[Clinical effects of lividomycin on respiratory tract infections, primarily wet cases of bronchiectasis (author's transl)].

Patients with various respiratory infections, primarily wet cases of bronchiectasis, were treated with lividomycin (LVDM)  at a dose of 1 g/day for about a week. The results obtained are as follows: 1. Of the 15 patients with refractory bronchiectasis who had previously been treated with various other antibiotics, 11 patients (73.3%) responded to LVDM. Although there was no patient who responded to LVDM excellently, good cures were achieved in 5 pateints and fair cures in 6 patients. 2. In bronchiectasis patients having infections in association with pulmonary tuberculosis (mixed infections), LVDM did not show any remarkable effects, excepting that fair cures were achieved in 3 patients. 3. In the 7 patients with acute bronchopneumonia, excellent, good and fair cures were achieved in 1, 5 and 1 patient, respectively. Although LVDM was effective in all of the patients with the said infection, the number of the patients responded excellently was meager and the onset of action seemed to be somewhat slow. 4. In one patient with lobar pneumonia, LVDM was not effective. 5. The MIC values of LVDM for clinically isolated various organisms are summarized below: Pseudomonas aeruginosa 50 mcg/ml, Klebsiella pneumoniae 3.13 to 6.25 mcg/ml, Haemophilis influenzae 1.56 to 6.25 mcg/ml, Diplococcus pneumoniae 50 mcg/ml, alpha-Streptococcus 50 to 100 mcg/ml, beta-Streptococcus 100 mcg/ml, and Staphylococcus aureus 1.56 mcg/ml. 6. In spite of the fact that a majority of the patients participated in this study were the aged, LVDM's side effects were limited to an increase of BUN (one patient) and eruption (one patient). Any noticeable changes in hepatic and renal function, hearing acuity, etc. were not observed. As indicated above, LVDM was effective against, respiratory infections as well as infections of the urinary tract on which a considerable number of research has already been reported. Thus, it is considered to be worthwhile to use LVDM for the treatment of respiratory infections.


Effects of prostaglandin E2 on the electrical property of the pregnant mouse myometrium.

At any stage of gestation, low concentrations of PGE2 increased that frequency and number of spikes in a train discharge without any marked change of the membrane potential. An increased concentration depolarized the membrane and produced continuous spike generation. A further increase in concentration of PGE2 produced a depolarization block of spike generation. The sensitivity of the myometrium to PGE2 was markedly increased during the progress of gestation so that at the late stage of gestation, the sensitivity was more than 100 times greater than at the early stage. The longitudinal muscle showed a higher sensitivity to PGE2 than the circular muscle. However, both muscles showed a similar sensitivity to oxytocin. In the longitudinal muscle, desensitization to PGE2 occurred more quickly than to oxytocin. When PGE2 produced a slight depolarization of the membrane, the membrane resistance was increased. However, when the membrane potential was displaced to the control level by applying a hyperpolarizing current, the membrane resistance was slightly reduced. Displacement of the membrane potential to the level before drug application restored spike generation. However, the membrane resistance was still reduced. In Na-deficient Locke solution or in Ca-free Mg-Locke solution, the depolarization induced by PGE2 was suppressed but not suppressed by, in K-deficient Locke solution.


An intermediate in the photolytic process of extracted squid rhodopsin.

To clarify the formation process of acid metarhodopsin in the cephalopod rhodopsin cycle, changes in the difference spectrum of squid (Todarodes pacificus) rhodopsin in acid (pH 5.7, or pH 6.1) and alkaline (pH 10.2) solutions were studied at various temperatures by applying the flash photolytic technique. An intermediate with an absorption maximum at about 475 nm was transformed from lumirhodopsin prior to the formation of acid metarhodopsin independently of the pH of the solution. In alkaline solution, some of the converted acid metarhodopsins were then transformed to alkaline metarhodopsins. The conversion of lumirhodopsin to acid metarhodopsin seemed to be a first-order chain reaction.


Effects of beta-adrenergic receptor blocking agents on blood pressure in conscious hypertensive rats.

The effects of beta-adrenergic receptor blocking agents administered i.v. on the blood pressure in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and normotensive Wistar strain rats (NR) were studied. dl-Propranolol and dl-YB-2, 1 mg/kg i.v., caused a sustained rise in blood pressure in SHR and RHR. The maximum response of each beta-blocking agent after phentolamine, 10 mg/kg i.v., in SHR and RHR was significantly larger than that in NR. The potency ratio for the hypertensive activities of the 1- and d-isomers of propranolol and YB-2 was similar to the ratio of their beta-blocking activities. The pressor effects of the beta-blocking agents after phentolamine were significantly inhibited by adrenalectomy, reserpinization and pretreatment with hexamethonium. The results suggest that the pressor effect of the beta-blocking agents may be due to their beta-blocking activities and the unmasking of alpha-receptor activities of the blood vessels. Furthermore, the greater pressor effect of the agents observed in hypertensive rats is attributed to a greater activity of the sympathetic nervous system in these rats as compared to normotensive rats.


[Electric counter shock therapy as a rehabilitation stage for patients with surgically treated acquired heart diseases].

A total of 910 case-reports on electropulse treatment of fibrillation arrhythmia are analyzed in the light of rehabilitating patients operated upon for acquired heart diseases. Experience has shown that re-establishment and retention of the sinus rhythm is of decisive importance in the restitution of physical activity and capacity for work. However, investigations have confirmed that the electropulse therapy helps achieve but good immediate results, whereas the remote ones remain unsatisfactory. The problem of stabilizing the rhythm still awaits its solution. The application of agents blocking the beta-adrenoreceptors has but insignificantly reduced the incidence of recurrent episodes of auricular fibrillation.


[Some characteristics of the state of the sympatho-adrenal system in various hemodynamic variants of hypertension].

In 40 patients with umcomplicated hypertension their general haemodynamics was compared with the excretion of catecholamines and their metabolites. On the initial stage of the disease the hormonal link was found to prevail over the mediator one; the decreasing excretion of bound catecholamines after the administration of Isuprel indicates that a disbalance between the secretion and inactivation of catecholamines develops as early as on this stage of the disease. Later, in resistance hypertension the administration if Isuprel resulted in an increased excretion of free noradrenalin, which is interpreted as a sign of increased reactivity of this link; no such reaction is noted in ejection hypertension. A study of all these links of the sympathoadrenal system is important for the understanding of the pathogenesis of hypertension and for the choice of this therapy.


On the physiological functions of teichoic acids.

The choline-containing teichoic acids of pneumococci can be modified by biosynthetic replacement of the choline residues with certain structural analogues, such as ethanolamine (EA) or the N-monomethyl-(MEA) and N-dimethyl-(DEA) amino derivatives of ethanolamine. Cells containing such analogues in their teichoic acids develop pleiomorphic alterations in several physiological properties, which include resistance to detergent-induced lysis and inhibition of cell separation (chain formation). We report here the results of physiological studies on the mechanism of these two phenomena. Our results are summarized in the following: (a) Pneumococci grown on various amino alcohols produce cell walls of identical amino sugar and amino acid composition. (b) Both choline- and EA-containing teichoic acids seem to follow the same conservative pattern of segregation during growth and cell division.(c)Lysis sensitivity of pneumococci requires the juxtaposition oflysissensitive (choline-containing) cell walls and endogenous autolysin at the cell wall growth zone. (d) Upon readdition of choline to ethanolamine-containing cells, lysis sensitivity and catalytically active (C-type) autolysin reappear in the bacteria with the same kinetics. (e) The chains of EA-grown pneumococci contain fully compartmentalized cells and normal cross walls.


Alcoholic head trauma triad.

An initial description of the alcoholic head trauma triad (fatty liver, acute pneumonia and acute subdural hematoma) is presented. The basic nosological features and pathophysiological interrelationships are discussed and areas for further study delineated.


Hormonal responses in ethanol-induced hypoglycemia.

Seven patients with clinical alcoholic hypoglycemia showed suppressed pretreatment plasma insulin levels and raised concentrations of somatotropin, hydrocortisone and pancreatic glucagon. A prolonged intravenous glucose infusion failed to elicit adequate insulin output and marked hyperglycemia supervened.


Disulfiram implantation in alcoholism treatment. A review.

The literature pertaining to the use of implanted disulfiram as a therapeutic modality in the treatment of alcoholism is reviewed.


Autonomic functioning in alcoholics. A study of heart rate and skin conductance.

Heart rate and skin conductance levels and variability were measured in alcoholics and nonalcoholics during a demanding neuropsychological task. Alcoholics without possible brain damage had a more variable heart rate and were more highly aroused. In the alcoholics with possible brain damage a negative correlation between heart rate variability and performance decrement and an inverse relationship between heart rate and skin conductance variability were found.


Plasma alcohol, smoking, hormone concentrations and self-reported aggression. A study in a social-drinking situation.

Plasma alcohol concentrations and the number of cigarettes smoked by men during social-drinking situations were significantly related to change in testosterone levels. Age, height, plasma alcohol and smoking were related to self-reports of prior assault and verbal aggression. Agression was not related to testosterone concentration.


The influence of alcohol and tobacco on the components of choice reaction time.

In smokers a low dose of alcohol slightly improved decision time on a choice reaction-time task and in combination with tobacco resulted in significant improvement compared with placebo conditions. In nonsmokers decision time deteriorated significantly after a moderate dose of alcohol but not in smokers. The results are attributed to the stimulant action of a smoking dose of nicotine interacting with low levels of alcohol.


The politics of prohibition on Namoluk Atoll.

The drinking patterns and the attempt to institute prohibition during 1969-71 on Namoluk Atoll, in the Eastern Caroline Islands, are described. The question of prohibition became a symbol of an intergenerational struggle for political power, which was eventually won by the younger antiprohibitionists.


Sardines and other fried fish. The consumption of alcoholic beverages on a Micronesian island.

Drinking parties are an integral aspect of life on Etal Island, despite official sanctions against them. The parties help to preserve certain traditional community values and provide an outlet for tension caused by political and social change.


Physicians and alcoholics. Factors affecting attitudes of family-practice residents toward alcoholics.

Family-practice residents rated alcoholics as weaker, sicker and more hopeless and aimless than average persons on an adjective semantic differential, and diabetics as sicker than average persons. The implications for the diagnosis and treatment of alcoholism are discussed.


Determinants of marital happiness and unhappiness rated by alcoholics and their wives.

