Kinetics of dimerization of the variable fragment of the Bence-Jones protein Au. The dimerization of the variable fragment of the Bence-Jones protein Au was examined in phosphate buffers at pH 6.8-6.9 And ionic strength of 0.1 M or 0.2 M at 20 degrees C. The dimerization constant was about 1 X 10(5) M-1. The reaction enthalpy was positive and the process was entropy driven. The association and dissociation rate constants were 9 X 10(6) M-1 s-1 and 1.5 X 10(2) s-1 respectively. Temperature-jump experiments exhibited the presence of two isomers of the dimer, which are present at equilibrium in a ratio of about 1:1. Isomerization occurred with a half-life of about 0.1 s.


Some properties of phospholipid exchange proteins from rat liver. The phospholipid exchange proteins of rat liver that catalyze the transfer of phosphatidylcholine and phosphatidylinositol from rat liver microsomes to liposomes, have been purified and characterized. Two proteins were detected with dual specificities catalyzing the transfer of both phosphatidylinositol and phosphatidylcholine. Both proteins showed a strong preference for phosphatidylinositol transferring 8 to 9 times as much of the microsomal phosphatidylinositol pool as the microsomal phosphatidylcholine pool. The two proteins had iso-electric points of 5.1 and 5.3 and were purified 300-fold and 500-fold, respectively. A protein that catalyzed specifically the transfer of phosphatidylcholine, was purified 7000-fold. This protein had an iso-electric point of 8.4 and a molecular weight of approximately 16000 calculated from Sephadex G-50 chromatography and sodium dodecylsulfate-polyacrylamide gel electrophoresis; the amino acid composition was determined. An antiserum against this protein was raised in rabbits. Treatment of a rat liver supernatant fraction with the antiserum immunoglobulin fraction demonstrated that 60% of the phosphatidylcholine transfer activity is due to this protein.


Snake venom toxins. Purification and properties of low-molecular-weight polypeptides of Dendroaspis polylepis polylepis (black mamba) venom. Twelve low-molecular-weight proteins, of which eleven have subcutaneous LD50 values of less than 40 mug/g mouse, were purified from Dendroaspis polylepis polylepis venom. Ion-exchange chromatography on Amberlite CG-50 and ion-exchange chromatography on carboxymethyl-cellulose and/or phosphocellulose was used for the purification. The amino-terminal sequences of these proteins were determined and used to indicate that five groups of low-molecular-weight polypeptides are to be found in black mamba venom. Proteins from two of these groups which have low toxicity individually, when used together show synergism, in that their toxicity in combination is greater than the sum of their individual toxicities.


The binding of specific ligands to adenosine-triphosphate phosphoribosyltransferase. Ligand binding by adenosine-triphosphate phosphoribosyltransferase was studied by different methods. 200000 daltons of enzyme bound approximately 3 molecules of histidine cooperatively with a Hill plot slope of 1.23 (half-maximal binding at 520 muM). AMP increased the affinity of the enzyme for histidine (half-maximal binding at 80 muM). In the presence of AMP the binding of histidine was strongly cooperative with a Hill plot slope of 2.3. The transferase binds a little more than 3 molecules of AMP per hexamer of enzyme with a dissociation constant of the transferase-AMP complex of approximately 25 muM. ATP was able to displace radioactive AMP from the enzyme only at a concentration ratio of 25 in favour of ATP. The transferase bound 3 molecules of ATP per 200000 daltons to an inhomogeneous population of sites, or by a mechanism of negative cooperativity. The binding of phosphoribosyladenosine triphosphate took place preferably at 1-2 sites per hexamer of enzyme, depending on several factors including the magnesium concentration.


Isolation of a crosslinked cyanogen-bromide peptide from insoluble rabbit collagen. Tissue differences in hydroxylation and glycosylation of the crosslink. A radioactive peptide has been isolated from cyanogen bromide digests of sodium boro[3H]-hydride-reduced collagen from rabbit bone, tendon and skin. It was identified as a crosslinked peptide linking the short C-terminal cyanogen bromide peptide alpha1-CB6B (17 amino acid residues) to alpha1-CB5 (37 residues) from the helical part of the chain of an adjacent molecule. Both peptides could be separated after cleaving the crosslink with periodate. Thus the crosslinked peptide alpha1-CB5 X alpha1-CB6B originates from an intermolecular crosslink between quarter-staggered molecules within collagen fibrils previously assigned as 'head-to-tail' link. The chemical nature of the reduced crosslinking component was identified and was shown to differ between peptides derived from different tissues: alpha1-CB6B X alpha1 CB5 from bone contains hydroxylysinohydroxynorleucine [o5Lys(o5omegaNle)] whereas the skin peptide contains hydroxylysinonorleucine [o5Lys(omegaNle)]. The peptide derived from tendon contains both components. The relation of o5Lys(omegaNle) to o5Lys(o5omegaNle) in the peptides corresponds to that of the original tissue. On the other hand, histidino-hydroxymerodesmosine which is a major reduced cross-linking component in skin and tendon, is completely absent in the isolated peptides. The crosslinking component in the skin peptide is completely glycosylated, mainly by glucosylgalactosyl residues and to a smaller extent by galactosyl residues. o5Lys(o5omegaNle) from the bone peptide is only partly glycosylated, containing equal amounts of the disaccharide and monosaccharide. Only slight glycosylation was found in the tendon peptide.


Daunorubicin inhibition of DNA-dependent RNA polymerases from Ehrlich ascites tumor cells. Two different forms of DNA-dependent RNA polymerase have been solubilized and purified from nuclei of Ehrlich ascites tumor cells. The purification procedure involves ammonium sulfate precipitation and gel filtration on Sephadex G-25. The separation of A and B activities is achieved by chromatography on DEAE-cellulose. Nuclei are prepared from cells, sensitive or resistant to daunorubicin. RNA polymerases A and B have an absolute requirement of divalent cations for activity. Native DNAs are better templates than heat-denatured DNAs for RNA polymerase A. On the contrary heat-denatured DNA is more transcribed than the native one by RNA polymerase B. The low level of transcription of total and nucleolar ascites DNAs is due to the DNA, the same results being obtained with ascites and calf thymus RNA polymerases A and B. The inhibitory action of daunorubicin on RNA polymerases A and B from Ehrlich ascites tumor cells has been studied in vitro. The same results are obtained with enzymes extracted from sensitive or resistant cells. Daunorubicin does not inhibit the binding of RNA polymerases to the DNA template, but prevents the transformation of the DNA-daunorubicin-RNA-polymerase unstable complex into the highly stable one. This inactive ternary complex has a dissociation rate faster than the stable complex formed without daunorubicin. The size of the RNA synthesized in the presence or absence of daunorubicin is the same.


Substrate specificity of the ultraviolet-endonuclease from Micrococcus luteus. Endonucleolytic cleavage of depurinated DNA. The ultraviolet-endonuclease isolated from Micrococcul luteus, specific for pyrimidine dimers, is able to attack not only ultraviolet-irradiated DNA (leading to 3'OH-5'PO4 single-strand breaks) but also superhelical covalently-closed circular DNA of phage lambda damaged by heating at 70 degrees C, pH 5.93. The number of endonuclease-sensitive defects in the DNA corresponds to the number of alkalilabile bonds (apurinic sites) induced by heating. Competition between ultraviolet-induced lesions and apurinic sites for ultraviolet-endonuclease is demonstrated; the affinity of the enzyme for pyrimidine dimers is about three times that for apurinic sites. Both activities of the ultraviolet-endonuclease are inactivated at 50 degrees C at the same rate. The ultraviolet-endonuclease is able to reduce the infectious activity of depurinated lambda DNA towards Ca2+-treated uvr+ and uvr A Escherichia coli cells. It is concluded that both pyrimidine dimers and apurinic sites can be recognized by one and the same enzyme (the ultraviolet-endonuclease).


The transient-state kinetics of two-substrate enzyme systems operating by an ordered ternary-complex mechanism. Transient-state kinetic equations, applicable to single-turnover experiments with limiting amounts of substrate and catalytic-suicide experiments with substrates in excess to enzyme, have been derived for two-substrate enzyme reactions occurring by an ordered ternary-complex mechanism. The relative magnitude and dependence on substrate concentrations of rates and amplitudes for the exponential transients corresponding to this mechanism. It is shown that ordered ternary-complex reactions under standard assay conditions may exhibit a biphasic transient rate behaviour, and the precise conditions under which two transients can be detected are described and discussed.


The effects of temperature and some inhibitors on the carnitine exchange system of heart mitochondria. 1. 11-Trimethylamino-undecanoyl-L-carnitine (Ki = 56 muM) and 6-trimethylaminohexanoyl-L-carnitine (Ki = 1.3 mM) are competitive inhibitors of the ox heart mitochondrial carnitine exchange system. The latter is itself a poor substrate, with a V about 0.7% of that for carnitine. These compounds have been used as 'stop inhibitors' in a study of the effect of temperature on the carnitine exchange. 2. The carnitineout in equilibrium carnitinein exchange has a temperature coefficient (Q10) of 8.5 and an activation energy of 176 kJ/mol which is constant from 0 degrees - 18 degrees C. The Km for L-carnitine (5.3 mM) is also constant over this temperature range. 3. The slow efflux (leak) of mitochondrial L-[14C]carnitine in the absence of external substrate has a similar temperature dependence and is also inhibited by 11-trimethylamino-undecanoyl-L-carnitine. It is probably mediated by the same system as the very much faster exchange with external carnitine.


4-Alkyldihydroflavin: coenzyme synthesis and modification of flavodoxin. A stable (i.e. non-oxidisable), reduced flavocoenzyme, 4a-(n-propyl)-4a,5-dihydro-riboflavin 5'-monophosphate, has been synthesized. The method of choice was selective photo-allylation in position 4a. Stabilization of this substituent was achieved by hydrogenation after N(5) protection, while hydrogenation of the unprotected compound would have led to removal of the allyl substituent. The mode of this substituent mobility has been checked with deuterated photosubstrate. Upon hydrogenation, the allyl substituent becomes firmly and irreversibly fixed to the flavin surface. The diastereomers thus formed have been separated and characterized by their ultraviolet, circular dichroic and nuclear magnetic resonance spectra. After subsequent side chain phosphorylation it has been shown that only one of the diastereomeric dihydro-flavocoenzymes is firmly bound by Peptostreptococcus elsdenii apoflavodoxin. This leads to the hypothesis that (a) the non-planar 4a,5-dihydro-flavin isomer and, therefore, C(4a) as active flavin center, may have biological relevance, while (b) the flavin site in flavodoxin is accessible to some extent for a stacking interaction with a redox-partner group.


