimental period with a terminal steep decrease. Except for an increase in serum alanin-aminotransferases and free hemoglobin, seen in the devascularized, but not in the anhepatic preparation, no differences between the two models were seen. It is concluded that the presence of necrotic tissue is of minor importance, but for technical reasons the devascularized preparation is the most suitable model for experimental hepatic failure.


Morphology, histochemistry and isozymes of monkey kidney cells during long-term exposure to cigarette smoke. Monkey kidney cells (Vero) in monolayer culture were exposed to 260 puffs of whole smoke from a mid tar range cigarette over a period of 240 days. Cell morphology was investigated at the light and electron microscopic level. The histochemical characteristics of several hydrolytic enzymes and dehydrogenases were examined, and the isozymes of LDH, MDH and G6PD studied. For all these parameters smoke exposed cells displayed the same features as sham exposed and negative controls. The cells were assessed as non malignant by their failure to form tumours in the nude mouse.


Physiologic evaluation of the HFPPV pneumatic valve principle and PEEP. An experimental study. In experiments in dogs the ventilatory and circulatory conditions prevailing with the ventilatory pattern in high-frequency positive-pressure ventilation (HFPPV) were investigated with use of a pneumatic valve principle and a ventilator system of an "open" character. Keeping the gas input constant the importance of insufflation frequency and insufflation time and the reactions to various levels of positive end-expiratory pressure (PEEP) were investigated in terms of changes in arterial pH, Pco2 and Po2. With the volumes of delivered gas kept constant, an increasing insufflation frequency from 60 to 100 per min gave a parallel decrease in tidal volume accompanied by lower maximum intratracheal pressures and a significant decrease in alveolar ventilation. Also taking into account the possibilities of inducing a suppression of the spontaneous respiration, higher ventilatory frequencies than 60 per min do now seem to introduce any further advantages. Including the associated effects on cardiac output and venous admixture, the cardio-pulmonary and circulatory parameters studied did not show any substantial changes with PEEP levels below 7.5--10 cm H2O. Thus the level of PEEP, which often is part of the ventilatory pattern in HFPPV, does not seem to have any untoward influence on the circulation (stroke volume, cardiac output, total peripheral vascular resistance) and oxygen transport (arterial oxygen content and oxygen flux) in normovolaemic dogs.


Some effects of sugar-flavored acid beverages on the biochemistry of human whole saliva and dental plaque. An investigation was made of the effects on some biochemical characteristics of human whole saliva and dental plaque resulting from the daily consumption of three commercial, acid-containing beverages. The beverages tested were a cola beverage ("Coca-Cola"), a carbonated orange drink ("Jaffa") and single strength orange juice. Each of the three test beverages as well as non-fluoridated tap water as a control, were consumed during four two-week periods. The test group consisted of 39 dental students. The mean consumption frequency lay in the range from 5.3 to 5.7 times per day. Orange juice was found to stimulate the salivary secretion rate most. All test drinks decreased the salivary pH immediately after consumption, but the pH did not generally drotase-like activity in oral fluid. Changes were observed in calcium, phosphate and fluoride concentrations in oral fluid samples, but these were due to variations in salivary secretion rate. A significant decrease in redox potentials of whole saliva was, however, observed after consumption of the drinks. The present results indicate that in healthy persons with normal saliva flow rate and buffer capacity the moderate consumption of acidic beverages failed to induce any remarkable caries-promoting changes in oral cavity. However, in persons with low salivary flow rate erosion may be a consequence of regular consumption.


Kinetics of the binding of salicylazosulfapyridine to human serum albumin. In order to elucidate the possibility of the dissociation rate of drugs from plasma proteins presenting a rate limiting step in the elimination of drugs by secretion (renal or biliary) and metabolism, the kinetics of salicylazosulfapyridine (SASP) binding to human serum albumin (HSA) has been investigated by stopped-flow photometry. Equilibrium dialysis showed that HSA has three classes of binding sites for SASP with 0.93, 2.3 and 8.4 sites, respectively, and association constants of 2.1.10(6), 1.4.10(5) and 3.0.10(3) M-1, respectively. The association rate constants for the first and second classes are 4.4.10(6) and 1.5.10(7) M-1 sec.-1, and the dissociation rate constants are 2.1 and 109 sec.-1. At SASP concentrations resulting from the usual therapeutic doses about 83% will bind to the first class binding sites. The dissociation "half time" for this class being 0.34 sec., leads to the conclusion that dissociation rates of this order of magnitude are unlikely to reduce the rate of metabolism or biliary secretion whereas it may reduce renal tubular secretion. Whether this is the case depends on the intrinsic rate constant of secretion.