Alcoholic husbands and their wives generally agreed that the major aspects of marital happiness dealt with the quality of interpersonal relations. "Undesirable vices (excessive gambling, drinking, etc.)" ranked first as contributing to marital unhappiness while their absence was ranked 27.5 by the husbands and 9.5 by the wives as contributing to marital happiness. The elimination of undesirable habits may resolve much marital misery but it does not necessarily follow that as unhappiness decreases happiness will increase.


Application of MMPI alcoholism scales to older alcoholics and problem drinkers.

The MacAndrew and Holmes alcoholism scales differentiated older domiciled alcoholics and residents with disciplinary problems related to problem drinking from nonalcoholics. It is suggested that the scales can identify older problem drinkers along similar dimensions as alcoholics and that they might be applied to studying problem drinkrs who have as yet not received diagnoses of alcoholism.


Emotionality in offspring of rats fed alcohol while nursing.

Lactating dams were given liquid diets containing ethanol and their pair-fed controls identical diets with isocaloric sucrose instead of ethanol. The female offspring of mothers given ethanol were more emotionally reactive than were the female offspring of control dams.


Patient-treatment interactions among alcoholics.

The ratins of the different aspects of an alcoholism treatment program by patients before discharge revealed differences in views of the program that were related to differences in personality.


A further failure to replicate an effect of oral anesthesia on alcohol consumption by rats.

Oral anesthesia by lidocaine has been reported to increase alcohol consumption in food-restricted rats by a substantial degree. Described herein is a second unsuccessful attempt to replicate the finding.


Some correlates of Al-Anon group membership.

A husband's membership in A.A. was related to greater marital happiness, superior ability as a father and less severe drinking problems.


Revascularization of the right coronary artery by retrograde perfusion of the mammary artery. An experimental study.

Although the internal mammary artery bypass seems an ideal coronary bypass vessel, it has not usually been possible to use this vessel to bypass distal lesions in the right coronary circulation. In this experiment, the right internal mammary artery was utilized in retrograde fashion to evaluate this anatomically more suitable vessel as a bypass graft to the occluded right coronary artery in the dog. Reversal of acute myocardial ischemia was demonstrated by mapping epicardial ST-segment elevation and measuring surface pH. Preliminary long-term experiments have also demonstrated patency and perfusion of the distal right coronary artery by this method.


Oxygen dissociation after transfusion of blood stored in ACD or CPD solution.

In 20 patients undergoing open-heart surgery, 2,3-diphosphoglycerate (2,3-DPG) concentrations, oxygen affinity of hemoglobin (Po2 at half saturation of hemoglobin with oxygen [P50]), hemoglobin concentration, and pH were measured repeatedly. Measurements were made before and at various times after open-heart surgery and replacement of blood loss with blood stored in acid-citrate-dextrose (ACD) or citrate-phosphate-dextrose (CPD) solutions for less than 72 hours (10 cases per group). Infusion of ACD blood caused P50 and 2,3-DPG concentration to decrease significantly after the operation. The infusion of blood stored in CPD did not significantly increase the oxygen affinity. No significant changes in hemoglobin concentration or pH were observed immediately after the operation in either group. To compensate for the increased oxygen affinity, there must be a rise in cardiac output or more likely a decrease in venous Po2. The transfusion of CPD blood, therefore, is more favorable in terms of oxygen supply, particularly in patients who have had cardiac surgery.


The fate of internal mammary arterial implants and bypass conduits for myocardial revascularization. Experimental angiographic, histologic, and ultrastructural observations.

Experimental angiographic, histologic, and ultrastructural observations were obtained from dogs to determine the fate of internal mammary artery (IMA) implants and aorta-coronary bypass (ACB) conduits in the 3 month postoperative period. Angiographic implant patency and evidence of implants forming collaterals with the coronary circulation did not accurately reflect anatomic luminal narrowing. Subendothelial fibrocellular proliferation similar to that described in saphenous vein grafts occurred with regularity in all IMA implants and ACB conduits. The intimal changes were much more severe in the IMA implants as compared to the ACB conduits: There was 25 to 95 per cent liminal narrowing in the IMA implants, whereas the ACB conduits rarely showed greater than 25 per cent luminal narrowing. Both reduced flow and surgical trauma appeared to be influential determining factors of the intimal proliferative process, whereas devascularization alone seemed less important.


Reversal of pulmonary circulation.

The preliminary results and the technique of total reversal of the pulmonary circulation (RPC) are presented. Total RPC is technically feasible and not incompatible with life. It affords a new experimental model for in vivo study of pulmonary pathophysiology. The influence of this reversal on blood oxygenation, on pulmonary vascular resistance, and on established pulmonary hypertension, as well as its reaction to hypoxia and acidosis, needs further investigation. RPC may have clinical implications in essential pulmonary hypertension and congenital pulmonary vascular anomalies.


The influence of pulsatile perfusion on oxygen uptake by the isolated canine hind limb.

The possible advantages of pulsatile over continuous blood flow have intrigued cardiac surgeons for years. This issue may have clinical significance for moderate to long cardiopulmonary bypass procedures. In spite of aggressive investigation, this problem remains controversial. A system permitting perfusion of an isolated canine hind limb with constant flow, Pao2, Paco2, oxygen delivery, temperature, and pHa but variable stroke volume was established. Under stable conditions, oxygen uptake by the limb was constant over a wide range of stroke volumes. Regression equations relating oxygen uptake to stroke volume were calculated and found to have a near zero slope. When the hydrogen ion concentration of the blood perfusing tissue is held constant, the oxygen consumption of that tissue is independent of the pulsatile nature of the perfusing blood.


Aorta-coronary bypass grafting with the internal mammary artery: clinical experience in 70 patients.

Clincal and angiographic results in 70 patients who received free internal mammary artery (IMA) grafts are reviewed. One postoperative death occurred, but it was not related to the free IMA technique. Forty-seven patients underwent postoperative arteriography. The average interval between operation and catheterization was 10.7 months, and the patency rate for 49 free IMA grafts was 89.8 per cent. Of the 29 patients who recieved free IMA grafts as the only revascularization procedure, 21 patients (80 per cent) progressed to Functional Class I and only 5 patients did not have improvement in their functional status.


[The application of interference contrast microscopy in biology (author's transl)].

Like phase contrast, Nomarski interference contrast microscopy can be used to examine unstained specimens in biology and medicine. The properties of both contrast enhancement techniques are illustrated by various examples. The phase contrast method is especially suited for thin specimens with small differences in refractive index, whereas the interference contrast method supplies good results even of thick specimens. Interference contrast is a valuable supplement to the phase contrast method, and expands the application of microscopy in biology


ipecacuanha-ipecauanha.

A survey was conducted among patients attending the casualty department of the Adelaide Children's Hospital to find the length of time which elapsed between the ingestion of a potentially toxic substance and the institution of measures to evacuate the stomach contents. This paper demonstrates that there is often an undue delay before effective treatment is instituted. To overcome this delay, the administration of syrup of ipecacuanha in the home as a first-aid measure in the management of accidental poisoning is advocated.


Suicide in Brisbane, 1956 to 1973: the drug-death epidemic.

A study of suicide in Brisbane between the years 1956 and 1973 reveals that there was a sharp rise in the incidence of deaths from barbiturate overdosage, which reached a peak in the mid 1960s. Since then there has been a steady decline in suicide rates from drug overdose and a smaller fall in the rate of other forms of suicide. The decline in the incidence of deaths from carbon monoxide poisoning since 1967 may be due to the use of non-toxic domestic gas. The frequent association between barbiturate suicides and previous ingestion of alcohol indicates the danger of the practice and the probability that many of the victims had major drinking problems. An examination of suicide deaths and the prescribing of barbiturates, benzodiazepines and antidepressant drugs between 1962 and 1973 suggests that the fall in suicide rates was due to the better recognition and treatment of depressive illnesses and to the introduction of the safer benzodiazepines in place of barbiturates. The study indicates that placing restrictions on non-violent methods of suicide does not necessarily result in an increase in suicides from violence.


[Isoenzymes of alaninarylamidase and gamma-glutamyl-transpeptidase in intrahepatic and extra-hepatic cholostasis (author's transl)].

In 43 patients with intrahepatic and extrahepatic cholostasis alaninarylamidase (AAP) and gamma-glutamyl-transpeptidase (GGTP) in serum were measured and the isoenzymes were determined in agar-gelectrophoresis. The isoenzyme-fraction 2 (in alpha-2-globulin running) of AAP was significant higher in the group of extra-hepatic cholostasis than in the group of intrahepatic cholostasis. Practical importance of the findings is diminished by large variation coefficients of the results. The importance of isoenzymes of GGTP for differentiation of cholostasis is not large. A special low quotient of two anodic isoenzymes of GGTP (fraction running with alpha-1-globulin  to fraction running with beta-globulin) indicates probably a neoplasm of pancreatobiliary tract if there is a high level of total serum-GGTP.


The steady state activity of succinate dehydrogenase in the presence of opposing effectors.II. Reductive activation of succinate dehydrogenase in presence of oxaloacetate.

The extent of the deactivation of the mitochondrial succinate dehydrogenase by oxaloacetate is a function of the redox state of the enzyme. Oxidized enzyme is deactivated by much lower concentrations of oxaloacetate than those needed to deactivate reduced enzyme. An accurate method for measuring this relationship is the redox titration of the enzymic activity of succinate dehydrogenase, carried out in the presence of oxaloacetate. For each concentration of oxaloacetate a different redox titration curve was reported with the apparent mid-potential decreasing with increasing oxaloacetate. These results are compatible with a model which proposes that both oxidized and reduced enzymes can form the catalytically non-active complex with oxaloacetate, but that the complex formed the the oxidized enzyme is more stable than that formed by the reduced enzyme. When the oxaloacetate concentration is low, reduction of the enzyme will lower the fraction of the succinate dehydrogenase-oxaloacetate complex, a reaction which we observe as reductive activation of the enzyme. If this experiment is repeated in the presence of high concentration of oxaloacetate, no activation of the enzyme takes place, but the low stability of the reduced enzyme oxaloacetate complex is revealed by the rapid exchange of the enzyme-bound oxaloacetate with the free ligand. The rate of this exchange is extremely slow at high positive potential and becomes faster upon lowering of the poise potential. The reductive activation of the succinate dehydrogenase is regarded as a two step reaction. In the first step the reduced non-active complex releases the oxaloacetate and in the second step the active form of the enzyme is evolved. These two steps can be observed experimentally; Reductive activation at a redox potential higher than the mid-potential of the oxaloacetate-malate couple (minus 166 mV) is characterized by Ea = 18 Kca/mole, the final equilibrium level of activation decreases upon lowering of the temperature. Reduction activation of the enzyme at minus 240 mV is a very rapid reaction which goes to completion at all temperatures tested and has an activation energy of 12.5 Kcal/mole. The mechanism of the reductive activation and its possible role in the regulation of succinate dehydrogenase in the mitochondria is discussed.


