Isolation and characterization of iron-binding proteins from rat intestinal mucosa. Two iron-binding proteins were isolated from rat intestinal mucosa. From determination of their molecular weights, their electrophoretic and iron-binding properties it was established that one was a mucosal ferritin and the other a mucosal transferrin. The mucosal ferritin is compared in its molecular weight, isoelectric point, amino acid composition and tryptic peptide pattern with the ferritins of rat spleen and liver. All three ferritins are distinctly different from one another. In addition the iron content of mucosal ferritin was found to be much lower than that of liver and spleen ferritins. Mucosal transferrin was separated into two components by isoelectric focusing, as was plasma transferrin. The plasma and mucosal transferrins differ in their isoelectric points and in their amino acid compositions. Differences were also found in vitro in the iron-binding of mucosal transferrin as compared with plasma transferrin. The role of these mucosal proteins in the absorption of iron is briefly discussed.


Size, complexity and abundance of a specific poly(A)-containing RNA of liver from male Xenopus induced to vitellogenin synthesis by estrogen. Estrogen treatment of Xenopus males leads to the appearance of a new species of poly (A)-containing RNA in the liver, at a stage when large amounts of the estrogen-induced yolk precursor protein, vitellogenin, is produced. This estrogen-induced RNA sediments at 28 S and migrates on gels in aqueous solution with an apparent molecular weight of 2.0 X 10(6). Contour length measurements under denaturing conditions in the electron microscope reveal a molecular weight of 2.34 X 10(6) compared to the mouse 28-S rRNA. Labeling experiments show that the estrogen-induced RNA has a stability than the average liver poly(A)-containing RNA and represents 10-20% of the poly(a)-containing RNA in the cytoplasm after 24 h of labeling. Hybridization of complementary DNA, synthesized on the isolated estrogen-induced RNA, with its template suggests a complexity corresponding to a single species of poly(A)-containing RNA of such a high molecular weight. Hybridization of the complementary DNA with cytoplasmic poly (A)-containing RNA from estrogen-treated Xenopus males and control toads show that the estrogen-induced RNA constitutes 12-15% of all cytoplasmic poly(A)-containing RNA, and is at least 2000-fold less abundant in untreated males. Size, complexity and abundance of the estrogen-induced RNA are characteristics expected for a mRNA coding for vitellogenin.


Intracellular degradation and deamidation of alpha-crystallin subunits. The subunites AA2 and N2, present in alpha-crystallin from the nucleus of young and old bovine lenses, were isolated and characterized. It was found that AA2 is identical to a shorter A-chain and hence it was designated as A1-101. The subunit N2 turned out to be identical with a shorter B-chain and was designated as b 1/2-170. Characterization of the subunit N1, present only in alpha-crystallin from the cortex of old bovine lenses, suggested that his subunit is a modified B-chain, probably a deamidation product; it was designated as B0. Con relation to the age of the fiber cells in old bovine lenses with that in calf lenses revealed that the observed specific limited degradation of the subunits of alpha-crystallin increased with older age of the tissue. The deamidation process was found not to be related to the aging of the tissue. Eventually, a clear picture concerning the heterogeneity and fickleness of the alpha-crystallin subunit structure was obtained.


Sulfate bile acids in germ-free and conventional mice. Sulfated and non-sulfated bile acids were determined in the intestines and in the feces of 7-month-old germ-free and conventional male mice. 1. The bile acid pools in the gall bladder and small intestine were 21.13 mg/100g body weight in germ-free and 11.50 mg in conventional mice. The bile acid pools in the cecum and large intestine of germ-free mice were 3.03 mg/100 g body weight as compared to 1.24 mg in conventional mice. Fecal bile acid excretion was 2.93 mg and 4.12 mg/100 g body weight in 24 h in germ-free and conventional mice respectively. 2. The major bile acids from germ-free mice were cholic acid, alpha-muricholic acid and beta-muricholic acid. Small amounts of chenodeoxycholic and allocholic acid were also present. In addition to these primary bile acids the following secondary bile acids were identified in conventional mice: lithocholic, deoxycholic and omega-muricholic acid. 3. In both germ-free and conventional animals significant amounts of chenodeoxycholic and cholic acid were present as the 7-monosulfate esters. The sulfate esters of these bile acids did not exceed 2% of the total bile acids in the small intestine, but accounted for approximately 50% of the bile acids in the cecum and the large intestine. In contrast, the muricholic acids were nearly exclusively found in the non-sulfate fraction. 4. Alkaline hydrolysis without prior solvolysis of the sulfate esters resulted in loss of bile acids and production of artifacts. Hence, the bile acids of the mouse cannot be analysed by methods involving alkaline deconjugation unless a solvolysis step is included in the procedure.