Rapid gas chromatographic assay of serum diazepam, N-desmethyldiazepam, and N-desalkylflurazepam. A rapid procedure for the measurement of serum diazepam (D), N-desmethyldiazepam (ND), and N-desalkylflurazepam (NF), levels in clinical samples is described. The single step extraction procedure yields quantitative extraction for the drugs mentioned above. No solvent evaporation step is needed. No interference of endogenous substances or generally used psychotropic drugs containing halogen atoms has been observed. The conditions provide excellent precision, due to a clear separation of the internal standard, medazepam, from the solvent front. The frequency response electron capture detector provides a linear response to the drugs over a 5 X 10(2) concentration range making serial dilution of the samples unnecessary. The automatic data reduction system indicates the serum levels directly in ng/ml without manual calculations.


The effect of adrenaline on acetylcholine synthesis after blockade of alpha- and beta-adrenergic receptors in vitro. The aim of the present work was to explain the mechanism of the stimulating effect of adrenaline (A) on acetylcholine (ACh) synthesis. This action is exerted most probably through the beta- adrenergic receptors, since propranolol and oxprenolol inhibit the stimulating effect of adrenaline on acetylcholine synthesis in the rat cerebral cortex in vitro. Dihydroergotamine does not show such effect. Practolol and phentolamine decrease the spontaneous synthesis of ACh in concentration several times lower than that inhibiting the ACh synthesis stimulated by adrenaline. It is suggested that adrenaline-induced stimulation of ACh synthesis in the rat cerebral cortex is not due to cyclic AMP, because noradrenaline (NA) does not increase ACh synthesis either in vivo or in vitro, although it activates the adenyl cyclase. NA on the other hand activates ACh synthesis in the calcium-free medium, which inhibits activating effect of NA on adenyl cyclase. Moreover it was found that cyclic AMP depresses ACh synthesis in the rat cerebral cortex in vitro.


Direct antilipolytic effect of acidosis in isolated rat adipocytes. The possibility that acidosis inhibits lipolysis indirectly by causing ionic shifts or by favouring the accumulation of an inhibitor has been tested in isolated fat cells. Lipolysis induced by 3 muM noradrenaline (NA) was inhibited by 40-60% and that induced by 1 mM theophylline (THEO) by about 75% when the pH was reduced to 6.6. Lipolysis induced by NA + THEO was inhibited by 20-30%. Changing the concentration of Ca++ or Mg++ did not alter the degree of inhibition. Reducing the K+-ion concentration enhanced the inhibitory effect of low pH on lipolysis induced by NA or NA + THEO, whereas cyclic AMP accumulation was uninfluenced. Omitting glucose from the incubation medium caused a slight enhancement of pH-induced inhibition of lipolysis (from 60 to 70%, p less than 0.01). Reducing the concentration of albumin, which binds inhibitory substances such as FFA, reduced lipolysis more at normal than at reduced pH. At high FFA/albumin ratios (5 or above) lipolysis was similar at normal and reduced pH. The antilipolytic effect of decreased pH was equally pronounced in perifused fat cells, where inhibitory substances are not allowed to accumulate. Our results suggest that the antilipolytic effect of acidosis is mainly a direct effect of the increase in H+ ion concentration. The inhibitory effect of acidosis on various responses to beta-adrenoceptor stimulation may be caused by a decreased formation of cyclic AMP in turn caused directly by the decrease in pH.


Psychic dependence? A different formulation of the problem with a view to the reorientation of therapy for chronic drug addiction. Disputing the concept of "psychic dependence", the authors review six motivations to use addictive drugs, four of which pertain to the moment of assumption of the habit, and two of which, identifiable with physical and psychic dependence, depend on breaking of the habit. While physical dependence is linked to withdrawal syndrome, psychic dependence, in the authors' opinion, is related to a longstanding previous state of true of masked endogenous depression (in this case it would be well termed "neuropsychological dependence"), and the drug taking is only a maladaptive self-medication. This thesis is substantiated by the literature reporting, in chronic drug addicts, the use of the whole series of antidepressants (i.e. tricyclics, doxepine, lithium, etc.) with noticeable therapeutical success. In accordance with other reports and with personal experience, the authors assign great importance to the drugs acting, directly or indirectly, on GABA, i.e. L-glutamine, piracetam, and, particularly, N-dipropylacetic acid.