Vasodilator therapy of idiopathic lactic acidosis.

Afterload reduction with sodium nitroprusside was performed in a patient with idiopathic lactic acidosis in whom sodium bicarbonate therapy had precipitated pulmonary edema. The drug reduced mean pulmonary-artery wedge pressure from 28 to 12 mm Hg, accompanied by a modest rise in left ventricular stroke work index from 33 to 43 g-m per square meter. Concomitantly, there was dramatic resolution of the metabolic acidemia, the arterial pH rising from 7.19 to 7.61, arterial carbon dioxide tension from 13 to 26 mm Hg, and bicarbonate content from 6 to 28 mEq per liter, and the anion gap falling from 32 to 11 mEq per liter. Metabolic improvement occurred despite a fall in cardiac output from 5.5 to 4.8 liters per minute. These findings support the concept that regional vasoconstriction plays a part in idiopathic lactic acidosis, and suggests that vasodilators may be an effective form of therapy for this almost uniformly fatal disorder.


Financial impact of physician assistants on medical practice.

A study of revenues generated and expenses incurred by 12 physician assistants (MEDEX) who had held salaried positions for at least one year was conducted to determine their financial impact on primary-care practices. Daily charge logs were used to make annual estimates of MEDEX-generated revenues. One method of estimating annual revenues produced a mean of $28,190 per year, and a second method yielded a figure of $30,210 per year. Financial statements were used in two different ways to estimate annual expenses related to the employment of the MEDEX. One procedure indicated average costs of employment were $15,900, and the other $20,100. Ten of the 12 practices in the study experienced substantial gains of estimated revenue over expenses ascribed to the activities of the MEDEX.


Defect in pyridine nucleotide dependent superoxide production by a particulate fraction from the cranulocytes of patients with chronic granulomatous disease.

Particulate fractions from normal human granulocytes preactivated with opsonized zymosan were found to catalyze superoxide production in the presence of reduced pyridine nucleotides. Similar preparations from three patients with X-linked chronic granulomatous disease produced no detectable superoxide. The failure to produce superoxide was not due to an inhibitor, since cell-free preparations from the patients' granulocytes had no effect on superoxide production by normal particles. Particles from the mothers of two of the patients produced superoxide at diminished rates; superoxide production by particles from the third mother was normal. These findings suggest that chronic granulomatous disease represents either a defect in a pyridine nucleotide-dependent superoxide-forming oxidase or a lesion in the apparatus responsible for activating the oxidase.


A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease.

Niemann-Pick disease is caused by a deficiency of sphingomyelinase in organs and tissues. Determinations of sphingomyelinase activity had required the use of sphingomyelin labeled with radiocarbon or radiohydrogen. These materials are expensive, and their use is restricted to laboratories with radioactive counting facilities. An analogue of sphingomyelin, 2-hexadecanoylamino-4-nitrophenylphosphorylcholine, was synthesized. This substance is hydrolyzed by highly purified sphingomyelinase, and by sphingomyelinease in extracts of human liver tissue, cultured skin fibroblasts, cultured amniotic cells and washed leukocyte preparations. Extracts of tissues and cells from patients with Niemann-Pick disease Type A do not hydrolyze this compound, whereas heterozygotes and patients with Niemann-Pick disease Type C have an intermediate level of hydrolytic activity. Thus, the analogue is a reliable chromogenic reagent for the diagnosis of patients with Niemann-Pick disease and the detection of heterozygous carriers of the Niemann-Pick trait.


Prenatal therapy of a patient with vitamin-B12-responsive methylmalonic acidemia.

Methylmalonic acidemia due to deficient synthesis of 5'-deoxyadenosylcobalamin was discovered in a mid-term fetus by culture of amniotic-fluid cells. Elevated concentrations of methylmalonic acid were also found in amniotic fluid and maternal urine. Treatment during the last nine weeks of gestation with large doses of vitamin B12 given to the mother reversed the increasing maternal excretion of methylmalonic acid, which was 23 mug per milligram of creatinine at 31 weeks' gestation. Just before delivery, the mother was excreting 5 mug, two to three times normal. At birth the methylmalonic acid content of the baby's urine (67 mug per milligram of creatinine) and serum (2.0 mug per milliliter) was only moderately elevated, and serum vitamin B12 concentration was very high. Acid levels rose in serum and urine in response to oral protein loading, but subsided after vitamin B12 administration. The infant is developing normally on a restricted protein diet alone at present. Prenatal therapy of methylmalonic acidemia is possible with large amount of vitamin B12 administered to the mother.


Decreased serum salicylate concentrations in children with rheumatic fever treated with antacid.

To determine if the common practice of giving antacids to patients on salicylate therapy has an effect on serum salicylate concentrations, we gave a widely used antacid, aluminum and magnesium hydroxide, and aspirin concomitantly to three children with rheumatic fever.  Urinary pH increased appreciably, and serum salicylate concentrations decreased by 30 to 70 per cent.  In five healthy adult volunteers concomitant administration of antacid had no effect on the bioavailability of aspirin.  Pharmacokinetic analysis revealed that the antacid-induced decrease of serum salicylate concentrations was due to increased renal clearance of salicylate caused by the rise in urinalry pH.


Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer.

Cimetidine, a non-thiourea-containing H2-receptor antagonist, was studied in seven patients with duodenal ulcer.  Oral doses of 100, 200, and 300 mg were tested.  Each dose significantly inhibited basal and meal-stimulated secretion.  After 300 mg, basal acid secretion was essentially zero for at least five hours.  The meal-stimulated three-hour acid output after the 300-mg dose was reduced by 67%. Cimetidine, 300 mg, decreased meal-stimulated acid secretion significantly more than an optimal effective dose of propantheline bromide (P less than 0.05). Inhibition of meal-stimualted gastric acid secretion showed a significant relation to peak blood cimetidine concentration (r is equal to 0.76, P less than 0.01).  Cimetidine did not affect meal-stimulated gastrin release.  No toxicity was observed after serial doses given during these tests.  Cimetidine may be useful in treatment of acid-peptic diseases provided no important toxicity appears on chronic testing.


Foam-stability test on gastric aspirate and the diagnosis of respiratory-distress syndrome.

Gastric aspirate, collected from 79 infants within 30 minutes of birth, was subjected to the foam-stability test. The lecithin/sphingomyelin ratio was determined in 27. The results were compared with the incidence of respiratory-distress syndrome as determined independently by different investigators. Of the 59 infants with a positive foam-stability test on gastric aspirate, three had transient respiratory distress, and one the respiratory-distress syndrome; 17 of 22 had lecithin/sphingomyelin ratios greater than 2.0. Of nine infants who had intermediate test results, three were normal, four had transient respiratory distress, and two had the respiratory-distress syndrome. In all the 11 infants with negative foam-stability tests the respiratory-distress syndrome developed. The three gastric aspirates tested in this group had lecithin/sphingomyelin ratios of less than 1.5. These data indicate that the foam-stability test on gastric aspirate is a reliable index of fetal lung maturity in infants whose amniotic fluid is not available.


Inhibition of growth of Aspergillus flavus and Trichoderma viride by peanut embryos.

Growth of Aspergillus flavus and Trichoderma viride on agar media was inhibited around embryos of green peanut seeds but not around embryos of cured seeds, intact peanut seeds, or testae. Both fungi were able to colonize intact seeds and testae. Substances inhibitory to A. flavus and T. viride were extracted with acetone from cotyledons of freshly harvested peanut seeds. Four compounds inhibitory to A. flavus were detected in crude acetone extracts. Three of the compounds demonstrated properties of phenolics. Results of this study suggest that inhibitory compounds in peanut cotyledons may play a role in protecting the peanut embryo from fungal infection.


Relations between the effects of histamine, pheniramin and metiamide on spontaneous motility and the formation of cyclic AMP in the isolated rat uterus.

Histamine (5 X 10(-6) to 10(-3) M) depressed the spontaneous motility of the isolated rat uterus in a dose-dependent manner. Under these conditions uterine cyclic AMP was raised up to 92%. Both effects, uterine relaxation and cyclic AMP accumulation after 2 min could be inhibited dose dependently by the H2-antihistaminic compound metiamide (1.7 X 10(-6) M to 1.7 X 10(-4) M). By contrast, the H1-antagonist pheniramin (4.4 X 10(-5) M) was ineffective. It was concluded that the histamine-induced inhibition of rat uterine motility is mediated by cyclic AMP which is formed in response to stimulation of H2-histaminergic receptors.


[Influence of pH and calcium of the environment on the electrical activity of an isolated muscle spindle].

The effects of external pH and Ca concentration were studied as applied to the receptor potential and impulse response of isolated frog muscle spindles. With a decrease in pH the amplitude and duration of the hyperpolarizing phase of the receptor potential increased, and the amplitude of the depolarizing phase decreased. The background firing anc evoked impulse activity decreased. An increase in pH decreased the amplitude and duration of the hyperpolarizing phase of the receptor potential; The background firing initially grew, then decreased up to 30-50 per cent of the standard. An increase in external Ca concentration increased the background firing in an alkaline medium and reduced the firing when pH was neutral or acid. The results are discussed in connection with possible alterations in the rate of the active (electrogenic) and passive transport of the Na and Ca ions


Fluid removal with negative-pressure hydrostatic ultrafiltration using a partial vacuum.

Removal of excessive fluid with a negative-pressure hydrostatic ultrafiltration technique using a partial vacuum was performed successfully in eight patients. The technique appears to be a satisfactory means of fluid removal.


Incomplete renal tubular acidosis: some clinical and physiological features.

