Depression in medical outpatients: use of the Zung scale.

Sixty-nine randomly selected medical outpatients were clinically evaluated for depressive illness. A Zung Self-Rating Depressive Scale (SDS) was also administered to each patient. The prevalence of depression in the sample was 42%. The SDS picked up 30% of those depressed while missing those whose depression was presented under the guise of somatic illness. The SDS is thus a suitable instrument only in screening of the non-depressed medical patients.


Deanol in minimal brain dysfunction.

The literature on minimal brain dysfunction is confused, confusing and controversial. The statements that the condition exists, needs treatment, and that treatment may be pharmacological, are more expressions of faith than accepted fact. We believe they are true (within limits not discussed in the article). Furthermore, there is evidence that some patients with MBD are hypo-aroused, while others are not. The role of deanol in the treatment of MBD is still unclear, because of the complexities of identifying appropriate patients in terms of levels of arousal, as well as identifying appropriate measures of response. There is sufficient support for an effect of deanol in the literature to justify further investigation. Further studies should attend to important methodological problems as discussed.


Deanol acetamidobenzoate (Deaner) in tardive dyskinesia.

A total of twenty-nine patients have thus far been treated with deanol in various dosage levels for periods ranging from five to thirty days. Clinical response has been pronounced, even dramatic, in seven patients, moderate but significant in nine patients, and slight to insignificant in thirteen others. Videotape rating and quantitative accelerometry, to the extent that they constitute novel and stress-inducing experiences may not be representative of global clinical changes. Deanol did not produce the anticipated elevation in choline levels postulated to be one mechanism of its action. The failure of deanol to achieve this effect may most probably be attributed to interval after last dose, to inadequate level of deanol or to some alteration in choline metabolism in the presence of deanol. The etiology of tardive dyskinesia at biochemical and structural levels is complex. For some patients improvement has been dramatic and clearly associated with deanol. Others appear to exhibit minimal response which cannot be differentiated from placebo or environmental effects. Our present strategy, in common with that of other authors includes the administration of a "challenge" dose of rapid acting injectable cholinomimetic agents (e.g. physostigmine) and dopamine-blocking agents (e.g. haloperidol) with placebo controls. In this manner therapy may be more rationally selected for long-term use and may logically include deanol. The correlation of such predictive challenges with response to long-term treatment is an area for much more well controlled study.


[No free water in the treatment of "hyperosmolar diabetic coma": treatment control by comparing serum and CSF (author's transl)].

Some serum and CSF concentrations were measured in five patients with severe hyperosmolar coma (mean blood sugar = 58.9 mmol/l; osmolarity = 406 mosmol/l). A gradual decrease of serum osmolarity prevented the development of an osmotic gradient between CSF and extracellular space. Insulin treatment (1-20 IU/h) with a motor infusion pump and infusion of hypertonic solutions decreased serum osmolarity by 2-4 mosmol/l X h. The faster fall of glucose in the extracellular space was compensated by hypertonic saline infusions (up to 365 mosmol/l). All patients survived.


[The effect of radiotherapy on various immunological features in genital and breast carcinoma (author's transl)].

Lymphocyte transformation under phytohaemegglutinin (PHA), spontaneous rosette formation and immunoglobulin concentration were measured in women with genital or breast carcinoma. It was found that (1) DNA synthesis of lymphocytes under PHA was normal in women with stage I and II cervical carcinoma, slightly decreased in stage III; (2) DNA synthesis of lymphocytes under PHA was slightly but significantly decreased in untreated patients with breast carcinoma; (3) after radiotherapy, both for cervical and body of the uterus carcinoma, there was a significant decrease of PHA-stimulated DNA synthesis of lymphocytes compared with healthy females and with patients at the same stage of tumour spread not treated by radiotherapy; (4) there was no significant difference in spontaneous rosette formation between radiated patients with cervical or breast carcinoma, on the one hand, and healthy controls and non-radiated patients, on the other; (5) IgG levels were slightly but significantly decreased in patients with ovarian carcinoma while in cervical, breast and body of the uterus carcinoma they were normal, IgA and IgM levels were significantly raised.


[Eight years of gardner's syndrome in a family (author's transl)].

In all affected members of a family with Gardner's syndrome the complete triad of skin tumours, osteomas and polyps of the colon has developed since 1968 when examination revealed an apparently bisymptomatic variant of Gardner's syndrome. In this family bony changes consisting of circumscript osteomas, diffuse sclerosing zones within certain bones, and ridge-like widening of the corticalis were noted, having developed during puberty but remaining constant thereafter. Similarly, no significant new skin tumours appeared after puberty. Most colonic polyps however, occurred in adolescence or thereafter, with malignant transformation after a variable interval of several years. The necessity of long-term observation of the colon, also in patients presenting with a bi- or monosymptomatic form, is stressed. Coloscopy has proven to be more useful diagnostically than radiological methods.


[Differentiation of non-Hodgkin's lymphoma: immunological, cell-kinetic, and physical methods (author's transl)].

Some aspects of division and cell density, expression and motility of certain surface structures were studied on lymphocytes of non-Hodgkin's lymphoma of high and low degrees of malignancy. The neoplastic lymphocytes of the two lymphoma types differed in these aspects.


[Primary and secondary exploratory laparotomy and splenectomy in Hodgkin's disease (author's transl)].

Exploratory laparotomy with splenectomy was performed on 275 patients with hisologically confirmed Hodgkin's disease. In 188 patients the laparotomy was a primary one to determine more precisely the state of the disease. A secondary laparotomy was performed in 87 patients 1-12 years after diagnosis and radiotherapy. In 17.5% of patients the state had to be revised after laparotomy with splenectomy. In 38 the disease had further progressed, while in ten it had slighty regressed. In four cases clinical stage I proved to be stage III. Even prognostically more favourable forms may have progressed at first diagnosis. There was no correlation between B-symptoms and histological type, but there was between B-symptoms and spread of the disease. Calculated spleen weight provided no clue as to spleen involvement. There was no clear relationship between spleen involvement and histological subclassification. Risk-effect analysis indicate that laparotomy with splenectomy was useful because it makes optimal treatment possible.


[Haemofiltration in the treatment of acute left heart failure in anuric patients (author's transl)].

Eight patients with acute left heart failure refractory to diuretics were treated by haemofiltration. Used conventionally the filtration membranes need a high pressure gradient. But the hollow-fibre kidney use in the last three patients required merely normal arterial venous pressure gradients. During an average heaemofiltration period of four hours 1000-2300 ml of plasma water were obtained. Pulmonary congestion improved in all patients; in five the arterial pressure returned to normal. Spontaneous diuresis was resumed in three. The clinical course was not influenced by haemofiltration in three instances. The advantages of haemofiltration are: reliable control of volume withdrawal, immediate effectiveness, technical simplicity, and absence of side effects.


[Incidence of obesity in hospitalised patients 1933-1972 (author's transl)].

Analysis of 31 686 patient records for obesity among hospitalised patients in the Second Medical Clinic of Düsseldorf University between 1952 and 1972 demonstrated a steep rise to a plateau of 24 +/- 2% in 1956-1972. Adding a corresponding analysis from the Bonn Medical University Clinic some 66 000 hospitalised patients could be included for a period of 40 years. Socio-economic conditions in the war and post-war period produced a marked fall in obesity to a minimum of 2% in 1946. The mean incidence before 1935 was 10%, by 1958 it had increased two-and-a-half fold. It is thought that this had been due not to a corresponding higher calorie intake by the population but rather a general reduction in physical activity. The increase in obesity among the population, reflected in these hospital statistics, is likely to lead to a parallel increase in cardiovascular risk factors and with it the ever-rising curve of death from cardiovascular disease in the Federal Republic of Germany.


[Serum and total body potassium during treatment with chlortalidone and hydrochlorothiazide. Influence of triamterene (author's transl)].

The serum and total body potassium was investigated in 25 patients with non-congestive cardaic failure before and during saluretic treatment. Treatment with triamterene (100 mg/d; n = 10) over a period of 3 weeks led to an increase of serum potassium (from 4.1 +/- 0.65 to 4.7 +/- 0.51 mmol/l) and of total body potassium (by 110 mmol). After treatment with chlortalidon for 7 days (100 mg/d; n = 6) serum potassium concentration decreased from 4.38 "/- 0.37 to 3.30 +/- 0.46 mmol/l (approximately 25%). The total body potassium decreased by 240 mmol (approximately 10%). Continuation of the treatment with a combination of chlortalidon (50 mg/d) and triamterene (150 mg/d) led to correction of the extra- and intracellular potassium loss after 1 to 2 weeks. No significant change of serum and total body potassium was found during and after 6 months of treatment with hydrochlorothiazide (50 mg/d) and triamterene (100 mg/d; n = 9). The results demonstrate the potassium loss which occurs in the early stage of saluretic treatment and show the antikaluretic potency of triamterene.


[Models of community participation in health programs].

Study of some Latin American experiences of community participation in health programs permit consideration of the following as minimum requirements for the establishment of interrelationships between local health agencies and the community: a local health system; a participating health team; respect for the community; contact with community organizations; and contact with private and governmental organizations at a local level. The models for community participation in health are manifold and the experiences have been countless. For teaching purposes and based on Latin American experiences several considerations are made regarding: community health volunteers; local health councils; local councils for community development; and health brigades. Finally, it is stressed that active and organized community participation in health activities is the best guarantee of success in implementing integral health programs.


[Effect of ionophore Brx537A on catecholamine liberation from chromaffin granules].

In the present paper the author studies the action of bromine analog of carboxil ionophore X-537A on the transport mechanism of catecholamines from isolated chromaffine granules. The transfer of catecholamines through artificial membranes was explained by the ability of ionophore and its bromine derivative to raise their permeability in organic solvents and to transfer them through the organic phase. A model for the action of Brx 537A on isolated granules was constructed. It was established that the ionophorex acted as a carrier, enhancing the transport of the protonated form of catecholamines, which in general diffuse slightly. The model transport system could explain the differences in releasing catecholamines and the favourable effect of cations in the transport through the membranes.