A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication. Repeated doses of 5 mg nitrazepam, 15 mg flurazepam, and 1 mg flunitrazepam improved subjective assessments of the ease of getting to sleep and the perceived quality of induced sleep in a population of 30 healthy volunteers. The subjective reports of improved sleep inducement were related to a perceived difficulty in awakening from sleep the morning following medication. This subjectively reported "hangover" is also shown in the impairment of mental arithmetic abilities as measured on the serial subtraction of sevens technique. However, complex psychomotor performance is unaffected by repeated administration of these three benzodiazepine derivatives, although these later results are somewhat equivocal. Evidence of a "rebound phenomenon" following 4 nights' withdrawal of active medication is shown in both subjective and objective measures of sleep and early morning behaviour.


Effects of clomiphene citrate administraiton on the hypothalamo-pituitary-gonadal axis of male chronic schizophrenics. The clomiphene citrate stimulation test was performed in 16 adult male chronic hebephrenic schizophrenics (10 off therapy from 3 months to 1 year and six on therapy with phenothiazines or haloperidol) and in five normal controls, matched for age. Clomiphene citrate was given orally at a daily dose of 150 mg, divided into three doses, for 8 days. FSH, LH and testosterone levels were assayed before the administration of clomiphene citrate and after 4 and 8 days of treatment. Schizophrenics showed normal increase of FSH levels during the clomiphene administration, while LH and testosterone responses were blunted. Phenothiazines or haloperiodol had no effect on the test.


Substance P-like peptides and vasopressin release from posterior pituitary lobe incubated in situ after intracarotid injections of hypertonic solution in rats. The experiments were performed on male rats, drinking 2% NaCl solution ad libitum for 12 days instead of tap water. The pituitary gland was exposed by the transpharyngeal approach under urethane-chloralose anaesthesia. The posterior lobe remained in neural and partial vascular connection with the hypothalamus, whereas the anterior lobe was entirely removed. Samples of the outflow medium from the incubated in situ rat posterior pituitary lobe were collected during 30 min intervals. Substance P-like peptides and vasopressin activities were assayed by the biological tests. Injections of hypertonic solution into the internal carotid artery did not change vasopressin release, but induced an increase in Substance P release from the posterior pituitary lobe into the incubation medium. Under conditions of unexcitability of the osmosensitive cells, triggering vasopressin release, the injection of hypertonic solution into the internal carotid artery stimulated the Substance P-like peptides release from the posterior pituitary lobe.


Neuronal aspects of opiate dependence and tolerance in comparison to central depressants. Some acute and chronic effects of opiates and of central depressants have been reviewed, in order that a comparison can be made between the actions of these drugs. Special emphasis has been given to opiate-induced changes at the neuronal level, which have been studied either by the direct microelectrophoretic application of drugs to single neurones or by application of drugs to the myenteric plexus/longitudinal muscle preparation of the guinea pig ileum. Available evidence suggests that chronic exposure of nervous tissue to opiates as well as to central depressants causes changes in neuronal excitability, which become apparent upon withdrawal of the drug. Although opiates and central depressants cause similar changes they appear to do so by different mechanisms. Such differences between the mode of action of opiates and central depressants may provide an explanation for the differing chronic effects of these drugs.


Effect of pH and lactate on glucose uptake by red and white skeletal muscle in vitro. The diaphragm muscle (the red muscle) and m. obliquus externus abdominis (the white muscle) were incubated in phosphate buffer at pH 7.4 and 6.8 in the presence of different concentrations of sodium lactate (0, 5, 10 and 30 mM). None of the used lactate concentrations changed significantly glucose uptake by the both muscles at pH 7.4.  At pH 6.8 lactate in a concentration of 30 mM decreased significantly glucose uptake by the white muscle. At pH 7.4 glucose uptake by the white muscle was significantly lower than that by the red one in the presence of 10 and 30 mM of sodium lactate while at pH 6.8 in the absence of lactate and in the presence of 5 and 30 mM of lactate. Acidosis affected in smaller degree glucose uptake by the red muscle than by the white one. It may be supposed that the impairement of glucose uptake by acidosis and lactic acid in strenously working skeletal muscles can limit the amount of energy sources available for the muscles. Subsequently, it may be one of the factors limiting the ability of the muscles to continue the exhausting exercise.