17 patients with recurrent calcium-containing renal calculi were studied using the short NH4Cl test and one subject with 'incomplete renal tubular acidosis' was identified. In retrospect the only clue to this diagnosis was a fasting, morning urine pH exceeding 6.0 units. Fasting morning urine pH, which is usually less than 6.0 in subjects who acidify normally, is proposed as a simple screening test for 'incomplete RTA'. Modified high dose NH4Cl tests and Na2SO4 tests were performed in this subject and other patients with either complete or incomplete distal renal tubular acidosis. These studies suggest that the ability to lower urine pH is impaired less with the incomplete than with the complete form of the disease.


Effect of correction of metabolic acidosis on bone mineralisation rates in patients with renal osteomalacia.

The role of metabolic acidosis in the genesis of renal osteomalacia was investigated by studying bone mineralisation and resorption rates with a combined isotope and balance technique in six patients, before and after the administration of alkali. Correction of blood pH was achieved in five cases and was associated with a significant rise in the bone mineralisation rates and a significant positive trend in the calcium balances. It is suggested that acidosis contributes to the pathogenesis of osteomalacia in renal failure by slowing skeletal mineralisation, possibly by inhibiting bone alkaline phosphatase.


The significance of histamine H1 and H2 receptors on the carotid vascular bed in the dog.

Intra-arterial histamine produced a dose-dependent increase in common carotid blood flow due to an active vasodilation. A supramaximal dose of mepyramine (H1-blocker) only partially suppressed the effects of lower doses of histamine without influencing those of its higher amounts. Both metiamide and burimamide (H2-blockers) effectively antagonized the mepyramine-resistant carotid vasodilator responses to histamine. The results permit us to conclude that two distinctly different types of histaminergic receptors (H1 and H2) are present in the carotid vascular bed and both of these receptor types are equally important in subserving histamine vasodilation. This fact may explain why, despite incriminating evidence for a pathophysiologic role of histamine, the usual antihistaminic agents are rather ineffective in migrainous headaches. It is suggested that the use of both types of antihistaminic agents concurrently may provide a new approach to the treatment of migrainous headaches, particularly cluster-type headaches.


Gynecologic implications of Burkitt's tumor.

We have described what we believe to be the first patient with Burkitt's tumor of the ovary to be reported in the gynecological literature. We have also reviewed the remainder of the medical literature in regard to pathology, incidence, epidemiology and clinical characteristics.


Computer assessed fetal heart rate patterns and fetal scalp pH. A preliminary study.

From the beginning of biophysical and biochemical monitoring of the fetus during labor, a continuing attempt has been made to determine if a reliable correlation exists between these measurements and the well-being of the fetus. If such a correlation did indeed exist, the combined use of the two approaches would permit efficient, relatively simple fetal monitoring. This preliminary report describes the use of computer processed fetal heart rate patterns to predict fetal scalp blood pH. Initial results show a 90% overall accuracy in predictions; when corrected for some of the bias of retrospective predictions, the accuracy is 91% for high pH and 72% for low pH.


Maternal and fetal hemodynamic effects of diazoxide.

Effects of diazoxide on systemic and uterine hemodynamics as well as on fetal circulation and blood respiratory gases were investigated in chronically instrumented pregnant sheep. Diazoxide was administered intravenously either to the ewe or directly to the fetus in doses calculated on the basis of body weight. Transfer of drug across placenta was also investigated. Results showed that: a) when injected into the mother, there was consistent hypotensive effect with increased cardiac output and decreased systemic vascular resistance; uterine blood flow might not change or might decrease slightly with moderate hypotension; when maternal systemic arterial pressure fell to critical closing pressure level, uterine flow decreased significantly; but despite these maternal changes, the fetal circulatory functions were not significantly altered; b) when injected into the fetus in doses up to 15 mg/kg, diazoxide failed to alter fetal circulation appreciably; c) diazoxide crossed the placenta when injected intoeither mother or fetus according to a definite gradient; fetal levels were always lower than maternal levels because of rapid loss of the drug by the fetus; d) moderate maternal and fetal hyperglycemia occurred after drug administration.


Experiments of the origins of optical activity.

Two recent reports claim that (1) aqueous L-aspartic acid polymerizes faster than D-Asp in the presence of kaolin at 90 degrees, and (2) L-phenylalanine is adsorbed by kaolin more extensively than D-Phe at pH 4(the reverse  being true at pH2). The novelty of these observations and their potential significance for the origin of optical activity has prompted us to duplicate these experiments using more sensitive methods. L- and D, L-Asp in 0.01 M solution were incubated with kaolin at 90 degrees for 8 days. Careful examination of the aqueous residues from such experiments failed to demonstrate any preferential polymerization of L-Asp over D-Asp, or indeed any significant gross polymerization of Asp at all. In other experiments 0.001 M solutions of  D, L-Phe at pH 6 and pH 2 were stirred with large excesses of kaolin for 24 hr, and the aqueous extracts from these mixtures were examined for gross adsorption using the amino acid analyzer. No significant gross adsorption was noted. We then looked for asymmetric adsorption in the aqueous residues using optical rotatory dispersion, gas chromatography and thin layer chromatography. By none of these analytical criteria could we find any evidence whatsoever for the preferential adsorption of D- versus L-Phe from either pH 6 or pH 2 solutions. Finally, in experiments bearing on the origin of optical activity by parity violation during beta-decay, we have irradiated solid samples of D-, L- and D,L-leucine in a 61700 Ci Sr-90 source at Oak Ridge National Lab. for 1.34 yr (total dose: 4.2 x 10(8) rad). Gas chromatographic examination of the (appropriately derivitized) recovered samples showed that the L-Leu was 16.7% decomposed, the D-Leu 11.4% and theD,L-Leu 13.8% decomposed. The recovered D,L-Leu sample had a gas-chromatographically determined enantiomeric composition of 50.8% D-leu and 49.2% L-Leu. These data, though very close to experimental error, may indicate a slight preferential radiolysis of L-Leu compared to D-Leu by the Bremsstrahlung from Sr-90 beta-decay. These high intensity irradiation experiments are being continued on a prolonged basis in order to reach more definitive conclusions.


[Study of individual variations of the composition of human parotid saliva collected under stimulation].

Human parotid saliva was studied for its qualitative and quantitative composition; alpha-amylase activity, immunoglobulin A and composition were investigated and showed significant variations from one individual sample to another. The same phenomenon was observed with the inorganic components: CA, P, K, Mg, Na, Cl. The influence of the frequency and length of collection of parotid saliva is discussed.


An outbreak of acute hemorrhagic conjunctivitis in Yugoslavia in 1973.

An outbreak of approximately 200 cases of acute hemorrhagic conjunctivitis is described in Prekmurje, a northern province in Yugoslavia. The epidemic was caused by enterovirus type 70, serologically identical with the causative agents of similar outbreaks in London and Japan. The origin of the outbreak could not be elucidated but a link was seen between this case and a small outbreak in Veenendaal in the Netherlands.


Coacervate-like microspheres from lysine-rich proteinoid.

Microspheres form isothermally from lysine-rich proteinoid when the ionic strength of the solution is increased with NaCl or other salts. Studies with different monovalent anions and with polymers of different amino acid composition indicate that charge neutralization and hydrophobic bonding contribute to microsphere formation. The particles also form in sea water, especially if heated or made slightly alkaline. The microspheres differ from those made from acidic proteinoid but resemble coacervate droplets in some ways (isothermal formation, limited stability, stabilization by quinone, uptake of dyes). Because the constituent lysine-rich proteinoid is of simulated prebiotic origin, the study is interpreted to add emphasis to and suggest an evolutionary continuity for coacervation phenomena.


Conditions of occurrence for primeval processes of transphosphorylations.

Model reactions of the phosphate group transfer through hydrolysis-condensation processes without enzymic catalysts are studied in dilute aqueous solutions. Tripolyphosphate and acetylphosphate are used as energy and phosphate donors to perform syntheses of pyrophosphate. Results are discussed in terms of the variation versus pH of the overall standard free enthalpy change.


Some physical parameters controlling cell size during the evolution of the procaryons.

Possible factors controlling cell size during the evolution of unicellular organisms have been examined. It has been shown that considerations of osmotic and membrane pressure eqilibria will predict minimal cell sizes which are in good agreement with those found in present day microorganisms. It has also been shown that the possibility of random proton 'noise' would not be a limiting factor for even the smallest organisms or structures. Maximum cell size would be governed by the requirements of diffusion and transport within the cell.


Studies on cystic fibrosis using isoelectric focusing. I. An assay for detection of cystic fibrosis homozygotes and heterozygote carriers from serum.

We have developed a standardized biophysical assay for the rapid detection of individuals homozygous or heterozygous for cystic fibrosis (C/F). The assay employs isoelectric focusing in thin layer polyacrylamide gels to analyze microliter quantities of whole serum for the presence of a C/F factor protein and for deletions in a group of proteins called proteins B, C, and D (Fig, 1). A pH 5-10 gradient is used (Fig. 2) and each sample is screened using a serum volume which contains 300 micrograms immunoglobulin G (IgG). Individuals homozygous or heterozygous for C/F are distinguished from normal unaffected individuals on the basis of the presence of a C/F factor protein band (Table 1). Heterozygous carriers for C/F are distinguished from C/F homozygotes 75 percent of the time, on the basis of a deletion in either band B, C, or D (Table 2). On the basis of screening 65 patients with cystic fibrosis, 61 heterozygous carriers for C/F, and 105 normal control subjects, it was concluded that no obvious correlation existed between either sex, age, or severity of the disease in the individual C/F patient, and the absolute presence or absence of the C/F factor. In addition, no correlation existed between sex or age and the presence of the C/F factor or deletions in proteins B, C, and D in the individual heterozygous carrier for C/F or normal control subjects. Analysis of serum samples from 68 patients with a variety of other diseases, many with clinical symptoms resembling those seen in the patient with cystic fibrosis (Table 3), indicated that the C/F factor protein described in this study appears to be diagnostic for C/F genotypes, with the possible exception of patients with certain types of leukemia.


Studies of methylmalonyl coenzyme A carbonylmutase activity in methylmalonic acidemia. I. Correlation of clinical, hepatic, and fibroblast data.