Isolation and properties of structured chromatin from Guerin ascites tumour and rat liver. The method proposed by Hancock for isolation of structured chromatin from tissue culture cells is modified and used for isolation of chromatin from Guerin ascites tumour and rat liver. Micrococcal nuclease digestion patterns and thermal denaturation of these chromatins are studied and compared wiith those of chromatins prepared by precipitation and extraction with salts (salt chromatins). In contrast to the multiphasic melting profiles and salt chromatins, the structured chromatins exhibit relatively homogeneous denaturation patterns under a variety of conditions, suggesting thhat their DNA is uniformly stabilized by histones and there are no free independently melting DNA stretches. Digestion of structure of the deoxyribonucleoprotein is intact. No discrete fragments are formed upon digestion of salt chromatin.


The use of mercurated nucleoside triphosphate as a probe in transcription studies in vitro. 1. Purified form A RNA polymerase and the endogenous, nuclear form A RNA polymerase are shown to incorporate 5-mercuri-uridine 5'-triphosphate (Hg-UTP) into RNA in vitro. The Km for both Hg-UTP and UTP are in the region of 10 muM for the purified enzyme. 2. The RNA products formed in nucleoli by endogenous RNA polymerase A have similar base compositions (G + C-rich) whether UTP or Hg-UTP is provided as the substrate in vitro. 3. Sulphydryl-Sepharose chromatography of RNA synthesised in vitro by nucleoli allows separation of this material from the endogenous RNA, when the former is synthesised in the presence of Hg-UTP. 4. In-vitro-synthesised nucleolar RNA hybridises with cot profiles similar to 28-S ribosomal RNA, when made with either Hg-UTP or UTP. 5. Hybridisation studies using DNA excess suggest that little competition occurs between the in vitro transcripts and the endogenous nucleolar RNA. 6. Size analysis of in vitro transcripts show that although some degradation occurs during isolation, purification and hybridisation of the RNA species, most of the RNA remains larger than 5 S throughout.


Studies on the formation of acetoin from acetaldehyde by the pyruvate dehydrogenase complex and its regulation. 1. Pyruvate dehydrogenase complex was isolated from pigeon breast muscle involving steps of isoelectric precipitation, poly(ethyleneglycol) fractionation and separation on a glycerine gradient in the ultracentrifuge. 2. Arsenite, a potent inhibitor of the dihydrolipoyl transcetylase, did not affect the formation of acetoin from acetaldehyde, indicating that the pyruvate dehydrogenase component was operative in this reaction. 3. Production of acetoin by the pyruvate dehydrogenase complex is subject to regulation by phosphorylation and dephosphorylation, the dephosphorylated form only being active. 4. The inhibition by acetaldehyde of the pyruvate dehydrogenase complex could be partly explained by the formation of acetoin as an alternative reaction.


Synthesis, separation, identification and interconversion of riboflavin phosphates and their acetyl derivatives: a reinvestigation. A reinvestigation of flavin phosphate synthesis, separation, identification, and interconversion was made in view of contradictory results in the literature. It has been confirmed that monochlorophosphoric acid is the best agent for selective 5'-monophosphorylation of riboflavin and derivatives. This reaction yields, however, invariably up to 20% of an isomer, which has been separated by preparative thick-layer chromatography and shown to be the 4'-monophosphate. All the earlier authors failed to detect this isomer which does not bind to flavodoxin. It equilibrates in dilute mineral acid to yield an 8:2 mixture of 5'-phosphate to 4'-phosphate by phosphate migration. The formation of 2',3',4'-triacetyl-flavin mononucleotide, according to Christie, S. M. H., Kenner, G. W. & Todd, A. R. (1954) J. Chem. Soc., 46-52, upon acid-catalysed acetylation of pure FMN, was confirmed. The same reaction under base catalysis, however, does not yield 2',3',4'-triacetyl-flavin mononucleotide as claimed by Khomutova, E. D., Shapiro, T. A., Mezentseva, M. W. & Berezovskii, V. M. (1965) Otd. Obshch. i. Tekhn. Khim., 241-244, Chem. Abstr. 65, 5516a, but in fact up to 80% 2', 3'-diacetyl-flavin 4':5'-cyclophosphate as the main product, which is stable under neutral and weak acidic conditions and does not hydrolyse to 2',3'-diacetyl-flavin 5'-monophosphate as claimed by McCormick, D.B. (1974) J. Heterocycl. Chem. 11, 969-974. The various flavin phosphates and their acetyl derivatives have been identified by pH-titration, electrophoresis, and proton magnetic resonance spectrometry, which direct analyses of crude reaction products as well as a rapid purity check of commerical FMN.