[Nuclear bodies of lymphocytes in the lymph nodes of guinea pigs treated with phytohemagglutinin in vivo].

Nuclear bodies (NB) were studied in guinea pigs regional lymph node cells after a single subcutaneous application of Phytohaemagglutinin Difco (PHA). A distinct reaction of the lymph node cells was established on the 3rd, 6th and 9th days consisting of increased number of lymphoblasts and large basophilic cells (LBC). Ultrastructural descriptive and morphometric methods were used. Authors revealed nuclear bodies to be present mostly in activated lymph node cells (lymphoblasts and LBC). Predominance of NB having RNP particles (complex type NB) was found. Simple NB (without RNP particles) had been seen rarely in small (resting lymphocytes. It was established NB to be larger, but leis im member. It is discussed on the participation of NB (Complex type) in the nuclear part of the protein synthesis.


[Experimental hypertension in rats and their adrenal activity].

The authors examined dynamically the arterial pressure and plasma activity of 11-hydroxycorticosteroids in two groups of rats with pure hypertension and with hypertension on the background of beta-adrenergic activity. There was an elevation of arterial pressure in both groups, less manifested in the rats, treated with beta blocker. The values after six months were equally high in both groups. The content of 11-hydroxycorticosteroids was increased with a maximum at the sixth month. The authors make an inference that beta blocker-obsidan lowers blood pressure, but does not affect the level of 11-hydroxycorticosteroidids in plasma.


[Effect of the preparations amiodarone, pexid and CERM-1978 on sinus rhythm and atrioventricular conduction in unanesthetized dogs].

The author examined the influence of Amiodarone, Perexiline maliate (Pexid) and the preparation CERM-1978 (Bepiridil) on the sinus rhythm and atrioventriular conduction of trained dogs with preliminary implanted electrodes for electrostimulation of the right atrium under the conditions of chronic experiment. The three preparations in doses of 2,5 and 5 mg/kg of body weight prolonged the refractory period of the atrioventricular zone, estimated by the method of "the maximal atrioventricular frequency". The br dicaric effect was also present, more manifested in a dose of 2.5 mg/kg of body weight. The established negative chrono- and dromotropic action had their maximum 15 minutes after the administration and lasted more than 2 hours.


[Neurophoarmacologic profile of an aminotetraline derivative].

The authors examined the effect of the piperasine derivative of 2-aminotetraline N-(trans-3-hydroxy--1,2,3,4-tetrahydro-2-naphthl)--N--(3-oxy-3-phenyl 1--2 methyl propyl)--piperasine (P11) on nobred white mice and rats of the Wistar strain and found interesting and specific neuropharmacological activity. The compound P11 inhibits the central nervous system, diminishes the muscular tonus, attenuates aggressiveness, potentiates hexobarbital sleep, possesses its own analgetic activity, but weakens the morphine analgesia. Without changing spontaneous motor activity the compound sharply lowers the motor activity, raised by phenamine as well as phenamine toxicity. P11 enhances the reserpine and apomomorphine hypothermia and phenamine hyperthermia. The neurological effects of the compound P11 are discussed, taking into consideration its structural similarity with dopamine and its manifested beta adrenoblocking properties.


[Electrophysiologic shifts in the functional antagonism between phosphororganic pesticides and their antidotes].

The authors carried out studies on 18 nonanesthetised and anesthetised cats under the conditions of complete imobilization with tricuran and under artificial respiration and examined the temporary consequence of the effects on the spontaneous and induced cerebral activity after poisoning with lethal doses of phosdrine and treatment with Doline, which is the therapeutic antidote of phosphorganic pesticides. The authors established that after lethal poisoning with phosdrin the secondary induced cerebral hypoxia enhanced deepening of the disintegration in the intercerebral interrelationships, which caused the appearence of epileptiform activity. The antidote Doline within 1-2 minutes, after its muscular administration abolished effectively the generalized epileptic seizure and repaired quickly the electrophysiological indices-peculiar for the normal EEG.


[Effect of beta-adrenergic blockade on acid-base balance in experimental hypertension].

On rats with experimental hypertension by method of Selye, modified by Kolarova, distributed in two groups--treated by obsidan and untreated, the following parameters on the 1st and the 3rd month after the operation were studied: pH, BB, SB, AB, BE, PaCO2, TCO2, PaO2, and SaO2. In the hypertonic animals we establish a decompensated metabolic acidosis on the 1st month and a metabolic acidosis with a marked respiratory compensation on the 3rd month. The hypertonic animals, treated by obsidan, demonstrate a sharp tendency to normalise the parameters of the acid-base status on the 1st month and normal values on the 3rd. The protective obsidan effect observed on the hypertonic rat we discuss as a result of metabolic and functional influences of the beta-adrenergic blockers.


Effect of testosterone on compensatory renal hypertrophy in the rat.

The effect of testosterone on compensatory renal hypertrophy (CRH) remains controversial. We therefore examined the effect of exogenous testosterone on CRH in adult male and female rats after unilateral nephrectomy. The influence of endogenous testosterone was studied by comparing the degree of CRH in normal male, castrated male, and in testosterone receptor deficient male pseudohermaphrodite rats. Furthermore, serial determinations of serum testosterone levels were performed after unilateral nephrectomy in male rats. Compensatory renal hypertrophy was comparable between male rats--with or without exogenous testosterone administration--and between normal male, castrated male, and psuedohermaphrodite male rats. In contrast, exogenous testosterone administration in female rats enhanced CRH. Serum testosterone levels fell markedly after unilateral nephrectomy or sham surgery, but increased to 183% and 234% of control values at 1 and 2 days after surgery in the unilaterally nephrectomized rats. At no time, however, did they exceed the range of normal values. The results indicate a different effect of testosterone on CRH in male and female rats.


Direction of estradiol metabolism as a control of its hormonal action--uterotrophic activity of estradiol metabolites.

The uterotrophic activities of the catechol metabolites of estradiol 2-hydroxyestrone, 2-methoxyestrone and 2-hydroxyestradiol were measured under conditions of continuous administration of sc implanted paraffin pellets. The activity of these estrogens was compared to that of estradiol-17beta and its other principal metabolites estrone, estriol and 15alpha-hydroxyestriol (estetrol). The major catechol estrogens, 2-hydroxyestrone and 2-methoxyestrone, and the pregnancy metabolite, 15alpha-hydroxyestriol, exhibited no uterotrophic activity. The minor catecholestrogen, 2-hydroxyestradiol, showed some activity whose character was different from that exhibited by implants of estradiol, estrone and estriol all of which were equipotent uterotrophic agents. Implants of 2-hydroxyestrone in the presence of estradiol or estriol pellets did not diminish the response to the latter indicating that the 2-hydroxyestrone is not antiestrogenic under these conditions. It is concluded that the direction of estradiol metabolism can have a profound influence on the expression of peripheral hormonal activity with hydroxylation at C-2 terminating and hydroxylation at C-16 extending it.


Bioassay for prolactin: densitometric analysis on polyacrylamide gels of milk protein production by mammary explants in vitro.

Mammary explants from mice in midpregnancy cultured in a synthetic medium containing insulin and hydrocortisone respond to the addition of prolactin by the synthesis of milk proteins. The secretory response in alveolar lumina has served as a histologic endpoint in a sensitive bioassay for prolactin developed by Kleinberg and Frantz (J Clin Invest 50: 1557, 1971). This report demonstrates that the quantitative densitometric analysis of stained milk proteins (caseins) made in response to prolactin is a useful modification of that bioassay. Electrophoretic analysis of the proteins extracted from the explants permits a quantitative estimate of casein content. The amount of casein present after 5 days of incubation was found to be a measure of the prolactin concentration in the medium. No radioactive isotopes are used. The use of electrophoretic analysis has practical advantages over the histologic scoring used earlier, and has approximately the same range of sensitivity.


Preprolactin represents the initial product of prolactin mRNA translation.

mRNA isolated from a line of functional rat pituitary tumor cells (GH3) added to a cell-free protein synthesizing system derived from wheat embryo directed the biosynthesis of only one protein which is immunoprecipitated by prolactin antiserum. This protein, 2000--3,000 daltons heavier than prolactin and referred to as preprolactin, appeared to represent the initial, authentic product of translation since [35S]methionine donated by initiator Met-tRNAi was documented to be incorporated into the N-terminal portion; the molar ratio of leucine: initiator methionine was estimated to be 25--28:1, while prolactin contains 22 leucine residues. The mRNA coding for preprolactin was demonstrated to migrate at approximately 12--13S using rate zonal centrifugation. These data are compatible with the postulate that preprolactin represents the intact, initial product of prolactin mRNA translation.


Osmotic control of vasopressin release by rat hypothalamo-neurohypophyseal explants in organ culture.

The rat hypothalamo-neurohypophyseal system (HNS) in organ culture has been used as an in vitro system for studying the osmotic control of vasopressin (VP) release. The HNS retains osmotically sensitive components as demonstrated by changes in the rate of VP release following alterations in the osmolality of the culture medium. Increasing the osmolality from 295 to 305 mosmol/kg H2O by the addition of NaCl resulted in a 2.5-fold increase in VP release. VP release was significantly decreased subsequent to reducing the osmolality from 295 to 280 mosmol/kg H2O by the addition of distilled water. Also, VP release was stimulated when the osmolality was increased to 300 mosmol/kg H2O by the addition of mannitol, but not by additions of urea or glucose which resulted in comparable increases in the tonicity of the culture medium. These studies demonstrate that the HNS in organ culture responds appropriately to osmotic challenges within the physiological range, and support Verney's concept of an osmoreceptor inasmuch as both NaCl and mannitol were effective osmotic agents.


Properties of the cytoplasmic progestin-binding protein in the rabbit uterus.