Reiteration frequency of the histone genes in the genome of the amphibian, Xenopus laevis. Radioactive RNA was obtained from Xenopus laevis gastrula-stage embryos which had been labelled by microinjection of [3H]uridine. A 9-12-S RNA fraction was isolated by phenol extraction of whole embryos followed by sucrose gradient centrifugation of the RNA and polyacrylamide gel electrophoresis. This RNA was identified as histone mRNA on the basis of its chemical and physical properties. On polyacrylamide gels the labelled RNA could be subfractionated into different components with electrophoretic mobilities similar to those of histone mRNAs of the sea urchin. 9-12-S RNA lacked poly(A) sequences. In a protein synthesis system in vitro the RNA fraction directed the synthesis of the histones H4, H2A, H2B, H3 and, possibly, of H1 protein. The Xenopus gistone mRNA was challenged with Xenopus DNA under conditions of vast DNA excess. A cot1/2 of between 110 and 250 mol-s-1(-1) was obtained from the RNA trace curve, indicating that the histone genes were 20-50-fold reiterated in the haploid genome of the species. This value indicates that although amphibians have several embryological and morphological features in common with sea urchins, the reiteration frequency for Xenopus histone genes is closer to the value of 10-20 established for mammals than the value of 400-1000 determined for sea urchins.


Error structure of enzyme kinetic experiments. Implications for weighting in regression analysis of experimental data. Knowledge of the error structure of a given set of experimental data is a necessary prerequisite for incisive analysis and for discrimination between alternative mathematical models of the data set. A reaction system consisting of glutathione S-transferase A (glutathione S-aryltransferase), glutathione, and 3,4-dichloro-1-nitrobenzene was investigated under steady-state conditions. It was found that the experimental error increased with initial velocity, v, and that the variance (estimated by replicates) could be described by a polynomial in v Var (v) = K0 + K1 - v + K2 - v2 or by a power function Var (v) = K0 + K1 - vK2. These equations were good approximations irrespective of whether different v values were generated by changing substrate or enzyme concentrations. The selection of these models was based mainly on experiments involving varying enzyme concentration, which, unlike v, is not considered a stochastic variable. Different models of the variance, expressed as functions of enzyme concentration, were examined by regression analysis, and the models could then be transformed to functions in which velocity is substituted for enzyme concentration owing to the proportionality between these variables. Thus, neither the absolute nor the relative error was independent of velocity, a result previously obtained for glutathione reductase in this laboratory [BioSystems 7, 101-119 (1975)]. If the experimental errors or velocities were standardized by division with their corresponding mean velocity value they showed a normal (Gaussian) distribution provided that the coefficient of variation was approximately constant for the data considered. Furthermore, it was established that the errors in the independent variables (enzyme and substrate concentrations) were small in comparison with the error in the velocity determinations. For weighting in regression analysis the inverted value of the local variance in each experimental point should be used. It was found that the assumption of proportionality between variance and valpha (where alpha is an empirically determined exponent) was a good approximation for the weighting. The value of alpha was 1.6 in the present case. The weight function was tested in the fitting of a rate equation to a kinetic-data set involving variable substrate concentrations. Recommendations are given regarding the establishment of the error structure in a general case and its application in regression analysis.


Epoxides derived from various polycyclic hydrocarbons as substrates of homogeneous and microsome-bound epoxide hydratase. A general assay and kinetic properties. A general assay for epoxide hydratase using epoxides derived from polycyclic aromatic hydrocarbons as substrates is described. Addition of dimethylsulphoxide to the incubation mixture after incubation allowed unreacted epoxide and its phenolic by-product to be extracted into light petroleum whilst the product dihydrodiol remained in the aqueous phase. The product was then extracted into ethyl acetate and estimated radiochemically. This assay gave low extraction blanks (0.8-3.8%) when six K-region epoxides of polycyclic hydrocarbons were used, with high recoveries of the corresponding dihydrodiol in the ethyl acetate phase (65-89%). Radiochromatograms demonstrated that all the radioactivity in the ethyl acetate extracts of active incubations above that of boiled enzyme blanks was confined to a single band that always cochromatographed with the authentic trans-dihydrodiol. Using this assay, the kinetic parameters of six K-region epoxides were estimated. In all cases the apparent Km was low (2-5.9 muM). This is about 100-fold lower than the known apparent Km of epoxide hydratase for styrene oxide, an alkene oxide that is widely used as a substrate for epoxide hydratase. The rate of hydration varied with the substrate. Thus the maximum velocity for hydration of phenanthrene 9,10-oxide greater than 7-methylbenz[a]anthracene 5,6-oxide approximately benz[a]anthracene 5,6-oxide approximately benzo[a]pyrene 4,5-oxide greater than 3-methylcholanthrene 11,12-oxide greater than dibenz[a,h] anthracene 5,6-oxide. This relationship between the individual epoxides was found in microsomal fractions from both rat skin and rat liver, although the activity was always much lower in skin microsomes. All six arene oxides derived from polycyclic hydrocarbons were substrates for the homogeneous epoxide hydratase that was isolated from rat liver microsomal fractions using styrene oxide, an alkene oxide, as substrate to follow the purification.


A case for the medical administrator of an intensive therapy unit to be trained in intensive therapy. It is suggested that there should be available post-graduate training schemes for members of the profession who ultimately wish to work on an Intensive Therapy Unit at Consultant level. The duties of the Medical Unit administrator are described and schemes are suggested for further training of an anaesthetist or physician particularly interested in critical patient care.


A modified balance chart -- ordering and charting intravenous fluids by "B numbers". Most difficulties with intravenous fluid charting are due to the inability to identify which bottle/bag on the balance sheet corresponds to the bottle/bag on the order sheet. These can be eliminated by allocating every bottle/bag a number in sequence and charting intravenous fluids in START and FINISH columns against a time scale. Accumulation of the Running Total minimises arithmetical errors as only two numbers are added together on any one occasion. A definitive balance form and order sheet, printed on both sides of a single sheet of A4 paper illustrates the "B Number" method with a reasonably complicated example of fluid balance.


The management of septic abortion in an intensive care unit. The value of ICU treatment in the management of septic abortion has been assessed. Of patients subjected to hysterectomy, the mortality is now 20%, as opposed to 37% prior to the advent of ICU. It would therefore appear that these patients can benefit from intensive nursing and medical attention.


Bacteroides infection in a patient requiring extracorporeal membrane oxygenation. A case of fulminant bacteroides plus anaerobic streptococcus bacteraemia is reported. Therapy included the use of extracorporeal membrane oxygenation for the resultant acute respiratory failure. The problem of bacteroides infections is reviewed.


A study of mortality and urinary excretion of oxalate in male rats following acute experimental intoxication with diethylene-glycol. Preliminary report. Acute intoxication by diethylene glycol (LD 50) in male rats is associated with a considerable urinary excretion of oxalate, which is significantly decreased by alkalinisatin and/or intraperitoneal injection of ethanol with hydration. Mortality during the five days following intoxication is significantly decreased by major hydration only or together with pyridoxine administration, but is cancelled by major hydration together with alkalinisation or intraperitoneal administration of ethanol, plus hydration, with or without alkalinisation. -- It might be inferred that diethylene glycol has the same metabolic pathway as ethylene glycol and treatment of acute intoxication by diethylene-glycol should be the same as that of acute poisoning with ethylene glycol.


Studies of malformation syndromes of man XXXXIIB: mother and son affected with the ulnar-mammary syndrome type Pallister. We report mother and son with the ulnar-mammary syndrome type Pallister: both had postaxial polydactyly in one upper limb and absence or hypoplasia of the axillary apocrine glands bilaterally. The mother had total lack of the mammary gland tissue and absence of one kidney. Her son also had unilateral oligodactyly, an absent ulna and hypoplasia of the ipsilateral shoulder girdle.


The syndrome of partial trisomy 14q.

The syndrome of partial trisomy 14q. The case of a 4-month-old male with de novo partial trisomy for chromosome 14 involving the p13 leads to q24 portion is reported. He presented with growth and psychomotor retardation, peculiar facies due to nose-mouth anomalies, monolateral microphtalmia, high arched palate, and anomalies of hands and feet. These symptoms are found also in the other 8 cases of partial trisomy 14 reported in the literature. This confirms a characteristic chromosomal syndrome although the breaking points on the extra chromosome 14 are not the same in the 9 cases. The clinical picture of our case calls for careful investigations of the chronology of bone age and of the immunologic situation in further cases of total and partial trisomy 14.


Septicemia in the newborn due to gram-negative bacilli. Risk factors, clinical symptoms, and hematologic changes. The case histories of 17 newborns developing septic shock due to gram-negative bacilli were studied for pre- and perinatal risk factors, clinical symptoms, and hematologic changes. Immaturity, resuscitation procedures, and hypothermia on admission were found to be the risk factors most frequently preceding septicemia. A skin color fading and changing from reddish-pink to yellow-green was the most early noticeable clinical symptom in all patients. The total leukocyte counts as well as the relative proportion of bands increased significantly at the onset of illness. When septicemia advanced, a marked drop of leukocytes was found, while the relative proportion of bands increased further. Only 1 in 12 cases showed a decrease in the platelet counts at the height of septicemia. A procedure for the early diagnosis of a neonatal septicemia is proposed: (1) Registration of perinatal risk factors. (2) With perinatal risk factors a skilled and attentive clinical observation is necessary. Particular attention should be paid to changes of skin color. (3) White blood cell picture: (a) every day in patients with perinatal risk factors and (b) every 6 h in patients showing suspicious symptoms.


Development of subcutaneous fat in infancy. Standards for tricipital, subscapular, and suprailiacal skinfolds in german infants. In order to assess the nutritional status of healthy infants in Berlin, the tricipital (TRI), subscapular (SCA), and suprailiacal (SIL) skinfolds were measured at several instances (2--14 times) during regular presentations at the well baby clinic offices in 265 infants of normal gestation, 140 boys and 125 girls, using the Holtain skinfold caliper. The characteristic pattern of skinfold development in infancy includes a rapid increase in width of all diameters until 3--5 months of age, and a gradual decrease thereafter. This diminution of skinfold thickness is more pronounced at the trunk (SIL and SCA) than at the limbs (TRI), indicating a change in distribution of subcutaneous tissue during infancy. Compared to the present study, previous investigations in Great Britain and Sweden have shown a maintenance of maximal skinfold values rather than a decrease during the second half of the first year. It is suggested that differences of feeding habits and calorie intake may be responsible for these discrepancies. The results of this mixed longitudinal study, performed in 1974/1975, were computed to calculate centile curves of the skinfold development in infancy, which may serve as standards for infants living under similar socioeconomic and nutritional conditions.