Substituent effect on the oxidation of phenols and aromatic amines by horseradish peroxidase compound I. A stopped-flow kinetic study shows that the reduction rate of horseradish peroxidase compound I by phenols and aromatic amines is greatly dependent upon the substituent effect on the benzene ring. Morever it has been possible to relate the reduction rate constants of monosubstituted substrates by a linear free-energy relationship (Hammett equation). The correlation of log (rate constants) with sigma values (Hammett equation) and the absence of correlation with sigma+ values (Okamoto-Brown equation) can be explained by a mechanism of aromatic substrate oxidations, in which the substrate gives an electron to the enzyme compound I and simultaneously loses a proton. The analogy which has been made with oxidation potentials of phenols or anilines strengthens the view that the reaction is only dependent on the relative ease of oxidation of the substrate. The rate constant obtained for p-aminophenol indicates that a value of 2.3 X 10(8) M-1 S-1 probably approaches the diffusion-controlled limit for a bimolecular reaction involving compound I and an aromatic substrate.


Therapeutic properties.of haemodialysis and blood exchange transfusion in organophosphate poisoning. Human blood was contaminated with nitrostigmine, dimethoate and demeton-S-methyl sulfoxide. It was then dialysed, concentrations of organophosphates were determined and dialysance values calculated. The influence of blood exchange transfusion on poison elimination as well as on the cholinesterase activity of blood, brain and muscle was studied in rats poisoned with nitrostigmine. Haemodialysis was found to be quite an effective method for eliminating demeton-S-methyl sulfoxide and dimethoate, dialysance values of 52.98 ml/min and 59.07 ml/min being found for demeton-S-methyl sulfoxide and dimethoate respectively. Nitrostigmine could not be removed by haemodialysis. These findings suggest that haemodialysis could be of therapeutic value in the treatment of severe demeton-S-methyl sulfoxide and dimethoate poisoning in man. By blood exchange transfusion only 0.06% of the injected dose of nitrostigmine could be removed from the body of poisoned rats. Acetylcholinesterase activity increased only briefly in the period of blood exchange transfusion and decreased gradually afterwards. The enzymatic activity of brain and muscle was unaffected. Therefore, blood exchange transfusion has, if any at all, only poor therapeutic properties in nitrostigmine intoxication.


Studies in cerebrospinal acid base values in intensive care patients. CSF acid base homeostasis was studied in 22 patients in an Intensive Care Unit, to ascertain whether an assessment of this parameter was of any prognostic value. The only significant findings were a lower CSF bicarbonate concentration in those patients who demised, as well as a poor correlation between CSF pH and both CSF PCO2 and bicarbonate. It was concluded that an assessment of CSF acid base balance was of no prognostic value in this particular group of patients.


Continuous intravascular monitoring of pO2 and pCO2. A comparative in vitro-in vivo study. Two electrodes placed at the tip of catheters for in vivo determinations of PCO2 and PO2 respectively, were tested in dogs. Results were satisfactory when compared to a highly accurate reference method, correlation coefficients were close to 1 (P less than 10(-9)). Means of the differences were respectively --1.74 +/- 1.14 toor for the PO2 probe (P less than 0.01) and --1.62 +/- 0.72 torr for the PCO2 sensor (P less than 0.0001). While no drift was detected in the PCO2 electrode, that of the PO2 was significant but negligible compared to the variability of measurements. Thus, for PCO2 values between 20 and 85 torr, and PO2 values between 20 and 140 torr, in vivo monitoring is sufficiently reliable for clinical use.


Transcutaneous pO2 monitoring in anaesthesia. In 23 patients 18 to 73 years old transcutaneous PO2, relative local perfusion and cardiorespirogram during induction and end stage of anaesthesia were monitored. This method allows continuous sufficiently exact estimation of PaO2. The comparison between tcPO2 and corresponding blood gas analysis from arterial samples showed a good correlation of r=0.94. Thus continuous tcPO2 registration enables quick diagnosis of hypoxia and its therapy.