An exchange assay for the measurement of total cytoplasmic progestin binding sites has been developed on rabbit uterine cytosol using the highly potent progestin, R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) labelled to a high specific activity. This compound has several advantages over progesterone: it is not bound by plasma corticosteroid binding globulin; it has high affinity for the progestin receptor; it binds virtually as fast as progesterone to the receptor, but the complex formed dissociated 8 times slower; its binding is not displaced by more than 2% by compounds devoid of progestational activity (estrogens, testosterone, dexamethasone, aldosterone). Bound endogenous progesterone was exchanged by tritiated R 5020 in a time compatible with receptor stability. At 0 C, total exchange of filled sites occurred in less than 4 h; at this temperature the R 5020-receptor complex was stable for at least 28 h. The conformation of the R 5020-receptor complex was investigated in sucrose density gradients under various experimental conditions. Unlike progesterone, it was possible to detect a 7S peak in uterine cytosol obtained from rabbits injected with a tracer dose of [3H]R 5020 1 h prior to sacrifice.


Estrogen receptors in different target tissues: similarities of form--dissimilarities of transformation.

The time-related uptake, retention and intracellular distribution of estrogen by different target tissues of the intact immature female rat were studied. The cytoplasmic compartment of the uterus, hypothalamus and pituitary was shown to have a primary hormone receptor complex sedimenting as 8S by sucrose density gradient analysis. Nuclear extracts from all three target tissues contained two forms of estrogen receptor complex; a 5--6S form and a more slowly sedimenting 4S species. The heavier nuclear form accumulated subsequent to the 4S complex in a time-dependent manner which differed according to target tissue. The observed intranuclear differences in properties of the estrogen receptor system may be related to the physiologic responses which characterize dissimilar estrogen target tissues. The tissue content of such serum estrogen-binding proteins as alpha1-fetoprotein and albumin were also determined. The observed levels were evaluated as possible factors in tissue estrogen retention.


Insuppressibility of plasma glucagon by orally or intravenously administered glucose in diabetes mellitus.

In order to study the response of pancreatic alpha cells to the change blood glucose, plasma pancreatic glucagon levels were measured after glucose loading given orally (50g) or intravenously (25g) in twenty-two normal controls and eighty untreated diabetics. Basal plasma pancreatic glucagon levels did not differ significantly in the two groups. However, oral or intravenous glucose administration caused a decrease in plasma pancreatic glucagon in normal subjects but not in diabetics. In "moderate" or "severe" diabetics, plasma pancreatic glucagon tended to increase paradoxically following oral glucose loading. To evaluate the sensitivity of pancreatic alpha cells to glucose, we calculated the index, -sigma delta IRG/sigma delta BS, after oral glucose loading. It was 1.96 +/- 0.57 in normal subjects, and significantly higher than in "mild" (0.11 +/- 0.05), "moderate" (-0.002 +/- 0.06) and "severe" (-0.09 +/- 0.07) diabetics. These results demonstrate the insensitivity of alpha cells to hyperglycemia in patients with diabetes mellitus as compared with normal subjects.


Studies on diabetic syndrome and influences of long-term tolbutamide administration in Mongolian gerbils (Meriones unguiculatus).

Sixty-seven mongolian gerbils (Meriones unguiculatus), which seem to resemble the sand rats in the manifestation of diabetic syndrome, were used for observations on the development of diabetic process and on the effect of the long term administration of tolbutamide on it. The mean blood glucose (158.2 +/- 14.7 mg/100 ml), mean serum NEFA (0.70 +/- 0.34 mEq/l) and mean serum IRI (68.9 +/- 10.2 muU/ml) in mongolian gerbils were relatively higher than those in rats. Diabetes-like processes found in the pancreas of mongolian gerbils were roughly grouped into two main types: (1) the histopathological process in which the fibrosis, initially prominent at perivascular space, spread to the islets, finally producing the islet's cell degeneration, and (2) the process of diffuse islet's hyperplasia. These two processes were considered to differ from each other, the former being affected by tolbutamide and the latter remaining unaffected. After breeding on the diet containing 0.1 -0.2% tolbutamide for 6 months, there was a general inclination of an increase of cases of severe pathological findings, and the distribution probabilities of the cases carrying the severe fibrotic process in heart, that is, the process from endothelial cell swelling, medial fibrosis and obliterative changes in cardiac arteries which was resulting in the focal degeneration of cardiac muscle, was significantly higher than in the non-treated group. It was concluded that mongolian gerbil might be recommended as a model of experimental diabetes and that tolbutamide seemed to have some harmful effects on the diabetes-like process in mongolian gerbils.


Heterogeneity of rat luteinizing hormone revealed by radioimmunoassay and electrofocusing studies.

Radioimmunoassay of rat luteinizing hormone (LH) in the sera and the anterior pituitaries of normal and castrated males and proestrous females employing different batches of anti-LH sera gave the results suggesting heterogeneity of immunoreactive LH (IR-LH). Gel filtration analyses of anterior pituitary extract and pooled sera failed to give positive evidence for the heterogeneity. But when the extracts of normal rat anterior pituitaries were electrofocused and the fractions were assayed, the pituitary glycoprotein hormones, LH, FSH and TSH, were found to consist of several components with different isoelectric points. In electrofocusing patterns of IR-LH, distinct peaks were observed at pH 8.5 (component A), 8.8 (component B), 9.1 (component C) and 9.3-9.4 (component D), and less distinct peaks were observed at pH 7.9 (component A'), 9.6 (component E) and 9.8 (component F). There seemed to be some sexual difference in the relative amounts of these components. Orchiectomy caused marked changes in electrofocusing patterns of IR-LH, i.e., increase of components A', A, B, C and D. The blockade of LH release by estradiol benzoate and progesterone treatment in orchiectomized rats caused a marked increase of component A. At the proestrous LH surge, IR-LH components were evenly released. Radioimmunoassay of IR-LH components with multiple antisera indicated that these antisera had different affinities to these components.


A possible involvement of adrenaline in the facilitation of lordosis behavior in the ovariectomized rat.

In order to examine a possible role of adrenaline (AD) or noradrenaline (NA) in the control of lordosis behavior, lordosis quotient (LQ) was observed daily for 8 consecutive days in the ovariectomized rat given daily 1 or 2 microgram/0.1 ml oil of estradiol benzoate (EB) alone or together with 100 microgram/0.1 ml saline of AD or NA. AD but not NA treated together with EB caused a greater change in the daily LQ than the same dose of EB alone and the change in the daily LQ by daily treatment with both 1 microgram EB and 100 microgram AD was equivalent to that by daily treatment with 2 microgram EB alone. A half mg progesterone (P) could induce the lordosis behavior in the ovariectomized rat treated 48 hr prior with both 1 microgram EB and 50 or 100 microgram AD, but not in the one treated with 1 microgram EB alone. While 50, 100 or 200 microgram NA or 10 microgram AD had no effect, 50 or 100 microgram AD pretreated together with 2 microgram EB produced a markedly higher LQ after P than 2 microgram EB alone in the ovariectomized rat. This effect of AD on the induction of lordosis behavior was produced only when AD was pretreated simultaneously with EB and AD priming 24 or 43 hr after EB failed to elicit the effect. Therefore, it is suggested that a change of the brain target site in the estrogen sensitivity produced by AD plays a part in the control of lordosis behavior.


Ovarian 32P uptake in the homoplastic hypophysectomized catfish, Heteropneustes fossilis as an end point for gonadotropin bioassay.

Ovarian 32P incorporation in hypophysectomized Heteropneustes fossilis in response to pituitary gland extract pooled from same species and mammalian gonadotropic preparations were studied. Maximum 32P uptake by ovary was obtained when a tracer dose of radiophosphorus was given 30 minutes after LH injection and fish were sacrificed 12 hours after the tracer shot. A log-dose response was observed between ovarian 32P uptake and gonadotropic content of pituitary extract or LH in hypophysectomized H. fossilis. This response was specific because FSH, TSH, prolactin and growth hormone injections failed to induce dose dependent and significant 32P uptake by ovary in similar assay recipients. However, FSH along with LH at higher dosage yielded an additive response. Also a parallelism of log-dose response was obtained between fish pituitary gonadotropin and ovine LH. Index of precision (lambda) was less than 0.214. Since donors and recipients were of the same species this bioassay of 12.5 hours for estimation of total gonadotropic potency seems to be rapid, reliable, sensitive and free from phylogenetic species specificity interaction between hormone and its receptor.


Relation of lipoprotein lipase activity in adipose tissue to adipocyte volume and its influence in hypertriglyceridemia pathogenesis.

In the subcutaneous adipose tissue of 20 normal weight and overweight subjects with normo- or hypertriglyceridemia, the relation is examined between the lipoprotein lipase activity (LPLA) per gram adipose tissue and adipocyte volume. The following findings were obtained: 1. Significant positive correlations between the LPLA per gram adipose tissue and the adipocyte volume were ascertained in the groups of subjects having normal triglyceridemia or exhibiting hypertriglyceridemia. 2. The negative relation between the LPLA in the adipose tissue and the triglyceride level in serum described in literature could not be verified. Across a glyceride span of 76 to 600 mg% in serum we found a correlation coefficient of +0.34. 3. It can therefore be assumed that the LPLA per gram adipose tissue with increasing adipocyte volume does not represent an inhibiting factor to the triglyceride in serum breakdown in the development of hypertriglyceridemia.


Blood sugar and immunoreactive insulin in women with hypothalamic, maternal and simple obesity. Part I.

There were 46 women included in this experiment: 18 with simple obesity, 7 with maternal obesity, 8 with hypothalamic obesity and 13 of the control group (non-obese women). Changes of glycaemia and insulinaemia in blood serum during a test of oral glucose administration were ascertained. A plain handicap of glucose tolerance in simple obesity and maternal obesity groups was observed. In the case of the women with simple obesity an insulin increased secretion with one peak of the hormone release was found following the glucose administration. In the hypothalamic obesity group two peaks of insulin release were noted, and in the maternal obesity group a bigger maximal output of insulin was noted after the glucose administration together with two release peaks and a positive correlation between the total insulin area and anthropometric indices of excessive body weight.


Growth hormone secretion in women with hypothalamic, maternal and simple obesity. Part II.