Laurence-Moon-Biedl syndrome (?) and Prader-Willi syndrome (?) in a single family. Mental retardation, hypogonadism, obesity, and abnormal blood sugar regulation were common findings in two siblings. In addition, the 17-year-old female patient showed short stature, muscular hypotonia in infancy, and small hands with tapering fingers suggesting Prader-Willi syndrome, and the 12-year-old male patient showed retinitis pigmentosa, normal height, and normal muscular tonicity suggesting Laurence-Moon-Biedl syndrome, though polydactyly was absent. Possible consideration was discussed.


Trisomy 8 mosaicism. A case report and a proposed list of the clinical features. A 16-year-old boy with trisomy 8 mosaicism is presented. Increased birth weight, delayed psychomotoric and accelerated somatic development, and mental retardation were noted; he exhibited a prominent forehead, a broad-bridged upturned nose, an everted lower lip, low set dysmorphic ears, strabismus, slender trunk, narrow pelvis, osseous and joint anomalies, clinodactyly, deep skin furrows on the soles, and agenesis of the corpus callosum. The trisomic cell line was observed throughout the follow-up examinations from the fibroblast cultures between 1962 and 1973, but has disappeared from the lymphocyte culture. The clinical picture of this case is compared with the leading clinical signs and symptoms of the 25 cases with confirmed trisomy 8 so far published. A scheme is proposed in order to keep in mind the clinical picture suggesting trisomy 8.


Apnea in premature infants: recording by arterial catheter. Respirations and apnea were recorded through an arterial catheter and observed simultaneously in 13 premature infants. Based on simultaneous clinical observation and characteristic recordings of preapneic and apneic periods, three distinct mechanisms of evolution of apneic spells were noted. Studies to elucidate pathophysiologic changes during apnea should recognize varied mechanisms of their origin.


Multiple sclerosis and measles: a study of cellular sensitization. Lymphocyte sensitization to measles has been studied in comparable groups of multiple sclerosis, other neurologic disease and normal subjects. The macrophage electrophoretic mobility test has been used. No difference between the three groups has been found, though there is a small group of children with obscure neurological disease which might well be multiple sclerosis and which fails to mount an adequate response to measles. The role of measles (and other banal infections) in aetiopathogenesis of multiple sclerosis is briefly discussed.


Reduced CSF IgG in patients treated with phenytoin (diphenylhydantoin). In the CSF's from 13 out of 30 phenytoin-treated patients the IgG concentrations were lower than the lowest amont 20 controls, while only 3 out of 37 patients with brain lesions without epilepsy had so low IgG value. Titers of IgG antibodies to rabbit erythrocytes were similar in the three groups. It should be kept in mind, when evaluating results of IgG determinations in clinical neurology, that reduced IgG may be a consequence of phenytoin treatment. Reduced IgG concentrations without reduction of an antibody belonging to the IgG class indicate that the suppression of immunoglobulin synthesis by phenytoin may be selective.


Electrocardiographic findings in motor neurone disease. The electrocardiogram was analyzed in 31 patients with motor neurone disease. ECG abnormalities were encountered in 27 of the patients. The dominating ECG changes consisted of ST-T wave changes and supraventricular arrhythmias. The underlying mechanisms are discussed in relation to the neurological symptomatology.


Myasthenia gravis: a quantitative evaluation system. Disability status scale (DSS) applied for myasthenia gravis. On the experience of long-lasting personal observation of 350 myasthenic patients the author has applied the 'disability status scale' (known as Kurtzke or Bronx scale in multiple sclerosis practice) for myasthenia gravis. This system renders the quantitative evaluation of the different parameters possible. There are ten grades of gravity (from 1 to 10) and six functional systems (ocular, facial, bulbar, sceletal, respiratory and other functions).


Sensory and motor coduction in chronic carbon disulphide poisoning. The greater decrease of conduction velocity in sensory than in motor fibres of the peroneal, median and ulnar nerves (particularly in the digital segments) found in patients with chronic carbon disulphide poisoning, permitted the diagnosis of polyneuropathy to be made in the subclinical stage, even while the conduction in motor fibres was still within normal limits. A process of axonal degeneration is presumed to underlie occurrence of neuropathy consequent to carbon disulphide poisoning.


The use of psychotropic drugs in the treatment of chronic, severe pains. The results of long experience in the treatment of chronic and severe pains resistant to ordinary therapy with psychotropic drugs are reported. Out of 103 impatients with chronic and severe pains caused by neurological conditions, who were treated with a combination of thymoleptics and neuroleptics, 82 (approx. 82%) showed marked improvement. These encouraging results are compared with others published in this field. The pharmacological basis of this good action is briefly discussed, also the advantages of the use of psychotropic drugs, especially of the combination of thymoleptics and neuroleptics. A dosage schedule for in- and outpatients has been established, using imipramine (Tofranil) or chlorimipramine (Anafranil), and haloperidol (Haldol).


Retrograde perfusion as a method for myocardial revascularization. Retroperfusion of the superficial coronary venous system was studied in 44 canine fibrillating in vivo, normothermic preparations, with exclusion of the systemic circulation using cardiopulmonary bypass techniques in order to assess its value as a method of myocardial revascularization. Perfusion of either the isolated aortic arch via a brachiocephalic cannula or of the coronary sinus through the free end of a vein anastomosed to the atrial rim of the sinus was performed for 1 h at 100 cm3/min in groups II-IV following 30 min of anoxia. Oxygen uptake, vascular resistance, venous outflow and venous enzyme levels (CPK, GDH) were studied. Group I controls (antegrade perfusion, no anoxia) showed continued aerobic metabolism in contrast to group II (antegrade perfusion) and III (retrograde perfusion) which displayed negative lactate balance. Oxygen consumption was greater in group III than II (p less than 0.01) with a higher oxygen extraction in III (p less than 0.005). Group IV, which was given intravenously 30 mg/kg methylprednisolone prior to anoxia and then retroperfused, showed continued aerobic metabolism with low GDH venous levels and adequate oxygen consumption. Three dogs were then subjected to aortoatrial rim coronary sinus vein grafts with ligation of the left common coronary artery at its bifurcation with distal left circumflex and anterior descending artery-internal mammary vein anastomoses for venous drainage. The right coronary artery was left intact. Arterial inflow into the coronary sinus was associated with a left ventricular pressure of 70-80 mm Hg for up to 1.5 h while regular sinus rhythm was maintained. We conclude that retroperfusion of the coronary sinus represents a surgically feasible technique for providing oxygen delivery to the ischemic myocardium.


Lung function and morphology after bilateral hilar stripping in dogs. Acute changes of lung function and morphology were studied in 3 groups of dogs: after bilateral hilar stripping by ipsilateral approach (group 1), after right-side hilar stripping and left pneumonectomy by left-sided approach only (group 2) and in a control group. All dogs of group 1 showed a syndrome corresponding to functional hilar stripping with absent Hering-Breuer and cough reflex, slow respiration with increased tidal volume and discharge of fluid from the airways. Alveolar ventilation and oxygen tension, dead space/tidal volume ratio and pulmonary shunting did not change. Cardiac output and arterial oxygen tension were decreased. The lungs were heavy and histological examination showed lymphostasis and interstitial edema. The dogs of group 2 did not show significant changes in comparison to the control group.


Rationale for primary operations on the papilla of Vater. A procedure is described which allows to objectify the indication for primary operations on the papilla of Vater. During operations on the gallbladder or biliary tract, a radiomanometric examination of the common bile duct is carried out. The study comprises 255 patients. Based upon the results of radiomanometry in 77 patients, a transduodenal revision (papilloplasty) of the papilla was performed. Biopsies from the papilla revealed a high incidence of histological changes. There was a significant correlation between pathological findings on the papilla and abnormal bile pressures. Biochemical signs of cholestasis also correlated significantly with bile pressures. The results of intraoperative manometry allowed therefore conclusions on the functional and morphological state of the papilla. By this method, the indication for operations on the papilla can be objectified and unnecessary papillotomies avoided.


Telemetric estimation of the descending colon pressure changes on dogs before and after total and selective vagotomy. This experimental study describes the pressure changes of the descending colon before and after total and selective vagotomy combined with Finney's pyloroplasty as estimated by telemetry. The results obtained from the study of 20 dogs show that the motility of the descending colon is extremely reduced after total vagotomy with no change after selective vagotomy.


Role of mechanical stimulation in maintaining small intestinal mass in Thiry-Vella loops in the rat. Two 10-cm long Thiry-Vella (TV) loops were constructed in each of 20 rats. An elastic-plastic device, which served as a source of continuous intraluminal mechanical stimulation, was fixed in one of the loops. Two weeks later the jejunum, ileum and both TV-loops were biopsied. Wet and dry weight per 3 cm intestine, villus height and muscular thickness, were determined. Both TV loops were atrophic, but the wet and dry weight and muscular thickness were significantly greater in the mechanically stimulated ones. The villus height was not significantly effected by the mechanical stimulation. The experiments demonstrate that the effect of mechanical stimulation on the food-deprived small intestine is limited to a certain extent of muscular hypertrophy resulting in a lesser degree of atrophy expressed in terms of wet and dry weight of the intestine.


Induced fat embolism in rabbits: effects of defibrinogenation and thrombocytopenia. Fat embolism was induced in rabbits by giving an intravenous injection of radioactively labelled homologous retroperitoneal fat. One group was defibrinogenated by Arvin. A second group was made thrombocytopenic by treatment with Busulphan. After the animals had been made thrombocytopenic and had been defibrinogenated, respectively, fat embolism was induced. Macroscopic and histologic examinations were carried out, as well as recordings of wet weight and radioactivity content of the lung. There was a highly significant increase in the pulmonary wet weight of thrombocytopenic animals compared with controls. Macroscopic as well as histologic examination revealed a massive interstitial and alveolar oedema. Half of the specimens showed moderate to massive bleedings. Defibrinogenated animals did not differ from controls. Under the given circumstances, the results suggest that platelets are protective to the endothelial lining of the pulmonary capillaries during embolism. The presence or absence of fibrinogen initially does not seem to be of major importance for the pulmonary damage induced by fat injection.