Methylmalonyl-CoA carbonylmutase (mutase) activity was measured in fibroblast extracts from 15 patients with methylmalonic acidemia and in extracts of postmortem tissues from 6 of these children. Propionate oxidation and synthesis of 5-deoxyadenosylcobalamin (AdoCbl, the vitamin B12 coenzyme that is part of the mutase holoenzyme) were measured in intact fibroblasts. Mutase activity was low in the absence of added AdoCbl in fibroblast extracts from both control subjects and patients. When the assay included supplemental AdoCbl, mutase activity increased in the control subjects (to 24.0 pmol succinate/mg protein/min) and in extracts from eight of the patients (20.8 pmol/mg protein/min), but showed almost no change in extracts from the other seven patients (0.16 pmol/mg protein/min). We have defined the eight fibroblast lines that showed normal mutase activity in the presence of AdoCbl as "responsive lines" and the other seven lines as "nonresponsive." In the liver or kidney extracts of postmortem tissues, mutase activity responded to AdoCbl supplementation if fibroblast mutase activity from that patient had responded, and failed to respond if fibroblast activity failed to respond. Mean propionate oxidation in intact fibroblasts was much higher in control lines than in either responsive or nonresponsive lines (0.728 vs 0.097 vs 0.080 nmol CO2/10(6) cells/hr, respectively). AdoCbl synthesis was normal (0.27 pg AdoCbl/mg cells wet weight) in nonresponsive fibroblasts but was undetectable (less than 0.005 pg/mg cells) in the responsive lines. Thus, the deficiency of mutase activity in responsive fibroblast lines is due to the failure to synthesize significant amounts of AdoCbl, whereas the deficiency in nonresponsive lines is due to some other abnormality, presumably a defect in the mutase apoenzyme.


Ccomparison of cisternal and lumbar cerebrospinal fluid pH in high altitude natives.

Samples of cisternal or lumbar cerebrospinal fluid were obtained from 20 young male volunteers born and living at high altitude (3500 to 4800 m). The pH, carbon dioxide and oxygen tensions, and bicarbonate concentration were measured and compared with those in the arterial and jugular venous blood. A consistent difference between the two CSF compartments was noted, particularly a lower pH (0.05), a higher PCO2 (7 Torr), and a lower PO2 (7 Torr) at the lumbar site. Mean bicarbonate concentration was not significantly different at the two sites. The main factor is PCO2, which controls the pH variation. These differences were more marked in high-altitude natives than in man at sea level. The existence of a consistent inhomogeneity of CSF acid-base content emphasizes the inaccuracy of using lumbar CSF pH to estimate the ECF pH as regulator of pulmonary ventilation and determinant of cerebral blood flow.


Lactic acid permeation rate in working gastrocnemii of dogs during metabolic alkalosis and acidosis.

In isolated, blood perfused, supramaximally stimulated, isotonically working gastrocnemii of dogs lactic acid (LA) output and O2-consumption (V O2) were measured according to the Fick principle. Simultaneously concentration of muscle tissue was determined at rest and at different times during exercise. In one series of experiments metabolic alkalosis was induced by infusions of THAM of Na bicarbonate. As a result arterial pH increased to about 7.5 and standard [HCO3-1] to 31-35 mmol per 1. In another group of experiments metabolic acidosis was induced by HCl infusions. In these experiments pH decreased to 7.0-7.1 and standard [HO301] to 8-11 mmol per 1. During the first 3-4 min after the onset of exercise LA concentration of muscle tissue rose to 18-19 mumol per g wet weight in both series of experiments. During acidosis the highest average values for LA release from the muscle were about 1.1 mumoles per g per minute. During alkalosis LA permeation rate was nearly three times as high. As a consequence of increased rate of permeation, LA concentration of muscle tissue decreased more rapidly in alkalosis than in acidosis. In both series of experiments work per time and VO2 were practically equal during the first 5-6 min of exercise. Thereafter work per time and VO2 decreased more rapidly in acidosis than in alkalosis, a result which probably is due to higher LA concentration in muscle at this time in acidosis. It is concluded that LA permeation rate across muscle cell membrane is increased by high extracellular HCO3- concentration in combination with low H+ activity and vice versa.


Renin measurement in blood collected from the efferent arteriole of the kidney of the rat.

Plasma renin could be detected in 16 nl of rat plasma by incubating at 50 degrees C, pH 6.2 with 20 mul of a rat renin substrate. In 60 nl samples it could be estimated and differences in concentration of 20% could be detected. Plasma renin concentration was measured in blood from the superficial efferent arterioles of a rat's kidney. The concentration of renin in different efferent arterioles of the same rat were similar. The renin concentration of efferent arteriolar blood was 361 plus or (-1)89 (S.D.) ng Al ml minus 1 (blood) hour (-1) which was not different from the renin concentration of simultaneously taken femoral artery blood (340 +/- 217). Plasma concentration can be measured in efferent arteriolar blood and will allow the control of renin secretion to be studied.


Remote-controlled device for sampling arterial blood in unrestrained animals.

A device is described that allows remote-controlled sampling of arterial blood in unrestrained animals. An artery and a vein are dissected in local anesthesia and connected by a plastic catheter, the sampling catheter. The flow of arterial blood in this artificial shunt can be blocked by kinking the sampling catheter by a remote-controlled device. The blood thus trapped in the sampling catheter, of 0.45 ml volume is analyzed for PO2, PCO2, and pH using electrodes. The technique has been used in ducks and hens but can be applied to other vertebrate classes and to species of smaller body size.


Microperfusion study of the kinetics of reabsorption of cycloleucine in early and late segments of the proximal convolution of the rat nephron.

The proximal tubular reabsorptive capacity for the non-metabolizable amino acid, cycloleucine, was studied in the rat nephron by stationary microperfusion. Tubular reabsorptive rates were greatest near the glomerulus and declined progressively along the convolution. A kinetic analysis of cycloleucine reabsorption in terms of luminal concentration revealed that this reduced transport rate was associated with an increase in the half-saturation constant of the kinetic curve, rather than a decrease in the maximum transport capacity. Since our previous findings with the metabolizable amino acid, -L-histidine, were identical we can conclude that this decline in reabsorption of neutral amino acids as a function of distance along the convolution is an intrinsic property of the transport system and is not related to tubule cell amino acid metabolism. The transport curves for cycloleucine absorption did not give a simple Michaelis-Menten relation but rather followed a course suggesting that more than one transport system might be involved.


Studies on deoxyribonucleases from Saccharomyces cerevisiae. Characterization of two endonuclease activities with a preference for double-stranded DNA.

Two new endonuclease activities, endonuclease B and endonuclease C, obtained from yeast nuclear preparations have been separated and partially characterized. Endonuclease B has a primary requirement for Mn2+ which cannot be replaced by Mg2+ or Ca2+, and makes single-strand scissions in double-stranded DNA. Endonculease C is activated by either Mn2+ or Mg2+, and makes single-strand scissions with Mg2+, while with Mn2+, scissions are made which result in double-strand breaks. Neither enzyme is active on denatured DNA, and both are inhibited by yeast RNA. Both enzymes exhibit pH optima at pH 5.0 and PH 7.2, and leave 5'-phosphoryl termini.


Interaction of Mg2+ ions with nucleoside triphosphates by phosphorus magnetic resonance spectroscopy.

The interaction of Mg2+ with nucleoside triphosphates: ATP, GTP, CTP and UTP has been studied by phosphorus magnetic resonance spectroscopy in aqueous solution. The results show that these four nucleotides behave similarly. Purine and Purimidine bases have almost no effect on the phosphate groups even in the N7 pK region of ATP and GTP. The Mg2+ ion binds not to the alpha and alpha but only to the beta phosphate group. The fixation is stronger at neutral pH than at acid pH.


Nucleoside 5'-phosphordiamidates, synthesis and some properties.

A simple way of preparing nucleoside 5'-phosphordiamidate is described. The procedure is based on the ammonolysis of nucleoside 5'-phosphordichloridates by dilute aqueous ammonium hydroxide. The behaviour of nucleoside phosphordiamidates under acidic and alkaline conditions is also reported. Alkaline hydrolysis results in the formation of the parent nucleoside, whereas one amide group can be removed selectively by mild acid hydrolysis. This property of nucleoside phosphordiamidates served as a basis for the elaboration of a simple synthesis of nucleoside phosphoramidates starting from nucleosides.


Effect of disulfiram and sodium diethyldithiocarbamate on tyrosine and dopamine-beta-hydroxylases activities in rat brain and heart.

Tyrosine hydroxylase and dopamine (DA)-beta-hydroxylase activities in rat brain and heart after disulfiram (DS) or diethyldithiocarbamate (DDC) administration have been determined in vitro and in vivo. DS and DDC in vitro stronger inhibit DA-beta-hydroxylase than tyrosine hydroxylase activity. 50% inhibition of tyrosine hydroxylase activity needed about twice higher concentrations of DS and DDC than the same inhibition of DA-beta-hydroxylase. Inhibition of the above enzymes in the in vivo experiments was DS or DDC dose dependent.


Dependence of tyrosine and dopamine-beta-hydroxylases activities on disulfiram and diethyldithiocarbamate level in guinea pig brain and heart.

Tyrosine hydroxylase and dopamine-(DA)-beta-hydroxylase acitvities in guinea pig brain and heart were determined at various time after disulfiram (DS) and sodium diethyldithiocarbamate (DDC) injections. In the same tissues DS and DDC levels were measured. The linear relationship between the above enzymes activities and the levels of DDC in brain and heart has been found. The inactivation of the both enzymes is dependent on DDC content in tissues.


The central action of drugs affecting beta-adrenergic receptor. IV. The influence of intraventricularly administered drugs affecting beta-adrenergic receptor on blood pressure in rats.

Isoprenaline, propranolol, alprenol and sotalol administered intraventricularly (ivc) to anaesthetized rats induce hypotension. Propanolol and alprenolol given ivc to rats pretreated with isoprenaline increase blood pressure up to the values equal to those, previous to isoprenaline administration; another isoprenaline dose acts slightly hypotensively.


Purification of rabbit liver guanine aminohydrolase.

Rabbit liver guanine aminohydrolase has been purified 1250-fold by utilization of an affinity chromatographic separation on 9-(p-aminoethoxyphenyl) guanine-Sepharose with 50% recovery of activity. Polyacrylamide gel electrophoresis of the purified preparations revealed several protein bans which corresponded to regions of enzyme activity measured on gels which had been run under the same conditons. Gel concentration studies of the protein migration rate showed that the protein bans differed in molecular size. The minimum molecular weight was 100,000 from gel permeation chromatography studies. The pH optimum was near pH 8 and the Km, with guanine as substrate was 5.6 x 10-6 M. The latter values are in close agreement with partially purified preparations described in the literature.