Dynamic quality of HGH secretion in women with hypothalamic, maternal and simple obesity has been examined by means of the following tests: 1. glucose loading 2. hypoglycaemia following the insulin administration. Comparisons have been made with regard to normal, non-obese women. In all the obese women HGH mobilization was noted to be handicapped under the influence of the after-insulin hypoglycaemia. In some patients of all the obesity groups a paradoxical response of HGH secretion after the glucose administration was noted. In some cases of the hypothalamic and simple obesity groups there occurred a paradoxical response of HGH secretion relating to the insulin hypotlycaemia test. Differences discovered in the dynamics of HGH secretion with appropriateness to the etiopathogenetic forms of obesity are slight: their significance is rather quantitative than qualitative.


[Effect of insulin on stimulated lipolysis in obesity with normal carbohydrate tolerance and unimpaired thyroid function].

The effect of intravenous injection of 0.1 I.U./kg insulin on blood glucose response and on lipolysis, induced by intravenous infusion of 0.2 microgram/kg - min norepinephrine, were studied in 12 normal subjects and 17 obese patients with normal 50 g oral glucose tolerance test and normal thyroid function. In the obese group the insulin-induced hypoglycemia during norepinephrine-infusion was significantly less than in normal subjects. Moreover, the inhibition of norepinephrine-stimulated FFA and glycerol-release by insulin was significantly less in obesity as compared with the non-obese group. It is concluded that in obesity the action of insulin is decreased both in carbohydrate metabolism and in lipolysis. These results provide arguments for the role of an impaired antilipolytic insulin effect in the pathogenesis of hyperinsulinism in obesity.


"Upright hyperkalemia" in selective hypoaldosteronism.

A new phenomenon, increase of serum potassium in response to the upright posture in patients with selective hypoaldosteronism is described in the present preliminary report. Further studies are in progress concerning its possible clinical and pathophysiological significance.


Diagnostic value of nasopharyngeal endoscopy for the early recognition of tumours.

It is reported on own experiences gathered with the endoscopy of the nasopharyngeal space by means of an angular optic according to Hopkins (70 degrees). The nasopharyngeal endoscopy is indicated for an early diagnosis of malignant tumour growth and clears up a clinically uncertain nasopharyngeal picture. In addition to the generally known examination methods, the endoscopy of the nasopharynx enables a direct local finding.


Dilatation of benign esophageal strictures by peroral fiberendoscopic bougienage.

A low risk procedure for dilation of esophageal strictures is peroral bougienage under direct endoscopic vision with a flexible fiberscope. First the stricture is inspected using the foreward lens of the fiberscope, and then dilated with conventional bougies according to its nature and size under direct visual control. In this paper we report on the treatment of 16 patients with inoperable advanced benign stenosis. In a total of 86 sittings an average of three bougienages each were performed without complication.


Non-surgical treatment of cardio-esophageal obstruction--role of endoscopy.

The role of fiberendoscopy with regard to various dilatatory procedures is discussed. In particular detailed information is given for dilatation of tight asymmetrical fibrous strictures, with metal olives, for dilatation of advanced achalasia and for dilatation of obstructing gastro-esophageal malignancy, followed by positioning of a plastic prosthesis under endoscopic control.


Foreign body removal with the flexible fiberoptic bronchoscope.

Intrabronchial foreign bodies are occasionally encountered in adults but most available information in humans consists only of reports evaluating one or two cases. We surveyed our experience and found seven patients with intrabronchial foreign bodies who had been examined with the flexible fiberoptic bronchoscope, six of whom were managed successfully. Nine cases have been identified in the literature. Although there were no major complications in either our cases or those in the literature, several problems were identified which under other circumstances could have caused significant complications. We assessed all of these cases for situations which presented potential risk to the patient. These risks were grouped into the following problem categories: 1. selection of appropriate bronchoscope, 2. availability of appropriate instruments, 3. control of the foreign body, and 4. unexpected foreign bodies. Endoscopists planning to use the FFB in foreign body removal should be aware of the problems and hazards which may ensue if improperly managed, and should attempt to gain experience either in the animal laboratory or in models prior to approaching patients with foreign bodies with the flexible fiberoptic bronchoscope.


Acute multiple gastric ulcers in the pyloric antrum.

Acute prepyloric hemorrhagic erosions occasionally progress to symmetrical ulcers. Cytomegalic inclusion bodies were frequently seen, a history of alimentary allergens, excessive alcohol intake or coffee drinking was common. Hyperchlorhydria which decreased spontaneously was found in 89% during the acute attack.


Value of coloscopy in the detection of sigmoid malignancy in patients with diverticular disease.

Coloscopy was accurate in 83% of patients referred because of a radiological suspicion of malignancy in a diverticula-bearing sigmoid colon. In 17% the sigmoid could not be reached or inspected because of deformity or stenosis. All 13 coexisting carcinomas were correctly diagnosed endoscopically except for one which could not be reached. Coloscopy is therefore a valuable adjunct in detecting or eliminating cancer in colonic diverticular disease.


Colposcopy in the management of early cervical neoplasia.

An outline of the capacity of colposcopy in detection of early neoplastic changes at the ectocervix and the cervical os is given. Figures are presented of results reached by combined use of colposcopy and cytology in 6,536 women (divided into age groups of over and under 30 years) including histological findings. The results emphasize the need to use colposcopy as an additional method in cervical cancer detection.


A newly devised cutting probe for endoscopic sphincterotomy of the ampulla of vater.

A new diathermy cutting probe for endoscopic sphincterotomy has been devised. This consisted of a standard Teflon catheter with a diathermy wire and a metal-marked long tip. Using an Olympus duodenoscope and this cutting probe, endoscopic sphincterotomy has been successfully performed in 38 out of 40 patients with common bile duct stones without any serious complications. Advantages and clinical results of this instrument are presented.


Endoscopic treatment of stenosized anastomosis after gastrectomy.

Reflux-induced strictures of anastomoses are well-known complications of total gastrectomys. Since 1974 ten patients with postoperative dysphagia were treated by endoscopy. The enlargement of the obstructed anastomotic ring was done with the unopened diathermy-snare. This simple and uncomplicated method removed the heavy complaints of the patients immediately; no complications were registered until now. Follow-up was 3 to 32 months.


Villous adenoma of the duodenum. Endoscopic diagnosis and resection.

The authors report a new case of villous adenoma of the duodenum diagnosed by X-ray examination and duodenoscopy. Endoscopic removal allows an accurate histologic diagnosis. This endoscopic resection relieves symptoms and spares the patient a laparotomy. It seems to be an acceptable treatment of benign duodenal tumors.


Pancreas abscess: a fatal complication of endoscopic cholangiopancreatography (ERCP).

Endoscopic retrograde cholangiopancreatography (ERCP) is a popular and extremely useful technique for investigating the pancreatico-biliary tree. While the mortality is low, rare complications i.e., pancreatic abscess, may prove lethal. Surgical backup must be available to obviate recognized complications following ERCP.


Reduction of duration and severity of megimide seizures in rats on a folic acid deficient diet.

Folic acid deficient diet reduces the duration and severity of intravenous megimide seizures in the rat after 6 months of diet. Plasma and serum folate levels are strongly reduced after that period. The difference between Lactobacillus casei and Streptococcus faecalis activity in brain show a slight, but not significant, decrease after 12 months of diet.


Effects of change in dietary folic acid content on pentylenetetrazol seizure threshold in rat.

Pentylenetetrazol (PT) eeg thresholds were measured in rats on a folic acid (FA) deficient diet, normal diet, and a diet supplemented with large amounts of folic acid. The intraperitoneal dose per kilogram body weight of PT is significantly higher in the FA deficient group and significantly lower in the FA supplemented group than in rats on a normal diet. This indicates an effect of FA metabolism on PT epilepsy. The Lactobacillus casei minus Streptococcus faecalis activity of the brain is decreased in the FA deficient and increased in the FA supplemented group. The relation between brain folate metabolism and epilepsy is discussed.


Suppression of an eplieptiform type of electrocortical activity in the rat by stimulation in the vicinity of locus coeruleus.

Stimulation of the locus coeruleus, or in the vicinity of this nucleus or of its ascending tracts, could markedly suppress the appearance of epileptiform-like ECoG bursts. The latter were induced in rats by a subconvulsive dose of pentylenetetrazol. Electrode sites were identified histologically. A unilateral stimulus suppressed bursts bilaterally. An individual burst already in progress could be aborted, stopping within less than 0.5-1 sec after onset of a stimulus train. The antiepileptiform actions occurred with no evidence of any desynchronizing effect of the stimulus on the resting ECoG; they appear to be different in sites of origin and nature from those reported for stimulation of the reticular activating system. It is proposed that stimulation of the ascending noradrenergic system in the brain stem may limit the development and spread of hyperexcitatory, epileptiform states.


Comparison of effects of bicuculline, strychnine, and picrotoxin with those of pentylenetetrazol on photically evoked afterdischarges.

The effects of bicuculline, strychnine, and picrotoxin on photically evoked afterdischarges (PhADs) in rat visual cortex were compared with those of pentylenetetrazol (a known PhAD potentiator) and a diazepam (a known PhAD suppressor) challenge. Bicuculline was found to augment PhADs in a manner similar to that found with pentylenetetrazol, with the exception that potentiation only occurred at convulsive levels whereas pentylenetetrazol augmentation occurred at both subconvulsive and convulsive levels. Diazepam suppressed bicuculline-potentiated PhADs. Picrotoxin was found to have some limited augmenting effect on PhAD activity but in a manner unlike that observed with either bicuculline or pentylenetetrazol. Strychnine had no systematic augmenting effect on PhADs. These results were discussed in terms of the possible role of GABA in thalamic systems responsible for PhAD production.


Ictal tonic postural changes and automatisms of the upper limb during epileptic parietal lobe discharges.

Tonic postural changes of the upper limb accompanied by epileptic parietal lobe discharges are not well known. The authors report 3 such cases. In the 3 patients, a total of 18 spontaneous seizures were recorded, 12 by telemetry, from either scalp electrodes or stereotactically implanted electrodes. Of these 18 seizures, 14 included tonic postural changes of the upper limb accompanied by a contralateral parietal discharge. Combining these 3 cases with the 4 such cases in the literature, the authors found that the clinical pattern consisted of a tonic postural change in one upper limb associated with automatisms of the opposite upper limb. It was also found that the same patient might have automatisms involving the upper limb in some seizures and upper limb postural changes in other seizures, both accompanied by the same electrical discharge. It is concluded that tonic postural changes and automatisms in the upper limb may be interchangeable.