A simple device to obtain a pulsatile flow. Application to the vascular perfusion of dogs isolated intestinal segments. A simple device allowing a pulsatile flow to be obtained in isolated organ perfusion has been developed and applied to the vascular perfusion of isolated canine jejunal segments. The principle of the device consists of superimposing on a constant pressure produced by a roller pump, a pulsatile pressure of which the amplitude, frequency, and shape of the pulses can be adjusted separately and independently of the mean pressure value. The role of the arterial pulse in intestinal vascular perfusion has been studied by comparing the hemodynamic and metabolic behavior during alternate periods of pulsatile and nonpulsatile pumping. While no striking change in vascular resistance was observed, the O2 consumption was significantly increased under pulsatile flow. These results testify to better metabolic conditions and enhanced organ functions under pulsatile pumping and also argue for improved intestinal microcirculation despite the constancy of the vascular resistance.


The peritoneal reaction to starch and its modification by prednisone. A saline suspension of 1.5 g of starch powder (Biosorb) inoculated into the peritoneal cavity of rats produced a massive granulomatous reaction which persisted for up to 18 months. From 15 months onwards, starch particles could only be detected with PAS staining. Prednisone at a dosage of approximately 1 mg/kg daily by the oral route produced significant reduction of this phenomenon only when commenced 2 weeks before inoculation. Therapy commenced at the time of starch inoculation had only a minor effect on this response, but if commenced 2 weeks after inoculation failed to ameliorate the granulomatous reaction.


Studies of the presence of membrane receptors for complement, IgG and the sheep erythrocyte rosetting capacity on the same human lymphocytes. Normal peripheral blood lymphocytes were tested by a mixed rosette method, employing different sized erythrocytes as indicators to identify lymphocytes simultaneously possessing membrane markers found commonly on B and T cells. Only small populations of these lymphocytes were detected regularly in normal lymphocyte preparations. One type of lymphocyte (ranged from 0.5%-8%) was shown to possess the following markers: receptors for human and rabbit IgG, receptors for the third complement component C3b and C3b inactivator-cleaved C3b (C3d), and the capacity to rosette spontaneously with uncoated sheep erythrocytes (SRBC). Another lymphocyte cell type was shown to possess both SRBC and IgG receptors but lack membrane immunoglobulins and complement receptors. This population was detected in lymphocyte preparations depleted of complement receptor cells, and an increased number of these cells was found in rosette preparations incubated with human serum. The possible presence of some lymphocytes possessing both complement and SRBC receptors and lacking other markers was considered. The possibility that these small populations of human lymphocytes are sub-populations of T cells with certain cytotoxic function is postulated.


Immune response region-associated antigens of the mouse: biochemical properties of detergent and papain solubilized molecules. Immune response region-associated (Ia) antigens and classical H-2 antigens are glycoproteins which differ in their molecular weight and tissue distribution. Ia and H-2 molecules also show differences in overall charge, apparent isoelectric point and susceptibility to proteolytic degradation, acid treatment and exposure to 56 degrees C. In the present paper, Ia.11d antigens were shown to have a molecular weight of about 35000 after solubilization with nonionic detergents. Purified Iad antigens, solubilized by controlled papain digestion, display a molecular weight of about 26000 after final purification by indirect immune coprecipitation.  This figure corresponds to the molecular weight of a highly purified H-2 polypeptide fragment obtained after papain solubilization. The remarkable size similarity of proteolytic fragments from Ia and H-2 antigens could suggest that these genetically and functionally related molecules possess some structural features in common.


Immunoglobulins M and D as antigen-binding receptors on the same cell, with shared specificity. Antigen-binding cells specific for Type 3 pneumococcal polysaccharide were detected among normal human peripheral blood lymphocytes, tonsillar lymphocytes, and umbilical cord blood lymphocytes. By using mu and delta-specific antiserum it was shown that some specific antigen-binding cells simultaneously expressed both IgM and IgD on their surface. Both classes on individual cells were able to bind the same antigen, suggesting that the variable regions of each immunoglobulin class, when present on the same cell membrane, are coded by the same V gene.


Modifications of the thymocyte membrane during redistribution of concanavalin A receptors. The modifications of the thymocyte membrane which are induced by concanavalin A (Con A) were studied by means of the variation of electrophoretic mobility which the lectin induces on the cell. The electrophoretic mobility of thymocytes is increased when Con A is used under conditions expected to induce a cap formation and the subsequent endocytosis. This increase persists as long as the lectin is present in the medium and disappears as soon as the lectin is eliminated. The redistribution of the Con A receptors into spots and caps may partially explain this electrical modification. The ionized groups of the thymocyte membrane are drastically modified during these phenomena with: 1) a diminution by 61% in the density of the sialic carboxyl groups, 2) a decrease of 40% in the density of phosphate groups and of 60% in the density of amino groups, 3) a 20 times higher density of unidentified negatively charged groups. The electrophoretic mobility of normal human blood lymphocytes is similarly increased by Con A. A marginal difference exists in the shape of the dose response curves obtained when normal and cancerous thymocytes react with increasing doses of Con A. No measurable electrical modification was observed during redistribution of H-2 and Thy-1.2 antigens on EL4 cells. Some experiments suggest a possible correlation between the mitogenicity of the lectin and a measurable modification of the cell electrophoretic mobility.


Differential cytotoxicity of activated lymphocytes on allogeneic and xenogeneic target cells. III. Species specificity of lymphocyte target cell recognition in vitro. Cytotoxic effector lymphocytes were produced by stimulation of human peripheral blood or mouse spleen lymphocytes with PPD, PHA or PWM in vitro. The specificity of the lymphocyte target cell interaction was studied in vitro. The specificity of the lymphocyte target cell interaction was studied by adsorption of effector cells on various target cell monolayers. The cytotoxic activity of human lymphocytes against 51Cr-labeled human or monkey target cells was reduced by prior incubation on primate monolayers while it was much less affected by incubation on rodent monolayers. Conversely the cytotoxicity of mouse lymphocytes against mouse L cells was strongly reduced by absorption on mouse or rat monolayers but significantly less by that on human monolayers. This suggests that this species-specific cytotoxicity reflects recognition by activated lymphocytes of some common surface structures present only on cells of the species of the effector cell donor, or on cells from phylogenetically closely related species. Lymphocyte-mediated cytotoxicity against xenogeneic target cells was studied after stimulation with PWM. The capacity of human lymphocytes to kill 51Cr-labeled mouse cells was reduced by adsorption on either rodent or primate monolayers. Conversely, prior incubation of mouse lymphocytes on either human or mouse monolayers led to inhibition of 51Cr release from labeled Chang cells. These results suggest that the mitogen-activated effector cells which are cytotoxic for more distantly related xenogeneic target cells have receptors for structures which are common for these cells and for target cells of the species of the lymphocyte donors.


Immune complex nephritis in Schistosoma mansoni-infected mice. Swiss outbred mice infected with 80-100 cercariae of Schistosoma mansoni developed in 60% of the cases a wide range of glomerular lesions involving mainly the mesangium. The lesions were associated with the presence of granular deposits of murine immunoglobulins and C3, suggesting an immune complex mechanism. In addition, nephritic glomeruli in about 20% of the cases could be stained by a specific rabbit antischistosoma serum after removal of excess host immunoglobulins. The presence of circulating immune complexes in the serum of infected animals was suggested by the increased molecular weight of circulating C3. The onset of the immunopathologic lesions appeared to be related to duration, intensity and type of infection. Single-sex parasite infection, in fact, led to significant reduction of glomerular lesions.


Membrane Ig on human lymphocytes: rate of turnover of IgD and IgM on the surface of human tonsil cells. The turnover of IgM and IgD molecules present on the membrane of human tonsil cells has been studied using immunofluorescence and peroxidase-catalyzed membrane radioiodination. With the first of the two techniques cells were treated with pronase to remove membrane immunoglobulin (mIg), placed in culture and stained at intervals to check the reappearance of membrane IgD and IgM on the cell membrane. These experiments showed that membrane IgD (in contrast to membrane IgM) are extremely susceptible to proteolysis. Furthermore, cells treated with a concentration of pronase found to be optimal to remove membrane IgM failed to re-express membrane IgD in vitro. The large majority of tonsil lymphocytes has both membrane IgM and IgD. Due to the different behavior of reappearance of the two membrane molecules after treatment with pronase, it was not possible to obtain the simultaneous re-expression of membrane IgM and IgD by the cells "stripped" with pronase. However, the two molecules were re-expressed in vitro by the cells treated with different pronase concentrations with a similar timing, i.e. 50% or more of the cells re-expressed membrane IgD and IgM after 8 h in culture. 131I-radioiodinated membrane IgD and IgM were also released from the cell surface with a similar timing, the half-life of permanence on the cell membrane being about 4 h for both molecules. These findings thus indicate that IgM and IgD molecules have a similar turnover and that a cell is capable of placing two different Ig molecules at a time on its surface.


Inheritance of antibody specificity: the IgM anti-lipopolysaccharide response in mice. Mice of different genotypes were immunized with Salmonella anatum. The cross-reactivity patterns of their IgM anti-S. anatum lipopolysaccharide (LPSAN) antibodies were characterized by their relative avidity toward heterologous LPS. When the LPS from S.cholera suis (LPSCHS) was used as the heterologous LPS, clear differences between mouse strains were found. DBA/2 and DBA/1 showed cross-reacting IgM, whereas C57BL/10, C57BL/6 BABL/c-Igb and B10. D2 had mainly noncross-reacting IgM. In C3H and C57BL/6-Iga, individual mice express either the cross-reacting or the noncross-reacting antibodies. The IgM antibodies from individual mice were further characterized for their cross-reactivity toward the LPS from S. strasbourg (LPSSTR) and S illinois (LPSILL). Only individual patterns with no correlation to the cross-reactivity pattern with LPSCHS were found.This shows that more than one antibody type is characterized by cross-reactivity.(B10.D2 X DBA/1)F1 mice showed a biphasic distribution of cross-reactivity. Of the F1 X DBA backcross mice 21% had IgM antibodies which showed no cross-reaction with LPSCHS. This still is in agreement with one locus controlling this phenotype. This locus segregates independently from Ig allotype since no correlation was found between allotype and cross-reactivity pattern in F1 X DBA backcross mice.