1-Haloacylpiperazines.

By direct acylation of piperazine with halogenocarboxylic acid chlorides in acid medium, the hydrochlorides of 1-haloacylpiperazines were obtained.


Lipoteichoic acid: a specific inhibitor of autolysin activity in Pneumococcus.

The choline-containing pneumococcal lipoteichoic acid (Forssman antigen) is a powerful inhibitor of the homologous autolytic enzyme, an N-acetylmuramyl-L-alanine amidase (EC 3.5.1.28, MUCOPEPTIDE AMIDOHYDROLASE). Low concentrations of deoxycholate can reverse the inhibition. Wall teichoic acid preparations are inactive at several hundred-fold higher concentrations. Activation of an inactive form of autolysin by in vitro incubation with choline-containing cell walls is also inhibited by lipoteichoic acid. Addition of lipoteichoic acid to the growth medium of pneumococcal cultures causes chain formation, resistance to stationary phase lysis, and penicillin tolerance. It is suggested that a physiological role of lipoteichoic acids may be in the in vivo control of autolysin activity.


Separation of two responses to auxin by means of cytokinin inhibition.

A continuous growth apparatus was used to measure the effect of cytokinin on auxin-induced elongation. The soybean hypocotyl segments elicited a bi-phasic response to auxin that appeared to be two overlapping responses. The first response, which began 12 min after auxin addition, was not inhibited by cytokinin, even after long preincubation in cytokinin, but the second response to auxin, which began about 30 min after auxin addition, was completely inhibited by cytokinin. Such overlapping reactions are shown, depending on the amount of overlap, to yield a variety of summation reactions, many of which resemble rate-time curves that have been previously reported. We have shown that the transient first phase of auxin-induced elongation is very similar to acid-activated growth, while the second phase is long lasting and very likely identical to the long-term response to auxin, as extensively studied in Avena, soybean, and other elongating cells.


Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

The antischizophrenic activity of phenothiazine drugs and their tendency to elicit extrapyramidal symptoms are thought to involve blockade of synaptic dopamine receptors in the brain. Space filling molecular models show how favorable Van der Waal's interactions between the side chain amino of phenothiazines and the 2-substituent on ring A can promote a conformation mimicking dopamine. These Van der Waal's attractive forces can expain (i) the greater potency of drugs with trifluoromethyl rather than chlorine as a 2-substituent; (ii) the enhanced activity of phenothiazines with piperazine instead of alkylamino side chains; (iii) the increased potency associated with hydroxyethylpiperazines as contrasted to piperazine side chains; (iv) the greater potency of cis rather than trans thioxanthenes; and (v) the crucial location of the ring A substituent at carbon no. 2. Potential energy calculations support the observations with molecular models and suggest an active conformation for the phenothiazines.


Increased particulate and decreased soluble guanylate cyclase activity in regenerating liver, fetal liver, and hepatoma.

We determined the activities of soluble and particulate guanylate cyclase [GTP pyrophosphatelyase (cyclizing); ?EC 4.6.1.2] IN REGENERATING RAT LIVER, FETAL AND NEONATAL RAT LIVER, AND HEPATOMA. TIn these tissues we found increased particulate and decreased soluble enzyme activities compared to normal adult rat liver. The particulate activity increased 12 hr after partial hepatectomy, reached maximal activity at 48 hr, and then declined. The soluble enzyme activity decreased within 8 hr and continued to decline. The activity of homogenates did not change. Guanylate cyclase activity was increased in plasma membrane and microsome fractions from regenerating liver. The increase in particulate activity was prevented with cycloheximide. Decreased soluble and increased particulate enzyme activities were found in fetal liver. After birth the soluble activity increased and the particulate activity decreased. Seven to 14 days after birth the activities of soluble and particulate fractions were similar to those of adult rat liver. In hepatoma 3924A, the activity of particulate guanylate cyclase was 9-fold greater and that of the soluble enzyme was 50% that of normal liver. These studies suggest that guanylate cyclase activity and its subcellular distribution may be related to liver growth through some unknown mechanism.


Cell surface changes accompanying viral transformation: N-acetylneuraminic acid ectotransferase system activity.

The activity of the sialyl ectotransferase system of normal chick embryo fibroblasts (CEF) and chick embryo fibroblasts transformed with the Schmidt-Ruppin strain of Rous sarcoma virus (SR-RSV) have been compared. Neuraminidase treatment of the intact cells increased the sialyl ectotransferase system activity of control and transformed cells two to three times. The ectotransferase system activity increased as the pH was decreased from 7.8 to 6.0. The temperature optimum for both systems was 40 degrees C. Approximately 60% of the 14C-sialic acid incorporated at pH 6.5 or above could be removed with neuraminidase. The activity of the transformed cell system with or without neuraminidase treatment was more stimulated by addition of Mn2+ ions, particularly above pH 7.0. This difference in ion sensitivity indicates that a different cell surface phenomenon is being studied after transformation.


Studies of properties and potential applications of some soluble salts of cellulose acetate phthalate. Part 1: rheological behavior and aging effect.

Rheological behaviour for solutions of the sodium, ammonium, and triethanolamie salts of cellulose acetate phthalate was studied. The comparative resistance to microbial growth and to changes in pH values exhibited by these solutions on storage was also investigated. The results indicated that the viscosities of these solutions were temperature and concentration dependent and that increasing the rate of shear produced only a slight increase of viscosity. Solutions of ammonium and the triethanolamine salts did not support any apparent microbial growth during storage at room temperature of three weeks, but the sodium salt appeared to suffer from microbial contamination. However, the use of a mixture of 0.15% methylparaben and 0.05% propylparaben prevented such contamination. The pH values of all the slat solutions studied appeared to decrease on storage.


Factors effecting drug release from inert matrices. Part 1: effects of surfactants on the release of quinine sulfate.

Dissolution rate studies of quinine sulfate from polyamide matrices, in simulated gastric and intestinal fluids, are carried out in the presence of hexadecyltrimethylammonium bromide, sodium lauryl sulfate and polyoxyethylene (50) stearate surfactants. The results obtained show that dissolution rate is dependent upon the pH of the disolution media and the type and concentration of surfactant. The solubilization effect of surfactants is also examined and the findings are discussed.


Characterization of the rabbit detrusor response to histamine through pharmacologic antagonism.

The various effects of histamine on smooth muscles and other tissues are thought to be mediated by two pharmacologically distinct receptors, H1 and H2 types. These receptors are defined in terms of thier susceptibility to blockade by pyrilamine (type H1) or burimamide (type H2). In this study selective antagonism of the spasmodic effects of histamine on isolated strips of rabbit detrusor has shown that the response is mediated by H1 receptors, with no evidence of H2 activity. The p-A2 of the pyrilaminehistamine antagonism is 9.3. The histamine response is susceptible to muscarinic blockade (atropine and propantheline) but not to nicotinic blockade (hexamethonium). Adrenergic blocking agents propranolol (10 minus 4 M) and phenoxybenzamine (10 minus 8 M) do antagonize the contractile response, but this does not appear to be indicative of adrenergic mediation.


Effect of release of endogenous gastrin on myoelectrical and mechanical activity of isolated canine stomach.

The myoelectrical and mechanical activities of the totally isolated, canine stomachs were recorded using five sets of bipolar silver-wire electrodes and one strain gauge. Stomachs were perfused extracorporeally with the blood of living supporting dogs which served as oxygenators and dialysers. Each supporting dog had a permanent antral pouch, accessible for the purpose of irrigation. To suppress the release of endogenous gastrin, this antral pouch and the antrum of the ex vivo stomach were irrigated with acid (pH 3). To induce the release of gastrin, one or both antra were irrigated with 0.2-percent acetylcholine or with 1 M glycine. To compare the action of endogenous gastrin with exogenous gastrin-like peptide, pentagastrin was infused into the gastric artery in doses of 4 mug/h and 8 mug/h. Control recordings were done during the acid irrigation. Endogenous gastrin released from antra by acetylcholine or glycine caused identical changes in the recordings as exogenous pentagastrin. There was a marked increase in the frequency of electrical control activity and of gastric contractions recorded as increased mechanical response. The results indicate that the ex vivo stomach can be used for study of the effect of endogenous gastrin musculature activity under the experimental conditions described.


Evaluation of a new oral beta2-adrenoceptor stimulant bronchodilator, terbutaline.

A double-blind crossover comparison was made of the effect of orally administered terbutaline (a new adrenergic drug with major action on beta2-receptors), ephedrine, and placebo in 15 patients with obstructive airways disease. Serial determination of ventilatory tests, arterial gas tensions, arterial blood pressure, ECG, blood chemistries, and urinalysis were made before and after administration of the tested drug. Terbutaline (5 mg) was found to be an effective bronchodilator with minimal side effects and an earlier onset and longer duration of action than ephedrine (25 mg).


Network analysis of dendritic fields of pyramidal cells in neocortex and Purkinje cells in the cerebellum of the rat.

The connectivity within the dendritic array of Purkinje cells in the cerebellum and pyramidal cells of the neocortex of the rat, stained by the Golgi-Cox method, has been quantified by the method of network analysis. Connectivity was characterized either by applying the system of Strahler ordering, which assigns a relative order of magnitude to each branch of the arborescence or by the identification of unique topological branching patterns within the tree. The former method has been used to define the entire dendritic array of the Purkinje cell and the apical system of neocortical pyramids. It has been shown that the relation between the numbers of branches of successive Strahler order in Purkinje cells form an inverse geometric series in which the highest order is unity and the ratio between successive orders approximates to 3. On the other hand, the apical dendrites of neocortical pyramids exhibit two bifurcation ratios, i.e. a ratio of 3 between low orders and a ratio of 4 between higher orders. A computer simulation technique was used to generate networks of a size comparable with the Purkinje cell networks and grown according to two hypotheses namely, a 'terminal growth model' in which additional segments were added randomly to the terminal branches only and a 'segmental growth model' in which additional segments were added randomly to any branch within the array including terminal branches. Subsequent ordering of the simulated trees revealed that the relation between the numbers of successive orders for networks generated according to the 'segmental model' tended towards an inverse geometric series with a ratio of 4 and that generated according to the 'terminal model' tended towards a ratio of 3. This result showed that the dendritic tree of Purkinje cells grow in a manner indistinguishable from a system adding branches to random terminal segments and that neocortical apical dendrites add their collateral branches to random segments of the apical shaft but that the collateral branches themselves grow by random terminal branching. The possibility that such conclusions may be influenced by loss of branches incurred by either a failure of impregnation, by sectioning, or by environmental influences was investigated by means of a computer technique...