Distribution characteristics of ethosuximide in discrete areas of rat brain.

The distribution properties of ethosuximide in four regions of the rat brain--cortex, midbrain, cerebellum, and pons-medulla--were investigated following chronic intraperitoneal administration of the drug (every 12 hr for 108 hr) at four dose levels (20, 40, 60, and 80 mg/kg). A gas-liquid chromatographic procedure was developed to quantitate ethosuximide levels in these tissues and plasma. The mean tissue/plasma ratios were 0.917, 0.942, 0.902, and 0.903 for cortex, midbrain, cerebellum, and pons-medulla, respectively. The distribution ratio for midbrain was significantly greater than that observed for cerebellum. For each brain region, the distribution ratio was independent of dose (20 to 80 mg/kg) and plasma concentration (8 to 135 microgram/ml).


Action of adenosine hosphates on the release of intracellular lactate dehydrogenase from human and rat lymphocytes.

Differences in the action of adenosine phosphates on the release of intracellular enzymes from human and  rat lymphocytes have been studied. The protective effect of ATP on the human cells was found to be less than on the rat cells. The greatest discrepancy was exhibited by AMP which exerted a protective effect on human lymphocytes, but increased enzyme efflux from rat lymphocytes. The activities of adenosine kinase, adenylate kinase, phosphoribosyl-pyrophosphate synthetase, pyruvate kinase, phosphoglycerate kinase and creatine kinase were compared in the cells of both species. Although significant differences were observed, they were too small to suggest the presence of a mechanism for the conversion of AMP into ATP in human lymphocytes not found in the rat cells. It seems therefore that the protective effect exerted by AMP on the human cells is not mediated by its conversion into ATP, and hence that some factor other than the intracellular energy content is concerned in controlling the release of intracellular enzymes from human cells.


On newborn hypothalamic phenylethanolamine-N-methyltransferase.

Phenylethanolamine-N-methyltransferase activity of rat hypothalami was assayed. The enzyme was present at birth, in traces, and gradually increased during the first 2 postnatal months. Exposure to recurrent stressful situations increased PNMT activity in a statistically significant manner. Persistence of exposure to stressful events resulted in higher adult PNMT activity. Assays of hypothalamic tissue cultures revealed that part of PNMT activity increase was due to temporary potentiation by local factors, and partly to increase of tissue concentration of enzyme by increased protein synthesis. One of the submolecular chain reactions generated by stress (and able to induce protein synthesis) was identified as: release of ACTH during stress, activation of local adenylate cyclase by ACTH to synthesize cyclic AMP. When released, this cyclic AMP increased the local cyclic AMP: cyclic GMP ratio, a process known to induce protein synthesis. A potent and selective competitive inhibitor, SK&F 64139, when added to tissue cultures, prevented increase of PNMT activity by prolonged stimulation.


Effects of thyroid hormones on the evolution of monoamine oxidase activity in the brain and heart of the developing rat.

The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.


Purification of L-type pyruvate kinase from human liver by affinity chromatography on Blue-Dextran-Sepharose column.

L-type pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase; EC 2.7.1.40) was purified from human liver by an original method. This purification included toluene extraction, a-monium sulphate fractionation, DEAE-Sephadex bactchwise, CM-Sephadex batchwise with elective elution by ATP and affinity chromatography on a Blud Dextran-Sepharose column with specific elution by fructose 1, 6-diphosphate. This purification procedure allowed us to obtain 6 mg protein with a specific activity of 420 IU/mg protein, i.e. 2,690-fold purification with an overall yield of 34%. This preparation was homogeneous as judged by immuno-diffusion, acrylamide and sodium dodecyl sulphate acrylamide-gel electrophoresis.


Lipid composition and enzyme activities of human arteriosclerotic femoral and iliac arteries.

Lipid composition and the activities of lipolytic enzymes and cholesterol acyltransferase have been examined in femoral and iliac arteries of surgically treated patients suffering from arteriosclerosis obliterans. Negative correlations for the contents of triglycerides and cholesterol esters, and for the ratios of triglyceride/cholesterol ester contents and cholesterol acyltransferase/cholesterol esterase activities, were found.


Comparison of aldolase isozymes in placenta, HeLa cells, and human fibroblast cultures.

The aldolase specific activity of the human carcinoma cell line, HeLa, against fructose 1,6-diphosphate as substrate is 4- to 5-fold greater than the specific activity of diploid human fibroblast cultures derived from skin and lung. HeLa aldolase is isozyme is predominantly the A type and its substrate preferences resemble human placenta. These findings provide further support for the oncofetal enzyme consitution of HeLa cells.


Change of protein reactivity in mammalian ribosomal subunits as a function of temperature.

Reductive methylation of rat liver ribosomal subunits was carried out at different temperatures and the reaction was followed as a function of time. The percentage of protein lysine residues which were methylated reached a definite plateau for each temperature, and was considerably increased by heating (four times at 40 degrees C). This increase was not observed when free ribosomal proteins were heated under the same conditions. Ribosomal subunits kept their biological activity (elongation steps of protein synthesis) even when methylated to a high extent. Half of the subunit activity was still found when 67% of the lysine residues were methylated. Proteins were divided into different classes on the basis of their alkylation in response to temperature. Those which reacted poorly within subunits even at high temperature should interact directly with rRNA. The results suggest that the protein reactivity modifications induced by heating (up to 37 degrees C), which were often totally or partially reversible, reflect a conformational change of the proteins themselves within the subunits. Besides protein unfolding, higher temperatures produced structural modification and inactivation of the subunits, which were restrained by the presence of aminoacyl tRNA.


Phosphorylation from inorganic phosphate and ATP synthesis of sarcoplasmic membranes.

The incorporation of inorganic phosphate in the fragmented sarcoplasmic membranes induced by the removal of calcium ions bound to high affinity binding sites at the cytoplasmic surface of the membranes gives rise to the formation of two species of phosphoenzyme. The properties of the phosphoproteins formed depend on the absence or the presence of a gradient of calcium ions across the membranes. The phosphoenzymes differ by the affinity of the protein for phosphate, the enthalpy of formation, the kinetics of phosphate incorporation, and by the sensitivity to ionophores and ADP. In the absence of a calcium gradient less than 0.5 nmol phosphoenzyme per mg protein are formed in media containing less than 5 mM phosphate at pH7 and 10 degrees C. Under the same conditions approximately 2 nmol of phosphoenzyme per mg protein are formed with an initial rate of 0.5 nmol mg-1-s-1 when a calcium gradient exists. When the gradient is abolished by the addition of the ionophore X537A, the level of phosphoprotein drops to the same value as observed in the absence of a gradient. On addition of ADP at concentrations increasing from 0.3 to 10 muM continuous ATP formation is activated to its maximum rate, and simultaneously, the level of phosphoprotein declines. These concentrations of ADP scarcely affect phosphoprotein formed in the absence of a gradient, the phosphoryl residue of which is displaced when the concentration of ADP exceeds 10 micrometer without the formation of an equivalent amount of ATP. Minimum mechanisms for the formation of gradient-independent and gradient-dependent phosphoprotein are discussed.


[Small-angle X-ray-scattering investigation and structural-model study of the fatty-acid synthetase from pig liver (author's transl)].

The structure of the fatty acid synthetase from pig liver was studied on models based upon structural and functional properties selected from pertinent results available from numerous investigations carried out with fatty acid synthetases from this and other sources. When comparing small-angle X-ray-scattering curves calculated with these models and curves obtained from small-angle X-ray-scattering experiments carried out with the pig-liver enzyme, we tried to select a model which would lead to an acceptable correlation between the calculated and the experimental curves and at the same time fulfil the known structural and functional requirements. The comparison of the curves was started with a model of low complexity. The observed discrepancy, together with arguments from the structural and the functional properties, helped decide which is the next most reasonable model to be considered. This procedure was repeated for five models of increasing complexity. In the model which led to the best fit the multienzyme complex is composed of two halves in an assymetric conformation including hollow spaces. This highly anisotropic model would imply that the two halves change their conformation each time a synthetic cycle is completed and that the growing fatty acid is handed over from one half to the other.


The peptidoglycan crosslinking enzyme system in Streptomyces strains R61, K15 and rimosus.

The DD-carboxypeptidase-transpeptidase enzyme system in Streptomyces strain K15 consists of: (1) a membrane-bound transpeptidase capable of performing low DD-carboxypeptidase activity; and (2) a set of DD-carboxypeptidases: (a) membrane-bound, (b) lysozyme-releasable and (c) exocellular, having low transpeptidase activities in aqueous media and at low acceptor concentrations. The DD-carboxypeptidases are related to each other and may belong to the same pathway leading to enzyme excretion. A similar enzyme system occurs in Streptomyces strain R61 except that the membrane-bound DD-carboxypeptidase activity is low when compared with the membrane-bound transpeptidase activity. In Streptomyces rimosus the enzyme system consists almost exclusively of the membrane-bound transpeptidase and the levels of membrane-bound, lysozyme-releasable and exocellular DD-carboxypeptidases are very low.


A 31P-nuclear-magnetic-resonance study of the phosphate groups in lipopolysaccharide and lipid A from Salmonella.

Untreated and partially deacylated lipopolysaccharides from various P- and P+ strains of Salmonella were studied with 31P nuclear magnetic resonance spectroscopy and by conventional analytical methods. The spectral signals were assigned to various phosphate groups in the lipid A moiety and in the oligosaccharide part. A signal at +2.3 ppm could be assigned to a phosphodiester linkage formed between 4-amino-4-deoxyl-L-arabinose linked via the glycosidic hydroxyl group to the 4'-phosphate group of the glucosamine disaccharide in the lipid A moiety. A strong pyrophosphate signal at +11 ppm in P- strains was identified as a pyrophosphoryl ethanolamine group at the glycosidic end of this glucosamine disaccharide unit. No evidence was found for phosphodiester or pyrophosphodiester bonds crosslinking lipopolysaccharide 'subunits'. A revised version of the lipid A structure of Salmonella is presented. By a combination of 31P nuclear magnetic resonance spectroscopy data and conventional analytical methods the extent to which the lipopolysaccharides are substituted by various phosphate groups on the lipid A and the oligosaccharide moiety could be estimated. It was thus shown that substantial heterogeneity, leading to several molecular species of lipopolysaccharides is caused by addition or omission of certain groups. Since changes in substitution were found to be dependent on the growth conditions, it is thought possible that the overall negative surface charge of Salmonella can be modified by addition or omission of neutralising amino groups from ethanolamine and/or 4-amino-4-deoxy-L-arabinose, and can thus be adapted to the environment.