Cellular reaction induced by "nonantigenic" substances. A previously designed isotopic in vivo method for measuring delayed hypersensitivity was used with nonantigenic (or weakly antigenic) phlogogenic substances. A strong reaction was observed in some circumstances, witnessing the fact that the method has a specific and a nonspecific component. The reaction is drastically augmented by a mild whole-body irradiation of the reacting animals. In the case of the studied substances (carbon, oil and bentonite) the reaction is bound by polymorphonuclear neutrophils (PMN), but it was found to be independent of the number of circulating PMN in the blood.


Long-term immunoglobulin G production by transplanted thymus cells. Two sublines of CBA/H mice congenic for the Igl allotype locus were used to study donor-allotype IgG2a concentrations in the serum of mice injected intravenously with thymus cells. High concentrations (up to several mg/ml) were found in x-irradiated recipients (exposed to 650 rad, or to 900 rad with a restorative injection of fetal liver cells). The highest concentrations were seen 1-2 months after injection, but detectable quantities were still present in most individuals after 377 days. No donor-allotype Ig was detected in non-irradiated recipients. Cell for cell, lymph node cells were about as efficient as thymus cells at transferring IgG production. Although pluripotent hematopoietic stem cells were found in the thymus, their concentration (about 10(-8)) was too low to account for the results. It is suggested that the thymus contains B lymphocytes, or their precursors, with considerably greater powers of self-maintenance and expansion than are possessed, on average, by the B lymphocytes in lymph nodes.


Efferent enhancement of a methylcholanthrene-induced sarcoma transplantable in strain 13 guinea pigs. The immunobiology of an antigenic methylcholanthrene-induced sarcoma (MC-D) of inbred strain 13 guinea pigs has been investigated. The induction of concomitant immunity by growing MC-D tumors was indicated by the suppression of small tumor inocula in the presence of a large tumor cell dose and by the regression of intradermal tumor nodules. Furthermore, it was demonstrated that this tumor was coated with antibody in vivo. Previous studies showed that MC-D tumors were infiltrated with killer T cells which were capable of complete tumor destruction in vitro, but could never induce spontaneous regression in vivo. On the basis of all these facts, antibody-mediated efferent enhancement is proposed to be the major escape mechanism of this tumor.


Polyclonal stimulation of lymphocytes by macrophages. To analyze the interaction between macrophages and splenic lymphocytes with reference to time and concentration, the Mishell-Dutton system was divided into two experimental steps. Step 1 consisted of the cocultivation of spleen cells with various doses of macrophages for different periods of time, while in step 2 macrophages were removed, spleen cells transferred to fresh petri dishes and cultivated until plaque assay. Cocultivation of spleen cells with high doses of macrophages for 4--8 h markedly enhanced the DNA synthesis and plaque-forming cell (PFC) response of sheep red blood cell-stimulated and unstimulated cultures. A cocultivation longer than 24 h resulted in an inhibition of both DNA synthesis and PFC response of spleen cells. These studies suggest a nonspecific function of macrophages on proliferation and differentiation processes in antibody formation.


Induction of immune responsiveness in a genetically low-responsive tumor-host combination by chemical modification of the immunogen. Trinitrophenylated Moloney virus-induced YAC cells induced a higher cytotoxic antibody response and better protection against small tumor cell doses in syngeneic, low-responsive strain A mice than nonmodified YAC cells that had been inactivated by irradiation or mitomycin C treatment. The results indicated that genetically determined low responsiveness to a virally induced antigen can be overcome, at least to some extent, by coupling the immunizing cells to a strong immunogenic hapten.


Isolation of a murine liver-specific alloantigen, F antigen, and examination of its immunogenic properties by radioimmunoassay. The autoantibody response induced in mice by alloimmunization with liver-specific F antigen is an example of the circumvention of humoral self-tolerance. The F molecule has been isolated and shown to be a protein with a mol. wt. of 40 000 Daltons which migrated as a beta-globulin. The purified antigen retains both the immunogenic and antibody-combining properties of crude liver homogenate. Successful iodination of the protein allowed the establishment of a radioimmunoassay which demonstrated high titers of antibodies in responder strains. At the same time it was clearly shown that no antibody could be detected, either as a result of syngeneic immunization or as a result of alloimmunization in nonresponder strains. The characteristics of the F antigen immune response distinguish it from that induced by other proteins.


Effect of anti-carrier antibody on carrier-determined tolerance. These experiments were originally designed to determine whether an anti-carrier antibody, e.g., anti-allotype could break hapten-specific tolerance in vivo. Tolerance to 2,4-dinitrophenyl (DNP) was induced in C57BL/6J mice using DNP-BALB/c IgG2a conjugate. When anti-allotype serum was injected in C57BL/6J mice one day after a single injection of DNP-IgG2a the mice were not tolerant. In contrast, when tolerance was induced by four weekly injections of tolerogen, the anti-allotype serum had no effect on the tolerant state. This effect was specific for tolerance-inducing carrier. Anti-carrier antibody injected in C57BL/6J mice one day after DNP-IgG2a produced a small but significant anti-DNP response without administration of the immunogen, whereas the tolerogen (DNP-IgG2a) by itself was not immunogenic. Similarly, despite multiple injections of DNP-IgG2a bearing the foreign allotype, only one out of 7 C57BL/6J mice showed a weak anti-carrier response. In contrast, a marked anti-carrier (IgG2a) response was obtained when the anti-allotype antibody was passively administered in C57BL/6J mice. In conclusion, these experiments suggest that tolerance to an antigenic determinant may be broken by an antibody directed not to this determinant, but to another on the same molecule. The significance of this finding in relationship to the mechanism of the carrier-determined tolerance and the breakdown of self-tolerance is discussed.


Genetic control of the immune response: ability of antigens of defined amino acid sequence to be recognized by the Ir-1 gene system. Mice were injected with a series of (T,G)-A--L[poly (L Tyr, L Glu)-poly DL Ala)--poly (L Lys)]-like compounds with side chains of homogeneous sequences: T-A--L, GT-A--L, GGT-A--L, and TG-A--L. T-A--L was not immunogenic. However, T-A--L was able to bind antibodies to (T, G)-A--L 509, and this binding could not be blocked by A--L. When complexed with bovine serum albumin, T-A--L, was immunogenic in both responder and nonresponder strains of mice. GT-A--L and GGT-A--L were both immunogenic and elicited the characteristic responder-nonresponder difference induced by (T,G)-A--L. TG-A--L was also immunogenic, but there was considerable overlap in the response of responder and nonresponder strains. On the average, responder mouse serum had a slightly higher antigen-binding capacity than nonresponder mouse serum. In contrast to antibodies against GGT-A--L, antibodies against TG-A--L bound heterologous antigens poorly. These data, along with the results of other investigators, are consistent with the hypothesis that there are multiple Ir- 1 genes which recognize different sequences. The specificity of the Ir- 1 genes is extraordinary. The polypeptides TG-A--L, TGTG-A--L and GTTG-A--L do not appear to be recognized by these genes.


Amino acid sequence studies on the branched, synthetic polypeptide antigens of the immune response- 1 gene system. Three immunogens with side chains of random amino acid sequence, poly (L Phe, l glu)-poly (DL Ala)--poly (L Lys) [(Phe, G)-A--L 223], poly (L Tyr, L Glu)-poly (DL Ala)--poly (L Lys) [(T, G)-A--L 509] and (T, G)-A-L 52, as well as two immunogens with side chains of defined amino acid sequences, GGT-A--L and TG-A--L, were sequenced using a Beckman automated sequenator. Despite the lack of a unique amino acid sequence for the amino terminus, reasonable results for the sequence studies were obtained using the Edman reaction. GGT-A--L and TG-A--L had 70% and 80% of their side chains respectively, with the desired sequence. The three compounds of random amino acid sequence were found to contain a large proportion of their A--L side chains unsubstituted. The side chains had a much greater probability of terminating in the aromatic amino acid than in the glutamic acid. The distribution of the length of side chains and their amino acid sequences was completely heterogeneous.


Mechanisms of phytohaemagglutinin-P-, concanavalin-A- and kaolin-induced oedemas in the rat. Subplantar administration of either Phytohaemagglutinin-P (PHA), Concanavalin-A (Con A) or kaolin into the rat hind paw produced a dose related oedema which was still present at 48 h. Both of the lectins were more inflammagenic than kaolin on a weight per weight basis. As a result of studies using mediator inhibitors and depletors it appears that 5HT, but not histamine, may play a role in the early phases (0.5-1.5 h) of both PHA and Con A responses. Neither mediator appears to be involved in the kaolin oedema. Kinins are also likely mediators of the inflammatory response to all three irritants and could be detected in irritant injected air blebs in the rat. Prostaglandins are unlikely to play a significant role in PHA or Con A oedema since indomethacin-induced inhibition of their synthesis has only a slight inhibitory effect on the lectin induced paw oedemas and only small amounts of prostaglandin-like material could be detected in PHA or Con A blebs. However, kaolin oedema appears to have a significant prostaglandin component since large amounts of prostaglandin-like materials were detected in kaolin blebs and also indomethacin reduced the kaolin induced paw oedema. Other mediators of the inflammatory process such as complement are likely to be involved in all three irritant induced oedemas.


Picrotoxin convulsions and GABA metabolism after injection of anticonvulsants in chicks. Two clinically effective anticonvulsants, phenobarbitone and diazepam, protected 5-day old chicks against picrotoxin convulsions without reducing brain GABA-transaminase activity or raising brain GABA concentration. Ethanolamine-O-sulphate and amino-oxyacetic acid, in doses which inhibited GABA-transminase by at least 63% and approximately doubled brain GABA concentration, did not significantly affect the ED50 for picrotoxin convulsions. The ED50 for picrotoxin convulsions was significantly raised by di-n-propylacetate (800 mg/kg) which inhibited GABA transaminase activity by 6% and elevated brain GABA concentration by 26%.