The effect of respiration on the monitoring of stroke volume and cardiac output by the electrical impedance technique. In six volunteers (5 male, 1 female) it has been shown that normal respiration made no statistical difference to the estimates of the mean stroke volume and the mean cardiac output as determined by the electrical impedance method of Kubicek et al, (1966). The coefficient of variation was usually increased by respiration. The use of those stroke volumes which occur only at end-expiration was not shown to yield a greater reproducibility with 3 other male volunteers. In the female subject it was found that the use of a digital averager triggered from the preceding R-wave of the ECG gave values for the mean stroke volume and cardiac output which were always lower than the conventional mean values obtained from a number of strokes. The expense of either of these approaches does not appear to be justified as a means of compensating for the effects of normal respiration on the impedance dZ/dt waveform.


Influence of early mobilisation of pulmonary function in surgical patients. This work confirms the generally known decrease in arterial oxygen following surgery. On the basis of a more rapid restitution of pulmonary function the superiority of mobilization to the usual respiratory exercises is clearly shown.


Syndrome of depressed vital functions in the immediate post-operative period of surgical patients: some aspects of its pathogenesis. Fifty adult male and female surgical patients (age 25--40 years) undergoing elective and emergency surgical procedures were subjected to isocapnoeic, hypocapnoeic and hypercapnoeic ventilation during anaesthesia; the PaCO2 ranged between 22--90 mm Hg. Three developed the syndrome of depressed vital functions in the post-surgical period by scoring less than 7 out of 10, the others recovered normally with complete resotration of reflex activity, consciousness and skeletomuscular tone, scoring on an average 8 out of 10 points. The role of muscle relaxant drugs in this syndrome and also the depression of the central nervous system is discussed.


Left ventricular function after acute myocardial infarction. 10 patients with their first AMI were studied within the first 48 hours and again after 3 weeks. Central and peripheral haemodynamics (CI, SV, SW, TPR) were examined, including indices of contractility (dp/dtmax) and wall stiffness (deltaP/deltaV, relation deltaP/deltaV to P) of the left ventricle. In the early phase CI and SW, as well as LV dp/dtmax were depressed in accordance with symptoms of LV failure. deltaP/deltaV was increased. Elevation of LVEDP correlated well with ventricular gallop rhythm, but less consistently with LV functional disturbance. During convalescence CI increased uniformly, both in digitalized and non-digitalized individuals. In contrast heart rate, aortic pressure, LVEDP and dp/dtmax remained unchanged. The increase of CI, SV and SW was accompanied by a fall of TPR and deltaP/deltaV. LV wall stiffness was still  elevated above normal after 3 weeks. The improvement of cardiac pumping during infarct convalescence may have been effected through a fall of TPR and LV wall stiffness. Recovery of depressed contractile performance was generally not observed, and does therefore not seem to contribute to recuperation.


Studies of malformation syndromes of man XXXIX: a craniosynostosis-craniofacial dysostosis syndrome with mental retardation and other malformations: "craniofacial dyssynostosis". We report clinical findings in 2 sisters and 5 sporadic cases with a "new" type of craniosynostosis/craniofacial dysostosis and shortness of stature. Premature closure of lambdoid sutures and posterior part of sagittal suture causes a posteriorly narrow, dolichocephalic skull with small, flat or bulging occiput and protuberance of the forehead; disturbance of the growth of basal skull structures leads to craniofacial dysostosis and (secondary) anomalies of the face. In one patient the coronal suture was also involved. One of the patients had a congenital heart defect. Four untreated patients had mental retardation; 3 had craniosynostectomy with more or less normal psychomotor development afterwards. Some patients had hydrocephalus and 1 had a brain malformation (agenesis of the corpus callosum with presumed interventricular lipoma). The observation of sisters with the same condition suggests autosomal recessive inheritance. This etiologic hypothesis is supported by the fact that 4 of 7 patients are of Spanish, Mexican, or Puerto Rican ancestry; this population probably has a rather high gene frequency and the trait should be relatively common in areas occupied by this population and their descendents. The condition has been designated craniofacial dyssynostosis.