The peptidoglycan crosslinking enzyme system in Streptomyces strains R61, K15 and rimosus. Kinetic coefficients involved in the interactions of the membrane-bound transpeptidase with peptide substrates and beta-lactam antibiotics.

The transpeptidation reaction performed by the membranes of Streptomyces strain R61 fits the general rate equation for an enzyme-catalysed bimolecular reaction. The same membranes (E) interact with beta-lactams (I) to form inactive penicillin-enzyme-membrane complexes (EI) of rather high stability, which subsequently break down (E + I leads to EI leads to E + degradation products). The enzyme is regenerated and the antibiotic is released in the form of an inactive metabolite. With benzylpenicillin, the degradation product is benzylpenicilloic acid. The reaction is heat-labile. The first step of the reaction (E + I leads to EI) is characterized by a second-order rate constant (kformation in M-1 s-1) and the second step (EI leads to E + degradation products) by a first-order rate constant (kbreakdown in s-1). The effects in vitro of various beta-lactams on the membrane-bound transpeptidase, as expressed by the relevant kformation and kbreakdown values, parallel the effects in vivo of the same antibiotics as expressed by their ability to prevent the germination and growth of conidiospores. The kinetic parameters of the transpeptidase that was solubilized with N-cetyl-N,N,N-trimethylammonium bromide with respect to its interaction with both peptide substrates and beta-lactam antibiotics are quantitatively different from those of the membrane-bound enzyme. Moreover, the solubilized enzyme fragments benzylpenicillin with formation of phenylacetylglycine, a reaction which is similar to that catalysed by the exocellular R61 enzyme. The membranes of Streptomyces strains rimosus and K15 possess an active 'classic' penicillinase. They were not studied but the kinetic coefficients of the corresponding solubilized transpeptidases were determined and compared with those of the solubilized enzyme from strain R61.


An evaluation of fitting methods for the sum of two hyperbolas: application to uptake studies.

Analysis of data in terms of the sum of two rectangular hyperbolas is frequently required in solute uptake studies. Four methods for such analysis have been compared. Three are based on least-squares fitting whereas the fourth (partition method I) is an extension of a single hyperbola fitting procedure based on non-parametric statistics. The four methods were tested using data sets which had been generated with two primary types of random, normal error in the dependent variable: one of constant error variance and the other of constant coefficient of variation. The methods were tested on further data sets which were obtained by incorporating single 10% bias errors at different positions in the original two sets. Partition method I consistently gave good estimates for the four parameters defining the double hyperbola and was highly insensitive to the bias errors. The least-squares procedures performed well under conditions satisfying the least-squares assumptions regarding error distribution, but frequently gave poor estimates when these assumptions did not hold. Our conclusion is that in view of the errors inherent in many solute uptake experiments it would usually be preferable to analyse data by a method such as partition method I rather than to rely on a least-squares procedure.


Aspects of microenvironmental compartmentation. An evaluation of the influence of restricted diffusion, exclusion effects, and enzyme proximity on the overall efficiency of the sequential two-enzyme system malate dehydrogenase--citrate synthase in its soluble and immobilized form.

Soluble bifunctional enzyme aggregates have been prepared by cross-linking the sequential enzymes malate dehydrogenase (EC 1.1.1.37) and citrate synthase (EC 4.1.3.7) using glutaraldehyde. The kinetic behaviour of this two-enzyme system in its aggregated and non-aggregated form was studied both in free solution and immobilized on Sepharose beads. This study was undertaken in order to distinguish between the following two factors which may account for the increased efficiency found in general in co-immobilized consecutive two-enzyme systems: (a) closer proximity between the participating enzymes and (b) establishment of a favourable microenvironment (such as higher local intermediate concentration caused by increased diffusional hindrance in the gel phase). It was found that in spite of a reduction of the distance between the two enzymes in the aggregated form by an estimated factor of 10(3), no kinetic advantage (shorter lag phase or higher steady-state rate) could be detected compared to the corresponding system with the two enzymes not linked to each other. However, both systems immobilized to Sepharose reached the steady-state rate of citrate formation almost immediately, in contrast to the corresponding free systems which exhibited pronounced lag phase. These results indicate that, at least in the above systems and under the conditions given, diffusional hindrance in the gel phase of the intermediate oxaloacetate, which is present in rate-limiting concentrations, is the dominant cause of the observed higher efficiency in immobilized systems.


Properties of the complex between histone H1 and poly(ADP-ribose synthesised in HeLa cell nuclei.

Preparations of H1 histone from HeLa cell nuclei incubated with [3H]NAD to permit poly(ADP-ribose) synthesis were electrophoresed on polyacrylamide gels. The incorporated radioactivity migrated as a sharply defined peak in association with a protein band which moved more slowly than H1, the major protein component. The following observations indicate that this complex is composed of two molecules of H1 and a single chain of poly(ADP-ribose) with one detectable covalent linkage of polymer to protein. 1. The [14C]arginine/[3H]lysine ratio is identical in H1 histone and in the protein moiety of the complex. 2. Protein is displaced from H1 histone to the complex during poly(ADP-ribose) synthesis. At least 90% of the protein in the complex (stainable protein and labelled protein) is derived from H1. 3. Sedimentation rate studies indicate a molecular weight of the complex about twice that of H1 histone. 4. The average chain length of the polymer is 15 ADP-ribose units and there are 7--8 ADP-ribose units for each molecule of H1 histone in the 'complex'. 5. Poly(ADP-ribose) glycohydrolase, which hydrolyses the polymer exoglycosidically from the AMP terminus, degrades the complex producing ADP-ribose and mono-ADP-ribosylated H1 histone which co-electrophoreses with unmodified H1. Although only one covalent linkage between protein and polymer has been detected, the 'complex' does not dissociate when electrophoresed on dodecylsulfate gels. Nor can the noncovalently linked H1 histone of the complex readily exchange with free H1. Complex formation does not occur when purified poly(ADP-ribose) and H1 are mixed.


Serum zinc concentration during childhood.

Serum zinc concentrations in subjects of different ages were estimated by neutron activation analysis to obtain reliable reference values for the diagnosis of primary or secondary zinc deficiency during childhood. In these healthy individuals a small age-dependent variation of the mean values was found. Serum zinc concentrations were lower in cord blood (mean value: 880 X 10(-9) g/ml) and in infant;s (mean value: 820 X 10(-9) g/ml) than in adults (mean value 1178 X 10(-9) g/ml). In comparison to these values, the serum zinc concentration in a patient with secondary zinc deficiency and 4 patients with acrodermatitis enteropathica was reduced to about 25% of normal.


The ontogeny of sensory perception in preterm infants.

The extra- vs intrauterine development of both visual and auditory cortical evoked response patterns was compared at 33, 37 and 40 weeks conceptional age. The maturation of visual cortical evoked responses is retarded in infants at 37 and 40 weeks conceptional age when born with a gestational age of less than 32 weeks, which thus implies a long extrauterine life span. The maturation of the auditory cortical evoked responses is not influenced by premature exposure to the extrauterine environment. The results are explained on the basis of the particular central nervous system growth spurt periods and a thus defined vulnerable period of different brain structures.


Persistent post-enteritis diarrhoea.

Clinical, biochemical, and gastroenterological data have been examined im 48 patients in two age groups, one under 12 months of age, the other between 12 and 30 months with persistent post-enteritis diarrhoea. In these patients, the illness consisted of chronic diarrhoea which followed acute enteritis. It brought about a mild malabsorption syndrome with impairment of growth, particularly in infants under one year of age. Chronic inflammation with mucosal damage due to alteration of the intestinal microflora by inappropriate diets and therapy seemed to be the cause of persistent diarrhoea in these patients.


Serum alkaline phosphatase isoenzymes in epileptic children receving anticonvulsant drugs.

In 40 epileptic children on long-term anticonvulsant treatment, serum alkaline phosphatase (AP) isoenzymes were separated semiquantitatively using a combination of L-phenylalanine inhibition and heat inactivation. Though mean total serum AP activity was significantly increased compared to age matched controls, only 4 individual values exceeded the upper limit (mean + 2SD) of the reference sample. In epileptics the mean activity of the heat-sensitive non L-phenylalanine sensitive AP fraction (non-LPSAP) was significantly increased (P less than 0.01) and the mean Q-value (i.e. percentage ratio of heat-stable non-LPSAP/non-LPSAP) was significantly decreased (P less than 0.05), thus indicating an enhancement of the bone isoenzymes during anticonvulsant treatment. In 4 patients the isoenzyme pattern was abnormal although total serum AP activity was normal and in 3 of them the deviation indicated enhanced bone isoenzyme. The data provide evidence that in anticonvulsant treated children the bone isoenzyme, rather than hepatobiliary isoenzyme fraction, may be increased even when total serum AP activity is normal. Thus, semiquantitative separation of serum AP isoenzymes may be a helpful guide as to whether or not an eplieptic child should be given vitamin D.


Comparison of RNA and DNA synthesis, spontaneous and PHa induced, between blood lymphoid cells of newborn infants, older infants, and adults. A study of scintillation counting and by autoradiography.

Spontaneous and PHA induced RNA and DNA synthesis was measured qualitatively by autoradiography and quantitatively by scintillation counting in blood lymphoic cells of newborn infants, older infants, and adults. Spontaneous RNA synthesis was found in transitional cells, large phagocytic lymphoid cells and lymphocytes. Transitional cells and phagocytic lymphoid cells also synthesized DNA spontaneously. Quantitatively, spontaneous RNA synthesis was active in both newborn infants and in adults, but significantly less so in older infants. PHA stimulation for 18 h increased RNA synthesis significantly in blood lymphoid cells of newborn infants and adults, and to a much lesser but still significant degree in older infants. Spontaneous DNA synthesis was significantly greater in newborn infants than in older infants and adults. PHA stimulation for 18 h had no effect on thymidine incorporation in any of the groups studied.