On the selective inhibition of serotonin uptake in vivo by Org 6582. In vivo blockade of 5-HT uptake was studied by investigating the effect of drug pretreatment on the ability of p-chloramphetamine to lower rat brain 5-HT levels. Org 6582 was approximately twice as potent as fluoxetine, five times more potent than chlorimipramine and 14 times more potent than desipramine in blocking the ability of p-chloroamphetamine to lower rat brain 5-HT content. Org 6582 also had a longer duration of action than either fluoxetine or chlorimipramine. Org 6582, whilst having no effect on amine steady state levels, decreased rat brain 5-HT turnover and also lowered rat brain levels of 5-HIAA. In contrast to both desipramine and chlorimipramine, Org 6582 was devoid of effect on the ability of 1-metaraminol and 6-hydroxydopamine to lower rat heart NA levels. The ability of intraventricularly administered 6-hydroxydopamine to lower rat brain NA levels was unaltered by Org 6582 pretreatment. The corresponding i.p. ED50 values for desipramine and chlorimipramine were 7.3 mg/kg and 28.8 mg/kg respectively. Like desipramine and chlorimipramine, Org 6582 had no effect on the ability of intraventricular 6-hydroxydopamine to lower rat brain DA content. Org 6582 had no effect on steady state levels or on the turnover of NA and DA in the rat brain. It is concluded that Org 6582 is a potent long acting selective inhibitor of 5-HT uptake in vivo.


Comparison of effects of drugs on dopamine metabolism in the substantia nigra and the corpus striatum of rat brain. The influence of apomorphine, chloral hydrate, haloperidol, morphine, oxotremorine, pargyline, probenecid and promethazine on DOPAC and HVA levels was studied in the substantia nigra (including the ventral tegmental dopaminergic regions) and corpus striatum of the rat brain. The time--effect curves of changes in HVA levels after pretreatment with apomorphine, haloperidol, morphine, oxotremorine or promethazine are presented. The time--effect curves for the substantia nigra showed an initial rapid HVA rise, which was not observed in the corpus striatum. Promethazine treatment caused a small but significant HVA rise in the substantia nigra only. Chloral hydrate, morphine and oxotremorine induced a similar percentage increase in DOPAC and HVA levels in the substantia nigra as well as in the corpus striatum. Haloperidol, however, caused a small percentage change in the metabolite levels in the substantia nigra when compared to the pronounced rise seen in the corpus striatum. The apomorphine-induced HVA decrease observed in both structures provides evidence for the presence of a dopaminergic receptor in the substantia nigra.


On the possible role of brain protein synthesis in functional barbiturate tolerance. Pentobarbital pellet implantation increased more than 200% the ED50 dose of pentobarbital required to induce loss of the righting reflex within 2 min of i.p. injection and increased the onset of barbital-induced sleep. Both tests of functional barbiturate tolerance were blocked by the intraventricular injection of cycloheximide. The effects of acute (45 mg/kg i.p.) and chronic (pellet implantation) pentobarbital treatment on the incorporation of 3/-lysine into the protein of various subcellular fractions of the cortex and subcortex were studied. In the subcortex, chronic pentobarbital treatment significantly stimulated protein synthesis 40-50% in the microsomal, soluble and mitochondrial fractions. Both acute and chronic pentobarbital treatments significantly increased (3H-lys)-protein accumulation in a fraction of synaptic plasma membranes derived from a population of nerve ending particles (NEP) enriched in gamma-aminobutyric acid (GABA). The possible significance of these data to pentobarbital tolerance and dependence development is discussed.


Suppression of renin secretion in the isolated rat kidney by cycloheximide. The effect of cycloheximide, an inhibitor of protein synthesis, on basal and stimulated renin secretion was examined in the isolated perfused rat kidney. Cycloheximide (0.05 mmol) was administered one hour before preparing the kidneys for perfusion. Both basal renin secretion and the response to intrarenal infusion of isoprenaline (0.06 nmol/min/g) or glucagon (0.1 nmol/min/g) were consistently reduced in the cycloheximide-treated group, suggesting dependence of these processes on protein synthesis.


Restoration of self-stimulation inhibited by neuroleptics. Pimozide-induced inhibition of lever-pressing for brain stimulation in the lateral hypothalamic area was differentially restored by the centrally acting anticholinergic, dexetimide and by different dopaminergic drugs. In addition, a differential antagonism towards chlorpromazine-induced inhibition of self-stimulation was shown. The results indicate that anticholinergis (non-competitive antagonism) or drugs which enhance endogenous neuro-transmission by increased release or by uptake blockade (competitive antagonism) are able to reserve the neuroleptic-induced inhibition of self-stimulation more effectively than are receptor agonists.


Cocaine cue in rats as it relates to subjective drug effects: a preliminary report. Using a food-reinforced two-lever operant method, rats (n=5) could be trained to discriminate 10 mg/kg cocaine from saline. Stimulus generalization experiments with lower doses (0.31-5.0 mg/kg) revealed that the cocaine cue is a dose-related phenomenon. Neuroleptic drugs were found relatively ineffective as possible antagonists of the cocaine cue, and no antagonistic effect whatsoever was obtained with dibenamine, propranolol, cyproheptadine and methysergide. iamphetamine (1.25 mg/kg) and apomorphine (0.31 mg/kg) were generalized with cocaine, and a dopaminergic involvement is discussed.


Sex specific differences in chlorimipramine inhibition of serotonin uptake in human platelets. The uptake of 14C-serotonin in platelet-rich plasma was similar in clinically healthy men and women. Serotonin uptake inhibition by chlorimipramine was significantly less in women than in men, the extent of inhibition correlating with the stage of the menstrual cycle.


Role of dopamine in the anorexigenic effect of DITA; comparison with d-amphetamine. The effects of d,1-alpha-methyltyrosine (alphaMT), haloperidol, phenoxybenazmine, propranolol, methysergide and cyproheptadine on the anorexigenic activities of DITA and d-amphetamine were studied in male mice. The pretreatment of mice with methysergide (10 mg/kg, s.c.), cyproheptadine (5 mg/kg, i.p.), phenoxybenzamine (10 mg/kg, i.p.), and propranolol (5 mg/kg, i.p.) failed to alter the anorexigenic effect of DITA and d-amphetamine. On the other hand, alphaMT (32 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) significantly antagonized the anorexigenic effect of DITA and d-amphetamine. Our data indicate that the anorexigenic activities of DITA and d-amphetamine are mediated mainly through the dopaminergic system.


The effect of a potent inhibitor of platelet aggregation, BL-3459, on adrenaline-induced myocardial necrosis in beagle dogs. The effect of a potent inhibitor of platelet aggregation, BL-3459, on adrenaline-induced myocardial necrosis was investigated in beagle dogs. BL-3459, an alpha-adrenergic receptor blocking agent, phenoxybenzamine, and a beta-adrenergic receptor blocking agent, propranolol, were compared for their ability to modify the effects of adrenaline on platelet function, arterial blood pressure and myocardial damage. Adrenaline infusion led to a dose-related myocardial damage, elevation in arterial blood pressure, elevation in screen filtration pressure (SFP) and fall in platelet count. BL-3459 inhibited the elevation in SFP and the fall in platelet count as well as limiting the extent of myocardial damage. Phenoxybenzamine significantly modified all adrenaline-induced changes except the elevation in SFP. Propranolol had little effect alone and seemed to antagonize the beneficial effects of BL-3459 when the two drugs were combined. These results suggest that while other factors may also be involved, platelet aggregation and transient hypertension are correlated with the extent of adrenaline-induced myocardial necrosis observed in this model. A potent inhibitor of platelet aggregation, BL-3459, and the alpha-adrenergic receptor blocking agent, phenoxybenzamine, appear to afford protection against the observed pathological effects.


Effects of inhibitors of prostaglandin synthesis on rebound excitation of guinea-pig small bowel. The prostaglandin synthetase inhibitors indomethacin and acetyl salicylic acid did not affect the post-stimulus rebound excitation of guinea-pig duodenal and jejunal circular muscle with transmural electrical stimulation at 1 min intervals. In the absence of any drug, sequential time-dependent changes in amplitude of the rebound contractions were: (1) progressive increase during first 10 min, (2) a plateau at 30 min, (3) progressive decline to almost no response over 3 h. The results indicate that, in the circular muscle layer, prostaglandin synthesis is not required for production of the rebound response following electrical stimulation of inhibitory neurons.


Disposition of propranolol isomers in mice. l-Propranolol was found to protect mice from hyperbaric oxygen-induced seizures. The disposition of effective doses of propranolol isomers in mice was followed using stereospecific antibodies with a radioimmunoassay procedure. Serum and tissue concentrations were determined and correlated with the protective effect. Following racemic administration, there were no differences in serum disposition of d- and l-propranolol, although there was initially a preferential uptake of the 1-isomer both into cardiac and brain tissue. The d-isomer exerted synergistic action on the 1-isomer protective effect.


Local anesthetic blockade of Ca2+ -mediated action potentials in cardiac muscle. The effects of local anesthetic agents (lidocaine, procaine, cocaine) and diphenylhydantoin (DPH) were studied on the slow electrical responses induced by isoproterenol or caffeine in cardiac muscle preparations rendered inexcitable by tetrodotoxin (TTX) or by partial depolarization with elevated K+ (26 mM). In such inexcitable cells, we previously demonstrated that addition of some positive inotropic agents, such as catecholamines, histamine, and methylxanthines, rapidly increase the number of available slow Ca2+--Na+ channels, thus allowing slowly rising electrical responses resembling the plateau component of the cardiac action potential. In embryonic chick (16-20-day-old) myocardial cells (ventricular) studied as intact perfused hearts or as reaggregated cell cultures of trypsin-dispersed cells, high concentrations (10-(3) M) of all of the above drugs blocked the induced slow responses with their associated contractions; low concentrations (10-(5) M) of these agents reduced the maximal rate of rise (+Vmax) of the slow responses and depressed the contractions. For comparison with their effects on the slow response, the actions of these drugs on the normal action potential were also studied. As with the slow response, all of these drugs depressed the rate of rise of the action potential (10-(4) M) or blocked it at higher concentrations (10-(3) M); in contrast, low concentrations (10-(5) M) of lidocaine and DPH increased +V max. These findings suggest that local anesthetics, which interact with the lipid phase of the cell membrane, lead to blockade of the slow Ca2+--Na+ channels as well as of the fast Na+ channels in the myocardial sarcolemma.


Effect of pentobarbital, verapamil and manganese on the frequency-force relationship of the isolated atrium and ventricle of the dog heart. The canine right atrium was perfused with arterial blood led from a carotid artery of the heparinized support dog and suspended in a bath filled with blood. In 5 non-spontaneously beating preparations, the frequency-force relationship was investigated by electric stimulation at a frequency range from 0.017 to 3 Hz. At a low frequency level, a large peak tension developed. At 0.5 Hz, minimum values of developed tension were obtained. At a range of 0.5-3 Hz, the developed tension increased with the frequency. Higher frequencies than 4 Hz usually caused pulsus alternans. The staircase phenomena were not influenced by treatment with propranolol or atropine. Therefore, there may be no participation of the autonomic nerve stimulation on the frequency-force relationship. Effects of pentobarbital, (+/-)-verapamil and manganese on the frequency-force relationship were investigated with both the blood-perfused, isolated atrium preparations and isolated ventricular preparations. Pentobarbital and manganese chloride produced a uniform depression of the developed tension at all frequencies but the depression with (+/-)-verapamil was greater at higher frequencies in both atrial and ventricular muscles.