The first cleavage site in pepsinogen activation. By incubation of porcine, bovine, canine, or chicken pepsinogens and calf prochymosin with pepstatin at pH 2.5, the first active protein generated on activation is trapped in an inactive complex. The first activation peptide liberated from porcine pepsinogen has been identified as residues 1-16 whereas that from prochymosin is derived from residues 1-27. This suggests that pepsin and chymosin are not formed by one-step conversions from their zymogens, but by (different) sequential, activation mechanisms.


Inactive renin--a renin proenzyme?

Inactive renin--a renin proenzyme? Human plasma contains an inactive form of renin with a m.w. of 55,000, as against around 40,000 for active human renin. After acidification to pH 3.0 or incubation with trypsin, the inactive renin becomes more active and the molecular weight falls to that of active renin. In human kidney extracts, an increase in renin concentration also occurred after acidification. The inactive form of renin may be similar to that of rabbit kidneys, which contain an inactive renin that can be activated by removal of an acid-labile inhibitor. The question as to whether the inactive material is a renin proenzyme is discussed.


Characteristics and functions of proteinase A and its inhibitors in yeast. A purification and some properties of proteinase A from yeast are described. A specific macromolecular inhibitor of proteinase A from yeast cytosol has been isolated and shown to be a protein (molecular weight 7,700) consisting of a majority of polar amino acids. Proline, arginine, cysteine and tryptophan were not detected in the inhibitor. Possible biological functions of proteinase A and the proteinase A-inhibitor (and of other yeast proteinases and their inhibitors) in the following processes are discussed: general protein turnover, catabolite inactivation of enzymes, enzyme degradation at starvation and at transition to spore formation, and activation of pre-enzymes and precursor proteins by limited proteolysis.


Comparison of the primary structures of acidic proteinases and of their zymogens. From the scattered information about primary structures of aspartate proteinases the following general features appear: 1) Sequence determinations show that two catalytically active aspartic acid residues are located in highly conservative surroundings. 2) Zymogens have so far only been found for extracellular aspartate proteinases of the vertebrates. The zymogens from the gastric mucosa are converted into active enzymes by a limited proteolysis releasing 42 to 44 residues from the NH2-terminus. A common pattern of basic and apolar residues is observed in this NH2-terminal segment. 3) In the presently known structures gastric proteinases and their zymogens have about 40% of all residues in common. The sequence of penicillopepsin shows 18% of identity with the gastric proteinases.


Acid protease and its proenzyme from human seminal plasma. An acid protease, with an optimum pH of 2.5, exists in seminal plasma in a proenzyme form. In acidic pH, the proenzyme is converted into the active form, resulting in the release of small molecular weight peptide. The extent and rate of proenzyme-active enzyme conversion is absolutely dependent on pH. Between pH 5 and 2, as the pH is lowered, the extent of conversion increases and reaches a maximum between pH 3 and 2. The kinetics of activation shift from first-order between pH 2 and 4 to more complexity with a lag period between pH 4.5 and 5. Under physiological conditions, the proenzyme might be activated by coming into contact with acidic vaginal fluid during ejaculation. The acid protease can hydrolyze the cervical mucus protein.


Intramolecular activation of pepsinogen. Two pathways for pepsinogen activation have been demonstrated. Intramolecular activation, which is kinetically first-order, predominates over the autocatalytic pathway if the pH is below 3 and the protein concentration is less than 1 mg/ml during activation. Intramolecular pepsinogen activation is inhibited either by pepstatin, a potent pepsin inhibitor, or by purified globin from hemoglobin, a good pepsin substrate. Also, pepsinogen at pH 2 can be bound to a pepstatin-Sepharose column and recovered as native zymogen upon elution in pH 8 buffer. Kinetic studies of the globin inhibition of pepsinogen activation show that globin binds to a pepsinogen intermediate. This interaction gives rise to competitive inhibition of intramolecular pepsinogen activation. The evidence presented in this paper suggests that pepsinogen is converted rapidly upon acidification to the pepsinogen intermediate delta.