Negative impact of growth-hormone deficiency on psychological functioning in dwarfed children and adolescents.

This study compares the psychological findings in three groups of dwarfed children and adolescents, namely those suffering from isolated growth-hormone deficiency, from multiple pituitary hormone deficiencies, and without endocrine disease. The study is based on psychometric data from one multifactorial intelligence test and several personality questionnaires. It was found that growth hormone deficiency had no impact on the psychological variables.


Generalized oedema of newborn associated with the administration of dipyrone.

In fourteen infants, aged 9--60 days, with generalized oedema seen during a one year period the common denominator was the administration of dipyrone one to two days prior to the development of oedema. None of the other causes of oedema in early life could be incriminated in any of these babies. Pediatricians should be aware of this iatrogenic cause whenever they encounter a young infant with generalized oedema. Oedema disappeared in all the cases following discontinuation of dipyrone but anuria lasted for more than four days in one case. This stydy re-emphasizes the need to without this potentially dangerous drug, especially during the neonatal period.


Intelligence level of patients with the Duchenne type of progressive muscular dystrophy (pmd-d).

The I.Q. of 129 patients with PMD-D and 27 patients suffering from Werdnig-Hoffmann disease were estimated. Among the patients with PMD-D there was one group without any complicating factors and 3 other groups with additional factors that might influence the intelligence level. Comparing mean values and distribution of I.Q. for all these groups, one can conclude that, besides additional unfavourable pathological and environmental factors in all cases, PMD-D itself causes a small decrease of the I.Q. by about 1 SD. The frequent changes of the EEG record in these patients could reflect involvement of the CNS by the pathological process.


Mexiletine in the management of ventricular dysrhythmias.

Mexiletine administered either intravenously or orally was found to be an effective antiarrhythmic agent. Unfortunately, important adverse effects occurred in approximately half of the patients. Adverse effects which appeared during oral therapy were dose related. Mexiletine controlled lignocaine-resistant ventricular dysrhythmias in more than half of the patients treated. Ventricular tachycardia and ventricular fibrillation occurred at plasma concentrations which were not significantly different from those associated with severe side-effects, suggesting that when mexiletine is used to control these major dysrhythmias the incidence of important side effects will be high.


A noninvasive study of the response of ischemic heart to exercise.

The response to exercise during increasing workloads (supine bicycling), was studied in 105 men, of whom 70 had ischemic heart disease and 35 did not, clinically classed into 6 groups. Heart rates, blood pressures and systolic time intervals (STI) were measured in relation to exercise tolerance and capacity. The ischemic heart disease (IHD) subjects differed from the nonischemic by an increased PEP/LVET ratio at rest and by a tendency of the diastolic blood pressure to increase upon exercise. Two main types of abnormal reaction of STI to workload were ascertained: (1) prolonged LVETc with respect to controls (prevailing in angina pectoris), and (2) prolonged PEPEc together with shorter LVETc (typical for left ventricular failure). The dominant feature appears to be the depressed contractility in the latter and a decreased compliance (or rate of relaxation) in the former. Estimation of STI may contribute to the evaluation of the exercise tolerance test in long-term examination of ischemic patients.


Figure-of-eight circulation in thoracopagus conjoined twins with a shared heart.

A pair of thoracopagus conjoined twins is described in whom a common heart with atrial and ventricular conjunction was demonstrated by cardiac catheterization and at autopsy. Each twin had an independent noncommunicating single ventricle with separate origins of the aorta and pulmonary arteries. A complex pattern of pulmonary and systemic venous return resulted in a fugure-of-eight circulation not previously described which precluded surgical intervention. This report demonstrates the feasibility of detailed hemodynamic assessment in thoracopagus twins and the value of selective ventricular angiography with careful observation of the venous phase in determining an accurate preoperative diagnosis.


Quantitative nuclear angiocardiography in valvular heart disease.

A noninvasive method of quantitative nuclear angiocardiography was developed using a camera system and a computer. The investigation, which can be performed on an out-patient basis within 10-15 min, includes the following steps: injection of 10 mCi 99mTc-labelled human serum albumin into a femoral vein, and external recording of the passage of the bolus through the central circulation by a sequence of scintigraphic frames taken during diastole. From time--activity curves over the right ventricle, the pulmonary artery and the left ventricle, peak-to-peak times and mean circulation times were calculated. The method was applied to 424 patients with valvular heart disease proven by heart catherization. The following results were obtained: (1) The method proved to be highly sensitive in stating whether there was a hemodynamically significant valvular disease or not. But differential diagnosis concerning the different forms of valvular disease was not possible. (2) The prolongation of the circulation times correlated with the hemodynamic severity of the disease. (3) The circulation times were directly related to the cardiac index, the enddiastolic volume of the left ventricle and the pressures in the pulmonary vascular system. (4) The method could be used to evaluate the effect of surgery and for follow-up after operation. Quantitative nuclear cardiography may help to fill the gap between the nonquantitative, rather unspecific and the specific but invasive methods of cardiologic investigation.


Radionuclide imaging of the heart in myocardial infarction and acute ischemia by 99mtechnetium diphosphonate.

99mtechnetium diphosphonate was used in 81 patients for myocardial imaging. 46 of the patients suffered, 2-6 days prior to the test, from an acute transmural infarction provided by clinical, ECG, and enzymatic evidence; the scintigram was definitely positive in 43, equivocal in 2, and negative in 1. In 16 patients with subendocardial infarctions, in 9 the scintigram showed a positive result, in 1 it was equivocal, and in6 patients negative. In 6 other patients who suffered from acute chest pain, followed by enzyme changes, but no ECG evidence of infarction throughout the hospitalization period, the scan was positive in all. In 13 patients with acute ischemia (unstable 'crescendo' angina), 9 had a positive, 1 an equivocal, and 3 a negative scan. We conclude that radionuclide imaging is a valuable addition to the methods already available for diagnosis of myocardial infarction. With the use of diphosphonate as the tracer, we found that acutely ischemic myocardium that later may recover, gives also positive imaging.


Angina pectoris in presumably healthy middle-aged men. Validation of two questionnaire methods in making the diagnosis of angina pectoris.

In 2014 presumably healthy men aged 40-59 yr the prevalence of previously undiagnosed angina pectoris was assessed by two angina questionnaires: (1) World Health Organization Questionnaire (WHO-Q) and (2) Greater New York Health Insurance Plan Survey Questionnaire (NY-Q). The angina prevalence given by the questionnaires singly or in combination varied between 1.15 and 4.7% (lowest prevalence by the WHO-Q interview version (WHO-Qi) and highest by the WHO-Q self-administered version and the NY-Q in combination), indicating a considerable variation in prevalence with variation in criteria used. Validation of the questionnaires by means of (1) coronary angiography, and (2) follow-up in selected cases, indicated NY-Q superiority over WHO-Q in predicting the presence of coronary heart disease (CHD). WHO-Qi had a particularly low sensitivity without being more specific. However, CHD-risk factor patterns in subgroups of individuals classified as angina-positive or -negative by the respective questionnaires were similar.


Attempted suicide with verapamil.

A 28-yr-old woman was admitted to hospital after a suicide attempt in which she had taken 5600 mg verapamil. On admission she exhibited bradycardia and pronounced hypotension; ECG revealed AV dissociation which persisted for 7 1/2 h after admission. She was discharged well 36 h later.


Paroxysmal reciprocating sinus tachycardia.

We present clinical and electrophysiological data on 9 patients with paroxysmal reciprocating sinus tachycardia (PRST) of whom only 6 described palpitations. Sinus node disease was present in 5 and cardiac ischemia and/or hypertension in another 3; the remaining case had apparently coincidental Wolff-Parkinson-White (WPW) syndrome. PRST could be initiated in all cases, and terminated in the 4 in whom it was sustained, by suitably timed atrial premature beats over a zone that was dependent on the effective atrial extrastimulus coupling interval (A1-A2) in the high right atrium (HRA). The sequence of atrial depolarization during PRST was similar to that of sinus beats although minor changes in both the P wave and the configuration of the HRA electrogram were observed in half the cases. During paroxysms, cycle length variation and sensitivity to alterations in vagal tone were common. In 6, paroxysms could be initiated by moderately rapid atrial pacing. Repetitive attacks were usually initiated by increases in the sinus rate and not be an antecedent premature atrial extrasystole. Verapamil suppressed sinus node reentry in 5 patients while small doses of atropine favored initiation in 3. PRST was seen in association with AV reentry tachycardias in the patient who had the WPW syndrome.


Treatment of hypertension successively with a diuretic, clonidine or a beta-blocking agent and hydralazine.

The present study was carried out in an homogenous group of 49 untreated hypertensive patients, all aged 45 years. Diastolic blood pressure was equal to or greater than 110 mmHg in successive measurements; eleven patients were classified as WHO group II, and the others as WHO group I. An initial placebo period of 3 weeks was followed by cyclothiazide medication with a good response in 6 patients. The remaining patients were given either clonidine or practolol, and by adjustment of the dose a good response was obtained in 31 patients. In these cases the treatment was exchanged after 6 weeks. The antihypertensive effect of relatively small doses of clonidine was equal to that of practolol. Since completion of the study practolol has been withdrawn because of the emergence of long term toxic effects. In 12 cases, hydralazine had to be added to obtain a satisfactory response. Mild side-effects were common, especially at the beginning of clonidine treatment, but they did not necessitate discontinuation of treatment. Further comparative studies of clonidine and beta-blockers should be carried out and more experience with the combination of clonidine and vasodilators in the treatment of hypertension is necessary.


Adverse reactions to practolol in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program.