Anticholinergic and cardiodepressive effects of levomepromazine and two of its metabolites on isolated rat atria. The effects of monodesmethyl levomepromazine on effective refractory period (ERP) threshold for electrical stimulation and contractile force on isolated rat atria were compared to the effects of levomepromazine and levomepromazine sulfoxide. All agents caused an apparently dose-dependent increase in ERP, and antagonized acetylcholine-induced reductions in ERP. Levomepromazine and monodesmethyl levomepromazine decreased excitability and contractile force to a similar extent.


The distribution and metabolism of chlorpromazine in rats and the relationship to effects on cerebral monoamine metabolism. Rats were injected with chlorpromazine (CPZ), 21 mumoles/kg (7.5 mg/kg) i.p., and killed after different time intervals up to 24 h. Mass fragmentographic methods were used to determine the levels of CPZ, monodemethyl-chlorpromazine (nor1-CPZ) and 7-hydroxy-chlorpromazine (7-OH-CPZ) in brain and blood and dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in the striatum. Significant correlations between the brain and blood concentrations of CPZ as well as its active metabolites and the levels of DOPAC and HVA were obtained at several time points. The similarity between the time curves for CPZ dominantly the unchanged drug in the brain which determines the acceleration of DA metabolism.


Acute effects of morphine on rat intestinal motility. Systemic injection of morphine (0.5-16 mg/kg) caused dose-related increases in intestinal intraluminal pressure in anesthetized rats. Injection of morphine into cerebral ventricles was no more effective than the intravenous (i.v.) route. Decapitation of the animals did not prevent the intestinal stimulatory effect of i.v. morphine. The intestinal stimulation induced by i.v. morphine and 5-hydroxytryptamine (5-HT), but not that induced by cholecystokinin octapeptide, was antagonized by methysergide. Morphine appears to stimulate contractions of intestinal circular muscle in the rat by release of local, endogenous 5-HT.


The effect of metyrapone on uterine prostaglandin output and smooth muscle activity. Metyrapone, at low doses (0.5-1.0 mM), stimulated the output of both PGE and PGF from the isolated uterus of the pregnant rat determined following extraction of bath fluid, chromatographic separation and bioassay of the prostaglandin. At higher doses (2-4 mM), metyrapone inhibited PGF output, but had no effect on PGE output. Uterine activity was rapidly inhibited by metyrapone in a dose-related manner. This inhibition was not related to PG output as, at 1 mM metyrapone, activity was inhibited and PG output stimulated. Both metyrapone and papaverine produced dose-dependent inhibition of the activity of the isolated rabbit ileum, papaverine being 10 times more potent than metyrapone. Propranolol antagonised the response of the ileum to isoprenaline, but had no effect on the response to metyrapone. These observations confirm earlier data, suggsting that metyrapone exerts a differential effect on uterine PGE and PGF production and indicate that metyrapone has a direct inhibitory effect on smooth muscle activity.


Mechanism of morphine block of electrical activity in ganglia of Auerbach's plexus. A study was made of the effect of morphine on electrical activity within single ganglia of Auerbach's plexus of guinea pig longitudinal muscle-myenteric plexus as monitored by means of external electrodes. Morphine produces a concentration dependent block of single spike activity. This effect is competitively antagonized by naloxone. The ED50 for morphine effect is about 7 X 10(-7) M. Naloxone and dextrorphan have no effect on electrical activity. Acetylcholine in the concentration range of 10(-7)--10(-5) M augments electrical activity of ganglia. Morphine has little if any effect on the enhanced stimulation produced by acetylcholine thus indicating that the drug does not act directly upon the ganglion. Our results suggest that a specific opiate receptor is present on the preganglionic nerve terminals and that morphine and other opiates block ganglionic transmission by inhibiting the release of preganglionic acetylcholine.


Changes in regional brain acetylcholine levels during drug-induced convulsions. Acetylcholine (ACh) levels were determined in the brain of rats killed by decapitation or focussed microwave radiation during drug-induced convulsions. During metrazol or strychnine-induced convulsions a diffuse decrease in ACh levels was found in rats killed by decapitation. When the rats were killed by radiation and the brain was only divided into three large regions, strychnine caused no changes in ACh levels; metrazol caused a decrease in the cerebral cortex and lower brainstem. When discrete brain regions were investigated in rats killed by radiation, metrazol-induced convulsions were associated with a decrease in ACh level in all regions dissected and strychnine-induced convulsions with a decrease in the hippocampus and caudate nucleus only. Picrotoxin-induced convulsions were associated with a decrease in ACh level in the cerebral cortex, hippocampus, midbrain and medulla-pons, those induced by bicuculline with an increase in ACh level in the frontal cortex, hippocampus, midbrain and medulla-pons, by dimefline with an increase in the frontal cortex, midbrain and medulla-pons and a decrease in the caudate nucleus. The experiments show that each type of convulsant affects ACh levels in discrete brain regions in a different way.


The influence of delta9-tetrahydrocannabinol on pilocarpine-induced parotid secretions of the rat. The effects of delta9-THC and its ethanol vehicle on pilocarpine-induced parotid gland secretions were investigated in rats. Single doses of delta9-THC (1, 2.5, 5 and 10 mg/kg) or 95% ethanol were administered i.v. prior to pilocarpine stimulation of saliva. Total flow, alpha-amylase and cation content of the induced saliva were determined at the end of the collection period; while heart rate and blood pressure were monitored throughout each experiment. The ethanol vehicle did not alter any of the parameters when compared to the pilocarpine controls. delta9-THC produced a bradycardia and hypotension which was not dose related in spontaneously breathing rats. Furthermore delta9-THC caused an increase in alpha-amylase concentration without a reduction in salivary flow. The results suggest that delta9-THC exerts a profound influence on the protein composition of parotid secretion which is independent of its cardiovascular effects and its ethanol vehicle.


Antagonism of arachidonic acid-induced bronchoconstriction in cats by aspirin-like analgesics. In cats, anesthetized with chloralose, vagotomized and relaxed by infusion of sexamethonium, bronchoconstrictor reactions were induced by the i.v. injection of arachidonic acid (50 to 200 mug/kg). These reactions could be completely suppressed by the following drugs: indomethacin (ED50 0.16 mg/kg), flufenamic acid (1.8 mg/kg), acetylsalicylic acid (2.4 mg/kg) and phenylbutazone (4.7 mg/kg), but paracetamol was only partly effective even in doses up to 50 mg/kg. The results show that rather small doses of most weak analgesics can effectively inhibit prostaglandin biosynthesis in the bronchi and make it likely that this inhibition is involved in the drug-induced bronchoconstrictor reactions, which have been observed clinically.


Conformational aspects of the antifibrillatory activity of procaine. The effects of procaine and four semi-rigid conformational analogs (compounds 1,2,3 and 4) were tested and compared on isolated rabbit atria. Procaine and the four analogs produced positive inotropic effects at all dose levels tested. The antifibrillatory activity of procaine and its analogs arranged in decreasing order of activity was compound 4 greater than 3 greater than 2 greater than 1 greater than procaine. The antifibrillatory activity of the compounds correlated to the distance between the ring nitrogen and the ester oxygen; that is, as the N-O distance increased the concentration required to reduce the following frequency decreased. However, the compound became more toxic as the N-O distance increased. Our data do not confirm the commonly regarded direct relationship between local anesthetic activity and antifibrillatory activity of procaine. Differences in activity displayed by the isomers of procaine could reflect differences in the ability of these analogs to bind to receptors responsible for the respective actions.


No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats. In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 mug), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 mug), but induced marked behavioural changes. Central pretreatment with mepyramine (200 mug, i.c.v.) or procaine (600 mug i.c.v.), reduced the hypotension evoked by clonidine (25 mug), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 mug, i.c.v.) or tolazoline (200 mug, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.


Spinal branching of corticospinal axons in the cat. Branching patterns of single corticospinal (CS) neurons were studied in the cat by activating these neurons antidromically from various regions of the spinal cord. 1. One hundred and ninety-three neurons were activated antidromically by microstimulation in the gray substance of the cervical cord and the majority of them were found in the forelimb area of the pericruciate cortex. 2. Branches to the lower levels of the spinal cord were found for 30% of the neurons projecting to the cervical gray matter. 3. The remaining 70% sent axons only to the cervical gray matter and some of them sent multiple branches to several segments in the cervical cord. 4. Only a few CS neurons located outside of the forelimb area could be activated from the cervical cord, but all of them also sent branches to the lower levels of the spinal cord. Neurons projecting to both the cervical cord and the lower levels were intermingled in the cortex with those projecting only to the cervical cord. 5. CS neurons activated from a given area of the cervical cord were often clustered together in a small area of the cortex, although some of these CS neurons sent their other branches to other parts of the spinal cord and neurons projecting to other parts were also intermingled among them. 6. The functional significance of multiple axonal branching of CS neurons is discussed in relation to cortical motor functions.


An experimental study of the corticofugal system following cerebral lesions in the albino rats. Following neonatal lesion in the sensorimotor and adjacent cortex (SMC) in the albino rats, a corresponding region in the contralateral intact cortex gave rise to a bilateral corticofugal projection to the pretectal area, superior colliculus, pons, gracile and cuneate nuclei, the nucleus of Bischoff, caudal medullary reticular formation and the spinal cord. The anomalous growth response was greatest when the initial lesion was made within the first three days after birth, but became much reduced as the initial lesion was made at a progressively older age. A significant amount of anomalous projection could, however, still be demonstrated in the pons even in animals first lesioned as late as 20 days postnatal. The sprouting phenomenon was precise and ordered and in the various regions studied, the pattern of anomalous projection mirrored that of the normal projection. The anomalous fibres reached their specific target cells either by deflecting ipsilaterally at the pyramidal decussation to reach the spinal cord and the caudal medulla or by running across the mid-line to the contralateral pons, superior colliculus, pretectal area and the thalamic ventrobasal complex. In contradistinction to the findings of Hicks and D'Amato (1975) no anomalous fibres could be traced to the trigeminal complex and the rostral reticular formation in the medulla. A mechanism of competitive occupation of vacant synaptic sites was proposed to explain the sprouting phenomenon.