The behavioural final common path.

In this paper it is argued that any model of the motivational (i.e. reversible) processes governing the behaviour of an animal can be represented by means of isoclines in a multidimensional 'causal-factor space'. The argument is axiomatic, based upon the two prime assumptions: that (1) it is always possible to classify the behavioural repertoire of a species in such a way that the classes are mutually exclusive in the sense that the members of different classes cannot occur simultaneously, and (2) these incompatible actions are uniquely determined by a particular set of causal factors. The isoclines join all points in the space which present a given 'degree of competitiveness' of a particular 'candidate' for overt behavioural expression. The competition between candidates is an inevitable consequence of the fact that animals cannot 'do more than one thing at a time', and is envisaged as taking place in the behavioural final common path. An empirical method of determining the motivational state (i.e. point in causal-factor space) is outlined. This is a 'relative' method, independent of the arbitrary calibration of the axes of the causal-factor space. It is shown that an arbitrary scale of measurement along any two axes of the causal-factor space is all that is necessary for empirical determination of the shape of a motivational isocline. Experiments in which this method has been applied to the measurement of hunger and thirst in doves are outlined, and the results are discussed in terms of their implications for motivation theory in general.


Composition and structure of the pericellular environment. Physiological function and chemical composition of pericellular proteoglycan (an evolutionary view).

Connective tissue cells exist in a meshwork of insoluble fibres, the interstices of which are filled with soluble, high molecular mass, anionic material of a predominantly carbohydrate nature. The interactions of fibres with the interfibrillar material are central to the discussion of connective tissue physiology. As with all soluble polymers, the interfibrillar polyanion tends to "swell' and the tangled mass of chains offers considerable resistance to penetration by the large insoluble fibres. The consequent pressure to "inflate' the fibrous network is important in giving elasticity to cartilage, transparency to cornea, etc. Branched structures (of proteoglycans) and straight-chain forms (of hyaluronate) are compared for their ability to fulfil these functions. Apart from their physical ("non-specific') roles proteoglycans and glycosaminoglycans are able to interact physicochemically with, for example, collagen in ways which show considerable specificity, and which presumably are important in the laying down of the fibrous network as well as in maintaining its mechanical integrity. It is proposed that the role played by radiation, particularly as mediated via the hydrated electron (eaq) was dominant in the pre- and post-biotic evolution of pericellular environments.


Structural and histochemical aspects of the pericellular environment in cartilage.

Mature cartilage contains pericellular regions of matrix of fine texture, consisting of filamentous material and granules containing proteoglycan. Intercellular matrix contains collagen fibres with structural elements resembling those of the pericellular regions in the spaces between the fibres. Membrane bound bodies may be present at the margin of the pericellular region. Histochemically, chondroitin sulphate is found in the pericellular region in all zones but keratan sulphate is similarly stainable only in the deep zones of ageing cartilage.


Connective tissue cells, cell proliferation and synthesis of extracellular matrix-a review.

The ubiquitous connective tissues contain a wide range of cells including fibroblasts, osteoblasts and chondroblasts. Recently it has been demonstrated that another principal cell of the connective tissue is the smooth muscle cell in several organ systems. These have been shown to be responsible for the synthesis of the connective tissue matrix components of the uterine myometrium and of the arterial system, including collagen, both elastic fibre proteins and glycosaminoglycan. Microtubule inhibitors such as colchicine and vinblastine, and iron chelators such as alpha,alpha -dipyridyl have been used to study their morphologic and chemical effects on collagen synthesis and secretion. Colchicine produces an increase in large Golgi-associated vacuoles, which sometimes contain material reminiscent of aggregates of collagen macromolecules. Vinblastine produces alterations in the endoplasmic reticulum cisternae similar to alterations seen in ascorbic acid deficiency, and alpha,alpha-dipyridyl increases the frequency of regions in cells, interpretable as potential sites of communication of rough endoplasmic reticulum cisternae with the cell surface. Ferritin conjugated anti-procallagen sera were used to localize procollagen in cells and demonstrated procollagen not only in the cisternae of rough endoplasmic reticulum but in all of the elements of the Golgi complex as well. The studies reported in this review have shown that in cell culture arterial smooth muscle will produce not only the microfibrillar protein of the elastic fibre but soluble and/or insoluble elastin as well. Recent studies on serum factors responsible for the proliferation of connective tissue cells have demonstrated that at least one of the principal factors responsible for fibroblast and/or smooth muscle cell proliferation in culture is derived from thrombocytes. Medium containing serum derived from cell-free plasma lacks most of this proliferative effect which can be reinstated when platelets are present during recalcification to form serum. This effect is due to the platelet release reaction as shown by combining supernatant factors derived from platelets exposed to purified thrombin to cell-free, plasma derived serum. Studies with macrophages have also suggested that phagocytic macrophages release factor(s) into a cell culture medium that may also participate in stimulating fibroblasts to proliferate in vitro. The means by which these factors stimulate fibroblast proliferation and connective tissue synthesis remains to be elucidated.


Measurement of pH and ionic composition of pericellular sites.

The development of ion selective microelectrodes has made it possible to measure the normal steady state in the pericellular environment together with ion fluxes in response to physiological or pathological disturbances. Combined intracellular and extracellular measurements indicate that there is a considerable range of ability between various types of cells in the efficiency with which they can tolerate changes in pericellular conditions. Macrophages are extremely tolerant while cells of the cerebral cortex require a very finely controlled local environment. Combination of ion selective probes with microelectrodes which measure substrate and oxygen availability extend the information which can be obtained about ionic composition of cellular environment and the factors which are important in its homostasis.


Electrostatic interactions at the plasma membrane.

Hydrogen-ion titration has been used to detect the presence of charged groups on the human red-cell plasma membrane. The findings are discussed in terms of the effect of the local environment on electrostatic interactions between the charged groups.


Influence of the cells on the pericellular environment. The effect of hyaluronic acid on proteoglycan synthesis and secretion by chondrocytes of adult cartilage.

The chondrocyte is a specialized cell that synthesizes proteoglycans of a type found only in cartilage and nucleus pulposus. These proteoglycans are distinct in forming multiple aggregates of unique structure in which hyaluronic acid provides a central chain to which many proteoglycan molecules are bound at one end only. Chondrocytes were isolated from adult cartilage and used in suspension culture to test the effect of compounds in the medium on the synthesis of proteoglycans. Hyaluronic acid alone, among a number of compounds extracted from or analogous to those in cartilage, reduced the incorporation of [35S] sulphate into macromolecular material. Oligosaccharides of hyaluronic acid of the size of decasaccharides and above also had this effect but hyaluronic acid already bound to proteoglycan did not. The proportion of total labelled material associated with the cells increased at the expense of that in the medium. Treatment of the cells with trypsin abolished the effect of hyaluronic acid but treatment with chondroitinase did not. It is suggested that hyaluronic acid interacts with proteoglycans at the cell surface by a specific mechanism similar to that involved in proteoglycan aggregation, as a result of which the secretion and synthesis of proteoglycans is reduced.


Glycosaminoglycan turn-over in articular cartilage.

Glycosaminoglycan turn-over has been studied both in vivo and in vitro, by using sodium [35S]sulphate as a precursor. The in vivo experiments were performed on rabbits and dogs, taking special care to monitor the 35S radioactivity in the serum throughout the experiment and to measure the radioactivity due to unincorporated inorganic [35S]sulphate in cartilage at the end of each experiment, in addition to that due to incorporated sulphate. The inorganic sulphate content of the serum was also determined as well as the distribution coefficient for the inorganic sulphate ion between cartilage and serum. From this information it was possible to calculate accurately the rate of sulphate uptake by cartilage in vivo and hence the turn-over rate. Experiments were then performed in vitro on cartilage from rabbits and dogs and the in vivo and in vitro results were compared. A very good agreement was obtained between the two sets of results. Studies were then carried out under exactly the same in vitro conditions on human articular cartilage and it was thus possible to obtain a turn-over rate for the latter which one could trust was close to the actual in vivo value. The mean half-lives thus obtained varied from 45 days for the young rabbit to 150 days for the adult dog and 800 days for the human femoral head. In human cartilage there were considerable variations in turn-over rate within a single joint as a function of depth below the surface, and between different joints. Thus, while the mean half-life for the human femoral head is 800 days, that for the femoral condyle is 300 days. Cartilage from osteoarthrosic femoral heads did not appear to differ much with respect to sulphate uptake from the normal specimens although the turn-over rates were somewhat higher.


The secretion of enzymes into the pericellular environment.

Connective tissue cells are capable of both synthesizing and degrading the macromolecular components of the extracellular matrix. The degradation of proteoglycan and collagen has been shown to be associated with the extracellular release of proteolytic enzymes, some of which are of lysosomal origin. The identity in carilage of two previously unrecognized proteases, capable of proteoglycan breakdown (CPGases), has recently been achieved by the use of a new assay for proteoglycan degradation. These enzymes have been shown to be synthesized and released in response to vitamin A. The third proteoglycan degrading enzyme of connective tissue cells, cathepsin D, has been located in the pericellular environment by trapping with specific antibody and the pattern of release studied in organ culture, experimental arthritis and in human rheumatoid tissues. The secretion of this enzyme and possibly also of the other CPGases is thought to be of importance in the local (pericellular) turnover of matrix macromolecules and, in association with collagenase, to be the cause of the excessive degradation in the pannus erosion of articular cartilage in rheumatoid arthritis.


Influence of the pericellular environment on the cells. The role of mucopolysaccharides in the protection of cartilage cells against immune reactions.