Adverse reactions to practolol were studied in 198 prospectively monitored hospitalized medical patients. The mean age of the practolol recipients was 57 years; angina and cardiac arrhythmias were the most common indications for therapy. Adverse reactions were attributed to practolol in 20 patients (10%). Fifteen of these twenty reactions involved impairment of cardiac function (bradyarrhythmias, heart block, congestive heart failure, hypotension), and in three instances the reaction was considered life-threatening. Three additional patients had cutaneous reactions attributed to the drug. Adverse reactions to practolol were not dose-related, but toxicity appeared to be more frequent among patients concurrently receiving quinidine. The frequency of cardiovascular complications of propranolol in a similar series of patients was nearly identical. However, no skin reactions were attributed to propranolol. The findings suggest that practolol and propranolol produce unwanted cardiovascular effects with nearly equal frequency among hospitalized patients. Cutaneous reactions to practolol are evident even during short-term use.


Pharmacokinetics of atenolol in patients with renal impairment.

The pharmacokinetics of atenolol, a new cardioselective beta-adrenoceptor blocking agent, were determined following both acute and chronic dosing in 33 hypertensive patients with widely differing levels of renal impairment. In patients with normal renal function the atenolol half-life was calculated to be about six hours following single 100  mg oral doses. This value increased markedly in patients with renal insufficiency and the blood clearance of atenolol was found to have a significant correlation with the glomerular filtration rate. This demonstrated the importance of the kidneys in the elimination of the drug. After 8 weeks oral treatment with atenolol (100 mg twice daily) a significant decrease in blood pressure, heart rate and plasma renin activity was observed, but no correlation was established between the blood levels of atenolol and any of its pharmacodynamic effects. A positive correlation was found however between the anti-hypertensive action of atenolol and the pretreatment value of the plasma renin activity.


Intestinal propulsive action of oxetoron.

In a double blind placebo controlled study of 40 patients, oxetoron was shown significantly to shorten the time required for movement of a small intestinal biopsy capsule up to the angle of Treitz.


Human experience of cetiedil, a new vasodilator with anticholinergic properties.

Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the 14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.


Dose dependent pharmacokinetics of prednisolone.

The pharmacokinetics of prednisolone elimination have been studied in both arthritic patients and normal volunteers using tritiated prednisolone alone, and in conjunction with unlabelled prednisolone in doses of 0.15 mg-kg-1 and 0.3 mg-kg-1 body weight. With increasing dose there is prolongation of the plasma half-life and increase in the volume of distribution and plasma clearance of prednisolone. It is proposed that these changes in pharmacokinetic parameters may be associated with non-linear binding of the steroid to plasma proteins.


The pharmacokinetics of cefuroxime after intravenous injection.

Cefuroxime, a new cephalosporin antibiotic which is stable to most beta-lactamases produced by gram-negative bacteria, was given by bolus intravenous injection to six volunteers in doses of 500 mg and 750 mg. The concentrations of cefuroxime in serum and urine were measured at pre-determined times after injection and the data analysed by a two-compartment open system model. A serum concentration of 8 microgram/ml was exceeded for 100.3 min (+/- 18.3) after a 500 mg dose and for 144.5 min (+/- 19.8) after 750 mg. The ultimate serum half-life was 1.1 h. Excretion of cefuroxime in the urine was almost complete in 24 h, the clearance being 150 ml/min/1.73m2. About 45% was excreted through the renal tubules. The injections were well tolerated and no changes in haematological or biochemical values were seen. The resulting data are compared with those published for some other cephalosporins. It is concluded that the favourable pharmacokinetics, especially the high concentrations of unbound cefuroxime in the serum, are likely to aid effective therapy of human infection caused by sensitive bacteria.


Dose dependence of the 14C-aminopyrine breath test. Intrasubject comparison of tracer and pharmacological doses.

Although the aminopyrine breath test has received much attention, the question has not yet been settled whether pharmacological or tracer doses of the drug should be used. Nine volunteers were given 14C-aminopyrine 9 mg/kg or a tracer amount, in a randomized sequence and according to a crossover design. The specific activity of 14CO2 in breath was significantly different only during the first hour. Up to the 8th hour the disappearance of 14CO2 from breath was smaller after the pharmacological (28.5 +/- SD 5.4%/h) than after the tracer dose (36.2 +/- 10.6%/h; p less than 0.05). The over-all disappearance of 14C-atoms from the subjects was significantly slower after the higher dose. In view of the smaller radiation exposure and the decreased risk of agranulocytosis, the use of a tracer dose appears preferable.


Improved method for comparative evaluation of aldosterone antagonists in healthy man.

A method of assessing the qualitative and quantitative activity of competitive aldosterone antagonists in healthy man is described. It requires intravenous infusion of aldosterone (0.5 mg/6 h), iv and oral water loading for six hours and fractionated collection of urine over eight hours. Aldosterone antagonists were administered orally 1.5 h before the start of the infusion (spironolactone 50, 200 or 800 mg) or added to the infused solution (potassium cnarenoate 300, 600 or 1000-1200 mg). The effect was assessed by changes in urinary sodium and potassium excretion and in urinary Na+/K+ ratio. The plasma levels and urinary excretion of canrenone, canrenoate and canrenoate ester glucuronide, respectively, were determined after administration of spironolactone and potassium canrenoate. Between 4-8 h (spironolactone) or 2-8 h (potassium canrenoate) after commencement of the infusion there was linear dose-dependent reversal of the mineralocorticoid-induced sodium retention and/or decrease in the Na+/K+ ratio. The plasma levels and urinary excretion of the metabolites measured were also dose-dependent. The method appears suitable for comparison of the potency of aldosterone antagonists and for defining the time course of drug action within the observation period employed.


The influence of prolonged treatment with D-penicillamine on the immune response in Wilson's disease.

Humoral and cell-mediated immunity were studied in a group of patients with Wilson's disease not previously treated with D-penicillamine, and in a group of patients treated with the drug for more than two years. The previously untreated patients showed an exaggerated humoral immune response, i. e. increased levels of IgG and, IgM, higher titer of antibodies to Kunin's antigen, and depression of cell-mediated immunity, namely a decreased response to DNCB, decreased lymphocyte transformation after stimulation with Con A, PPD, Candida and streptokinase and a reduced response to streptokinase in the MIF test. After treatment the humoral response returned to normal, and in the case of IgA and antibodies to S. typhi O antigen, it even dropped below normal values. The cell-mediated immune response returned to normal with the exception of lymphocyte transformation by PHA and Candida albicans. In in vitro studies it was found that D-penicillamine had no influence on lymphocyte transformation when PHA and Con A were used as mitogens. With PPD as antigen, lymphocyte stimulation and migration inhibition were inhibited by concentrations of penicillamine ranging from 6 to 1000 microgram/ml.


Effect of lidocaine on the absorption, disposition and tolerance of intramuscularly administered cefoxitin.

The use of lidocaine HCL solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.


Influence of nutritional status on plasma levels and relative bioavailability of tetracycline.

Relative bioavailability after oral administration of a single dose and Cmin levels of tetracycline in plasma after multiple doses were determined in groups of well-nourished and under-nourished subjects. The relative bioavailability of tetracycline, assessed by the area under serum concentration time-curves, did not differ in under-nourished and well-nourished patients. The plasma levels were not different in the two groups after the conventional dose of tetracycline HCL 250 mg at 6 hour intervals. However, in these studies under-nourished subjects received a higher dose per kg body weight, which could have compensated for any effect of a shortened half life of the drug. When the dose per kg body weight was reduced, the Cmin levels were lower. On the other hand, with the same dose per kg body weight at more frequent intervals, the plasma concentrations were similar to those in well-nourished subjects. These studies indicate that the dosage regimen should be based both on body weight and on the nutritional status of the individual.


Pharmacokinetics of phenobarbital in childhood.

In 14 neonates 1-4 weeks old, 30 babies aged 1-12 months, and 7 infants of 1-5 years of age, the serum levels of phenobarbital were determined by a gas chromatographic micro-method after intravenous injection of phenobarbital 5-10 mg per kg body weight. It was possible to calculate the pharmacokinetic parameters using a two compartment open model. The distribution volumes within the individual age groups and the rate constants k12 and k21 showed no significant differences, but the elimination half-life was significantly longer in neonates (118.6+/-16.1h) than in babies (62.9+/-5.2h) or infants (68.5+/-3.2h).


Pharmacokinetics of fluoride in man after single and multiple oral doses.

The doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a beta-slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15+/-0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 Or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%.


Immunological properties of two related fragments from human and equine growth hormones.

The immunological properties of a synthetic human growth hormone fragment comprising the amino acids 73 through 128 and of the homologous natural horse growth fragment formed by amino acids 73 through 123, have been comparatively studied. Antisera obtained in rabbits inoculated with the native human hormone or with the fragments, were used. By hemagglutination experiments both fragments have the same reactivity toward the anti-human growth hormone serum, but complement fixation curves detect the existence of at least two populations of antibodies presumably originated against the sequence 73-128 of human growth hormone. Of these, only one of the corresponding antigenic areas is present in the homologous region of equine growth hormone. The known cross-reactivity detected between both hormones is thus partially explained.


Identification of the effector cells in human blood displaying spontaneous cytotoxicity to chicken erythrocytes.

By combining velocity and linear density fractionations as well as target cell rosetting techniques we have isolated and morphologically identified the human effector cell type responsible for spontaneous, trypsin-augmentable cytotoxicity against chicken red cells and human myeloma cell line targets. This cell is a large lymphoid cell with strong alpha-naphthyl esterase activity concentrated in a limited area in the cytoplasm usually at the indentation site of a slightly reniform nucleus. Cells with this morphology also formed plaques on chicken erythrocyte monolayers. The cell is nonphagocytic and nonadherent, it carries Fc receptors but no complement receptors on its surface, and shows a weak affinity to sheep red blood cells (SRBC). The frequency of these cells based on morphological analysis is 3 x 10(4)--6 x 10(4)/ml in normal human blood. This cell shows similarities (surface Ig-, Fc+, C3-) with the human natural killer (NK) cells lytic to hematopoetic target cell lines but differs in that the cytotoxicity is augmentable by trypsin and the affinity to SRBC is lower. Therefore, we postulate that these two killer populations represent different subpopulations of human NK cells.