Changes in the protein metabolism of the CNS of a teleost following stimulation of the lateral-line organ. Unilateral stimulation of the lateral-line organ (LLO) of the teleost Scardinius erythrophthalmus by current water caused an increase in the afferent fibre activity in the stimulated organ of about 3.5 times as compared with the non-stimulated LLO. There was an increase of [3H] histidine incorporation as compared to controls following stimulation applied either at the beginning (1 h) or at the end (1.5-6 h) of various incorporation times. Following a 1 h stimulation period, the different areas of the LLO-system (lateral nerve, medulla oblongata, cerebellum and valvulae cerebelli), as well as the optic tectum, subtectum and spinal cord showed a significant increase of protein labelling; whereas after 12 h post-incorporation times only the lateral nerve showed highly significant differences as compared to controls. In animals stimulated at the end of a 12 h pre-incorporation period (1.5-6 h) there was a significant increase of protein labelling in all investigated structures of the brain as compared to controls.


Effects of stimulation of the midbrain reticular formation upon thalamo-cortical neurones responsible for cortical recruiting responses. 1. In lightly nembutalized cats, effects of high frequency (60-100/sec) repetitive stimulation of the midbrain reticular formation (RF) were tested upon the thalamo-cortical (T-C) neurones which project from the anterior ventral (VA) nucleus of the thalamus and its vicinities to the parietal association cortex and convey impulses responsible for cortical recruiting and spindling-like responses. 2. Tonic maintained or rhythmic grouped firings of the T-C neurones recorded as extracellular units with microelectrode in the thalamus were in the majority suppressed by high frequency RF stimulation during and often for a short time after the stimulation, and they showed later tonic discharges for many seconds or minutes. Intracellular recording from the T-C neurones revealed hyperpolarizing potential changes corresponding to the suppression on high frequency RF stimulation. Field potential analysis in the VA nucleus indicated that the hyperpolarization is ascribed at least in part to IPSPs elicited in the T-C neurones. Responses in some other types of thalamic neurones to the RF stimulation were exemplified to be compared and related with those of the T-C neurones. 3. Desynchronization of the parietal electrocorticogram coincided with the suppression of the T-C neurones and lasted for the time of the later tonic discharges, which contrasted with the rhythmic grouped discharges of the T-C neurones in association with recruiting and spindling-like responses of the cortex. Relations between the thalamo-cortical recruiting system and the ascending reticular activating system were discussed.


Electrical responses of the auditory area of the cerebellar cortex to acoustic stimulation. Single unit activity from the VI and VII lobuli of the cerebellar vermis cortex was studied following acoustical stimulation with sound signals of different parameters. Cerebellar neurons, as compared to those from the auditory system, showed low selectivity to sound frequency, intensity and duration. However, about 2/3 of the neurons were selectively sensitive to interaural time and intensity differences; about 1/3 of neurons showed a specific response to signals simulating sound motion in a definite direction. Thus, cerebellar neurons seem to be mainly responsive to those sound parameters which are essential for sound localization.


Autoradiographic studies on the uptake of 3H-noradrenaline and 3H-GABA in cultured rat cerebellum. Autoradiographic studies were made on the uptake of 3H-noradrenaline and 3H-GABA in rat cerebellum grown in tissue culture. GABA was taken up by Purkinje cells and interneurones as well as by glial cells. In contrast, 3H-noradrenaline was only accumulated by nerve fibres but not by neuronal cell bodies and by glial cells.


[Labyrinth nuclei as observed in dermatofibrosarcoma protuberans and fibroxanthoma (author's transl)]. In the electron microscope the nuclei of benign and malignant tumors as well as the nuclei of normal cells exhibit relatively various structural features. In this study the author reports on two mesenchymal tumors of the skin (one case of dermatofibrosarcoma protuberans and one of fibroxanthoma) with pecular nuclear polymorphism which can be visualized by electron microscopy only.


Sequential histopathological and biochemical events in rat caput epididymis after alpha monochlorohydrin administration. This paper presents sequential histological, histochemical and biochemical changes in rat caput epididymis after a single 100 mg/kg oral dose of alpha chlorohydrin. Desquamation of caput epithelium occurs as early as two days after drug treatment. The caput epididymis is blocked because of accumulation of testicular fluid containing exfoliated immature testicular cells and caput epithelium. There was no effect of drug on motility and morphology of spermatozoa examined from different segments of epididymis and vas deferens. Marked decrease in acid and alkaline phosphatases, nucleic acids and proteins have been registered after drug treatment. On the contrary increase in SDH, cholesterol and glycogen was observed after drug treatment. Decrease in phospholipids in initial stages has also been observed.


[Glutamic dehydrogenase activities in renal tissue during experimental and human ehronie pyelonephritis (author's transl)]. These studies are one part of systemic comparative investigations concerning biochemically feasible changes of renal cells and tissues due to chronic pyelonephritis (PN) as correlated to the histological results. The experiments aim at more detailed knowledge on the pathogenesis and conditions of the progressive chronicity of PN which could be of value for the further development of therapeutic measures. In previous papers (Esp. Path., vols. 8, 9 and 10) the author reported on the acid and alkaline phosphatase as well as on the glutaminase I activities. In the present study the glutamic dehydrogenase (GIDH) activities are analyzed. In 139 adult male rabbits (body weight 2.4 to 2.8 kg) unilateral pyelonephritis was experimentally induced in the left kidney. In additional 19 rabbits no PN developed despite of similar technique. 37 animals were used for controls. The animals were kept on standard diet in individual cages. Dependent on duration of the disease the 139 rabbits affected by experimental PN were divided into 6 groups: 1. Sacrification after 20 days, 2. Sacrification after 31 days, 3. Sacrification after 64 days 4. Sacrification after 100 days, 5. Sacrification after 212 days, 6. Sacrification after 261 days. The 19 rabbits which did not develop PN WERE LIKEWISE SACRIFICED AT DIFFERENT TERMS: AFTER 64 DAYS (5 ANIMALS), AFTER 100 DAYS (7 ANIMALS), AFTER 212 DAYS (7ANIMALS). These rabbits were designated "B-series". From 31 human kidneys with clinically quiescent pyelonephritic renal shrinkage wedge-shaped tissue samples were removed. Furthermore, 20 tissue samples of surgical specimens of extirpated human tumor kidneys were removed far distant from the site of the tumor. Induction of unilateral PN in the rabbits was done after the method of LEPPER (5) as modified by PRAT et al. (14). Coli of the strain O 55 K 59 were used for infection in a germ suspension of 500 millions of bacterial/ml 0.9% sterile physiological saline (control of the germ suspension by means of nephelometry). 24 hours after unilateral renal ligation each animal was i.v. administered 800-1000 millions of germs. At the end of the test the left side lesioned kidney was removed within maximally 100 sec after having been rinsed bloodless by means of cooled physiological saline (0 to 2 degrees C) during this period. On an ice-cooled glass plate the decapsulation and preparative separation of the medulla from the cortex was done using a magnifier; remnants of the capsule, hilar and fatty tissue were removed. Simultaneously tissue samples were obtained from 70 impaired kidneys and from 6 animals of the B-series (see above) for histological examination. The medullary and cortical parts were immediately swabbed with filter paper and weighed in moist state. Preparation for enzyme analysis: The renal medulla was minced and homogenized after the method of SCHMIDT, SCHMIDT and WILDHIRT (17) for 5 min at 0 degrees C...


The influence of hyperthyroidism and hypothyroidism on the wound healing of experimental myocardial infarction in the rat. In hyperthyroid and hypothyroid rats myocardial infarction was produced by coronary artery ligature. At different times following the ligature the animals were given 3H-thymidine or 3H-proline. The following parameters were determined: the number of DNA- and tropocollagen-synthesizing connective-tissue cells at the infarction border and at the infarction site; the mean silver-grain density above the nuclei or cells; the duration of one cell cycle; and the number of mitoses. The labelling and mitotic indices as well as the percentage of the standard deviation from the mean values were estimated. The following results were obtained: 1. In hyperthyroidism wound healing is accelerated. The number of DNA-synthesizing connective-tissue cells is increased. The cell-cycles are shorter. The release of tropocollagen by the fibroblasts takes place at a strikingly fast rate. 2. In hypothyroidism wound healing is delayed. The 3H-thymidine and mitotic indices are lowered. The release of tropocollagen is slowed down. The granulation tissue contains localized accumulations of mucopolysaccharides.


[Influence of carbohydrate load on enchondral ossification (author's transl)]. Several authors reported disturbances in skeletal growth due to disorders in carbohydrate metabolism. In this study changes in enchondral ossification due to fructose and glucose load are to be demonstrated and analyzed by X-ray examination and by light microscopic morphometric analysis.


The effect of cyclophosphamide on the experimental inflammation induced by the toxic mushroom Cortinarius speciosissimus in the rat kidney. A single intraperitoneal dose of cyclophosphamide (150 mg/kg) given at the same time as an oral dose of Cortinarius speciosissimus prevented the renal inflammation induced by this toxic mushroom in the male rat. Furthermore, a scar formation around dilated collecting ducts was clearly reduced by cyclophosphamide treatment. In general the only lesions observed in the cyclophosphamide treated animals were dilated collecting ducts in the outer medullary zone, the epithelia of which were either in regenerative mitosis or were atrophic. Apparently the primary sites of action of Cortinarius toxins in male rats are the collecting ducts of the outer medullary zone. When inflammation and the subsequent scar formation is prevented by cyclophosphamide, the damaged tubules can regenerate by mitotic activity and perhaps restore normal function.


An electronmicroscopic study of experimental hematogenous pyelonephritis. This paper consists of an electronmicroscopic study of hematogenous experimental pyelonephritis. In the first 5 days cell degenerations mitochondrial swellings, slight lysosomal increase, rupture of the apical cell membranes, deterioration of the basal labyrinth and a leucocyte-predominant cell infiltration into the interstitial tissue were observed. On the 10th day, beside these common findings, the complete necrosis of the tubular cells was also observed and was supposed to be the result of an increase of lysosomes directly proportional with elapsed time and of the destruction and extreme contraction of the basal membrane. The cause of these destructions was supposed to be primary schaemia and probably the antigen-antibody-complement complex.