Problems related to rheumatoid arthritis have been investigated by a group at Cambridge using the organ culture technique. Since auto-allergic reactions may be concerned in the chronicity of the disease, the effects of reactive complement-sufficient antisera (AS+C') on embryonic and post-foetal cartilage were examined. The cartilaginous limb bone rudiments enlarged to several times their original volume in control medium, but in the presence of AS+C' they gradually disintegrated, owing to the breakdown of the cartilage matrix; only the superficial cells of the enveloping soft connective tissue were killed, however. Provided breakdown had not advanced too far, the effects of AS+C' were reversible. It was not clear how AS+C' produced these changes, since cartilage matrix is impermeable to molecules as large as the immunoglobulins. To find whether there was a difference in permeability between embryonic and post-foetal cartilage, similar experiments were made on the articular cartilage of young pigs. AS+C' had no effect on pure articular cartilage, and it was shown immunohistochemically that IgG did not penetrate beyond the most superficial layer of cartilage. When, however, the explant was associated with soft connective tissue either as invading marrow or as an adjacent explant of synovium, the cartilage matrix was depleted of proteoglycan; IgG antibodies then entered the cartilage and reacted with the chondrocytes. After a lapse of 8-10 days, collagen also began to break down. If the degradation of collagen was not too extensive, the changes were reversible. Pure cartilage was depleted of proteoglycan by trypsinization and then cultivated in AS+C'. All the chondrocytes reacted with the IgG antibodies. The peripheral cells were killed, but those in the interior survived and rapidly secreted pericellular capsules rich in proteoglycan, which shielded them from further contact with antibodies. In other experiments, pure cartilage was associated with a synovial explant and cultivated in AS+C' for 10 days; this caused severe depletion of the matrix. The synovial tissue was then removed and the isolated cartilage cultured for a further 10 days in either AS+C' or control medium. If mainly proteoglycan had been lost during the primary culture period, breakdown did not continue in AS+C', and sometimes a little new matrix was regenerated, though less than in control medium; if, however, the collagen had been extensively degraded, breakdown continued even in control medium. It is suggested that in both the embryonic and post-foetal cartilage, degradation of the cartilage matrix was due to the enzymatic activity of the associated soft connective tissue which caused a loss first of proteoglycan, which enabled antibodies to reach the chondrocytes, and then of collagen. The possible relevance of these results to the pathogenesis of rheumatoid arthritis is discussed.


The existence during gestation of an immunological buffer zone at the interface between maternal and foetal tissues.

In mammalian pregnancy the trophoblast normally constitutes an uninterrupted boundary of foetal tissue in immediate contact with maternal tissue, including blood in some species, and is the decisive immunological barrier to rejection of the foetus as an allograft. The ability of the trophoblast to function as a barrier evidently results from its capacity to resist immunological attack by either alloantibody or alloimmune cells and to prevent immunocompetent cells from reaching and damaging the foetus but, as yet, there is no general agreement regarding the means by which it exercises these functions. In view of the dramatic hormonal changes that occur during pregnancy and the undisputed involvement of trophoblast in these endocrine events, the possibility exists of an interaction between the hormones of pregnancy and the immunological phenomena. The present account furnishes evidence that endocrine activity at the maternal surface of the trophoblast, the presumptive site of the immunological frontier between foetus and mother, may be a factor in its local survival at implantation. The placental hormones so far known that are capable of blocking the antigen receptor sites of the mother's lymphocytes and thus preventing the latter from reacting with the foetal antigens are the glycoprotein, human chorionic gonadotrophin (HCG) and the polypeptide hormone, human chorionic somatomammotrophin (HCS) or human placental lactogen (HPL), both of which are specific to the human placenta. The origin of these hormones, their spatial distribution and their probable interaction with placental steroid hormones are discussed. It is argued that the place of highest concentration of these hormones is on the surface of the syncytial microvilli and the adjacent caviolae of the apical plasma membrane, as well as on the surfaces of the persisting cytotrophoblastic cells of the basal plate (cytotrophoblastic shell), the cell islands and the septa-precisely where the immunological challenge of the foetal allograft to the maternal host occurs. An explanation is offered for the continuing production of the voluminous quantities of these hormones during human pregnancy.


The relation between connective tissue cells and intercellular substances, including basement membranes.

Basement membranes are distributed widely in the body forming an extracellular matrix for epithelial and endothelial cells. The collagenous and glycoprotein constituents of basement membranes are synthesized by these two cell types. Disturbance of the interactions between basement membranes and their associated epithelial and endothelial cells can lead to the pathological changes seen in diseases involving basement membranes. These changes are illustrated here by reference to glomerulonephritis induced by the deposition of immune complexes in the glomerulus of the kidney, and chronic inflammatory changes occurring in the lung after inhalation of asbestos. In these diseases basement membrane changes can occur in several ways. Hydrolytic enzymes released from inflammatory cells degrade basement membranes while other constituents by epithelial and endothelial cells. Alternatively the physical separation of epithelial and endothelial cells from their basement membrances by space-occupying substances such as immune complexes can interfere with feedback mechanisms leading to synthesis of basement membrane constituents and cell proliferation. Studies of these pathological changes at a cellular level should shed new light on the ways in which cells interact with their pericellular environment.


A possible model for cell-cell recognition via surface macromolecules.

Alternative possibilities for the establishment of the proper cell distribution during embryogenesis are summarized at the beginning, followed by an assessment of the examples known so far where cell-cell recognition is known to be mediated via cell surface components. In the second part the species-specific recognition process which occurs during the sorting-out of dissociated sponge cells is analysed since it may serve as a possible model for cell-cell recognition in higher animals. Three possible mechanisms for the establishment of proper cell distribution are considered. These include, first, chemotaxis: secondly, guidance of cell or cell sheet  movement by extracellular matrix or by surrounding cells and thirdly, random movement followed by recognition at the final point of destination. Recognition is necessary for both of the two latter processes, i.e. for cell guidance as well as for locking the cells into their final position after random movement. Two basically different recognition mechanisms should be distinguished from each other. On the one hand cells may recognize each other with the help of macromolecules situated in or just outside of the plasmamembrane which fit to each other like enzymes and substrates or antibodies and antigens. On the other hand, cells may exchange information by exchanging cytoplasmatic components via vesicles or gap junctions. The species-specific aggregation of dissociated sponge cells is considered to be a possible model for cell-cell recognition in higher animals. A proteoglycan-like intercellular macromolecule called aggregation factor seems to mediate recognition of a given species of cells in the reaggregation process of dissociated cells. The data available at the present time suggest that a monovalent surface macromolecule (baseplate) may mediate the recognition process probably by recognizing the carbohydrate side chains of the multivalent proteoglycan aggregation factor. A cell-free system was devised to mimic this aggregation process. Addition of aggregation factor to baseplate-coated sepharose beads of approximately the size of the original sponge cells has essentially the same characteristics as the cellular system. Macromolecule-coded surface information for the recognition between cells has not been established during the embryogenesis of higher animals and remains an interesting challenge.


Role of the cell surface in selection during transport of proteins from mother to foetus and newly born.

The transport of immunoglobulins from mother to foetus and newly born mammal involves selective events which are independent of molecular size, related to immunoglobulin class, structure, and species of origin, and involve considerable protein degradation. Such events are briefly described as background information to a discussion of how selection of proteins might take place during transport across the cellular barriers concerned, namely the yolk sac splanchnopleur, chorio-allantoic placenta, and small intesting. Until recently the Brambell hypothesis has been the most favoured explanation. This implies that selection occurs intracellularly, within endodermal cells of the yolk sac splanchnopleur and small intestine, and within the syncytiotrophoblast of the chorio-allantoic placenta, of certain species. It also suggests that specific receptors are present which give attached proteins protection from degradation when the vesicles containing them fuse with lysosomes; such protected proteins are then liberated from the vesicle by exocytosis. This hypothesis is examined in the light of what is now known about the mechanism of uptake and transport of proteins by the endodermal cells and syncytiotrophoblast. It is suggested that rather than being an intracellular event, involving protection from proteolytic degradation, selection takes place at the cell surface. Evidence is presented, some direct and some circumstantial, that proteins may be selectively endocytosed by coated micropinocytotic vesicles, and non-selectively endocytosed through a complex apical canalicular system leading to macropinocytotic vesicle formation. In the small intesting of the suckling rat these two processes appear to be segregated, selective uptake occurring in the proximal half and non-selective uptake occurring in the distal half. In the endodermal cells of the rabbit yolk sac splanchnopleur, and by implication in the syncytiotrophoblast of man and monkey, it is suggested that both selective, and non-selective, uptake of protein occurs. Non-selective uptake into macropinocytotic vesicles is regarded as an event leading to complete degradation of all contained protein and functioning so as to supply the foetus and newly born mammal with essential amino acids. Selective uptake into coated micropinocytotic vesicles is regarded as an event leading to the transport of immunoglobulins across the cell without any contact with lysosomes, and functioning so as to supply the newly born mammal with protection against invasive organism. Specific receptors are still required but only for the initial uptake and segregation of proteins into coated micropinocytotic vesicles. The role which the glycocalyx might have in such selective binding of proteins is considered and possible difficulties in characterization of specific receptors brought to light in view of the likely overwhelming need for non-specific binding to effect non-selective uptake.


Inhibition of adenosine 3',5'-monophosphate phosphodiesterase by nicotinamide and its homologues in vitro.

Inhibition of cAMP phosphodiesterase from rat liver by nicotinamide and its homologues was studied. Among the several compounds tested, such agents as nicotinamide, N2-ethylnicotinamide, N2-methylnicotinamide, N,N-diethylnicotinamide, 3-acetylpyridine, methylnicotinate, and ethylnicotinate showed potent inhibition of cAMP phosphodiesterase, with an over 90% inhibition by 5 mM ethylnicotinate when cAMP was used as substrate at a 0.48 x 10(-7) M concentration. A comparison of the inhibitory curves of theophylline, papaverine, and ethylnicotinate on enzyme activity showed them to be approximately coincident. Furthermore, the plots with abscissa of equal increments per concentration of ethylnicotinate in the presence of theophylline or papaverine coincided with that in the absence of these agents.


Fractures of the mandible. A review of 909 cases.

During a 5-year period, 909 fractures of the mandible were treated by the Department of Plastic Surgery at Groote Schuur Hospital in Cape Town. A simple technique based on Gilmer wiring was evolved to deal with those fractures where sufficient teeth were present. This technique is extremely simple and proved efficacious.


Neurotransmitter content of mouse brain after inactivation by microwave heating.

Mice were sacrificed by either microwave inactivation of brain enzymes or by cervical dislocation. The norepinephrine, serotonin, 5-hydroxyindoleacetic acid and homovanillic acid content of the brains of the irradiated animals was significantly greater than that of the conventionally sacrificed controls.