A cat head model with isolated perfusion by the animal's own blood. A model consisting of a cat head perfused in isolation with the animal's own blood is described. The use of endogenous blood allows the organ to function under physiological conditions for several hours. The blood is taken from the abdominal aorta of the anaesthetized animal and passed to the carotid arteries via an extracorporeal circulation system. The perfusion pressure can be varied at will and is regulated electronically. The volume of blood in the extracorporeal circulation system is only 6 ml. The tests performed on this model were designed to study the behaviour of the cortical EEG and the cortical micro flow. Neither of these parameters underwent any change after institution of the artificial perfusion, and the blood gases also remained fairly stable. The model is suitable for studying both physiological and pharmacological problems.


An in vitro method for predicting the bioavailability of iron from foods. An in vitro method for the determination of availability of nonheme iron from foods and diets was investigated. Food was extracted with pepsin-HCl at pH 1.35 and subsequently the pH was adjusted to pH 7.5 and filtered. Ionizable iron was determined in the pH 7.5 filterate by the alpha, alpha-dipyridyl method. The percent iron absorption from the same diets observed in the adult males. Ionizable iron at pH 7.5 was shown to increase in presence of ascorbic acid and meat extract while it decreased in presence of phytate and tannins, similar to the effects of these factors on iron absorption in human subjects. Based on these observations it is proposed that ionizable iron at pH 7.5 determined as described in this study can be used as a reliable measure of bioavailability of nonheme iron in foods.


Effect of pentagastrin infusion on gastric emptying rate of solid food in man. The effect of intravenous pentagrastin (4 microgram/kg-hr) on the rate of gastric emptying of solid food was studied in 6 normal men. A mean consisting of one 99mTc-tagged chicken liver mixed with beef stew and taken with 200 ml of water was followed on its passage through the gastrointestinal tract by intermittent scanning with a gamma camera. The rate of the linear gastric emptying pattern was slowed by pentagastrin in every individual. The pH and titratable acidity of the gastric contents were similar in the pentagastrin and the control infusions. Neutralization of the gastric contents with bicarbonate in the pentagastrin studies did not alter gastric emptying rates. The results indicate that pentagastrin slows gastric emptying of solid food in man by an effect apart from acid secretion. The myoelectrical correlates of such an observation are uncertain.


PH-dependent drug release from certain commercial tablets. A dissolution-dialysis profile for each of several brands of nitrofurantoin, hydrochlorothiazide and sulfisoxazole tablets was developed at three pH levels. The study used a two-compartment diffusion cell with a semipermeable cellophane membrane. Nitrofuratoin tablets were tested at pH values of 7.2, 4.7 and 1.2; sulfisoxazole tablets at 7.2, 5.5 and less than 1. Studies with hydrochlorothiazide tablets were terminated because the pH of the dissolution medium had no effect of practical significance on dissolution or dialysis rates. The dissolution rates of the nitrofurantoin and sulfisoxazole tablets were highly brand-individualized and complex. The effects of pH upon a particular formulation were unpredictable. The results suggest that dissolution testing at one fixed pH, as commonly practiced, may be insufficient for some products. This pH-dependent release characteristic may not correspond to a change in bioavailability in all cases, but it represents a potential problem which should be considered by the formulator.


Metabolic effects of constant hypertonic glucose infusion in well-oxygenated fetuses. In order to investigate the metabolic effects of a constant hypertonic glucose infusion in well-oxygenated fetuses, ten experiments were carried out in nine long-term experiments in fetal lambs. It appeared that a constant hypertonic glucose infusion did not significantly affect the fetal blood gases, pH, and plasma lactate levels when fetal glucose was kept below 150 mg. per 100 ml. It was also demonstrated that glucose infusions significantly increased the fetal lactate levels and decreased the blood pH when fetal plasma glucose was over 150 mg. per 100 ml. However, there was no decrease in fetal PO2 and pco2 until fetal glucose reached values over 300 mg. per 100 ml. These studies suggest that constant hypertonic glucose infusion does not improve fetal blood gases or pH and that fetal hyperglycemia over 300 mg. per 100 ml. produces severe metabolic acidosis.