Chondrodysplastic dwarfism, cleft palate and micrognathia in a neonate, a new syndrome? We describe a female infant with lethal, short-limb dwarfism, micrognathia, hydrocephalus with occipital encephalocele and a generalized spondyloepimetaphyseal dysplasia who probably has the same condition that was described by Rolland et al. (1972) and by Langer et al. (1976). This may be recessively inherited syndrome


Severe anemia due to transient pure red cell aplasia in early childhood. Arrest at the level of the committed stem cells? Five patients, 11 months to 3 4/12 years old with severe normochromic, normocytis anemia and reticulocytopenia are reported. At the height of erythropoietic arrest when erythroid precursor cells were completely absent, undifferentiated stem cells (transitional cells), accumulated in the bone marrow. They disappeared again upon spontaneous resumption of erythropoiesis. We suggest that the erythropoietic arrest had occurred at the level of the hematopoietic stem cell. All patients recovered within 1 week of diagnosis. No steroid therapy was given. Failure to recognize this clinical entity leads to unnecessary diagnostic and therapeutic procedures including the transfusion of blood.


The 18 p-syndrome. Report of four cases. Four children, two girls and two boys, were found to have a short arm deletion of chromosome No. 18. Three of them exhibit a typical dysmorphy of the face showing retraction of the midface, broad-based, flat nose, hypertelorism, epicanthus, "carp mouth", big, protruding, and low set ears, as well as a variable number of Turner-like features, failure of growth, mental retardation, and muscular hypotonia. A newly born child, who died at 2 days of age exhibited severe brain defects of holoprosencephalic series. The clinical and cytogenetic findings are compared with the reviewed data of the 18 p deletion. The hypothesis of "gene-dosis compensation" is discussed in order to explain the variable phenotypical expression of 18 p-syndrome as there is obviously to correlation between the extent of the deficiency and the expression of malformations.


Hereditary Amyotrophic Lateral Sclerosis. A report of two families. An aggregation of 14 cases of amyotrophic lateral sclerosis (ALS) was encountered in two families in Minnesota. Although the classical clinical features of ALS predominated, some members of one family showed, in addition, extrapyramidal signs, peripheral sensory impairment in the upper and lower limbs and mild mental fallout. Autosomal dominant inheritance with incomplete penetrance was the most likely mode of transmission. Pathological changes were the same as those seen in sporadic ALS although one patient also showed degeneration of the substantia nigra. These two families were compared to others in the literature and an effort was made to refine the classification of familial ALS.


Multiple sclerosis, diffuse lymphoplasmocytic encephalitis and Alzheimer's disease in a patient with progressive dementia. Female patient, aged 63 died after 5 years of progressive dementia. Autopsy revealed multiple sclerosis, diffuse lymphoplasmocytic encephalitis, and Alzheimer's disease. Possible pathogenetic connections between these disease entities are discussed.


Myasthenic syndrome in polymyositis.

Myasthenic syndrome in polymyositis. The case report of a 23-year-old man with polymyositis and some myasthenic features is presented. The biopsy findings suggest a preferential involvement of the neuromuscular junctions by the inflammatory process, a fact which explains the clinical syndrome.


Congenital non-progressive myopathy with type II fibre atrophy and internal nuclei. A particular form of congenital non-progressive myopathy in a 5-year-old boy is described. The morphological features include predominant atrophy and rarity of type II muscle fibres, internally placed nuclei and myofibrillar degeneration in affected fibres.


A solitary abscess of the medulla oblongata. A neuropathological description is presented of a solitary giant abscess located in the oblongate medulla of a child aged two. This abscess destroyed almost all the morphological structures in the medulla and caused considerable constriction and translocation of the IVth ventricle. Apart from the exceptional occurrence of an abscess in this brain region, the interesting features of this case are the slow development of the abscess (probably 8 months) and the existence of a well-formed connective tissue capsule, demarcating the lesion from its surroundings. The diagnostic difficulties and clinical and histopathological correlation are also discussed.


Material and design factors in thromboembolization in total artificial heart recipients living 100-2,000 hours. When total artificial heart (TAH) recipients live over 100 h it is possible to evaluate the thrombogenicity of design and biomaterials. In 20 consecutive TAH recipients of the Jarvik heart with Björk-Shiley valves we compared rough (Dacron fibril-coated Silastic) and smooth (Biomer and Avcothane) blood surfaces. The mean survival times with rough surfaces was 296 h, with smooth surfaces 545 h. The present designs necessitate a sharp angle junction between the diaphragm and housing, creating stagnation areas and turbulences which induce thromboembolization. The valve rings and struts are another constant source of thromboembolism. Of the 80 valves, 41% showed thrombus deposition independent of anticoagulation. The polyurethane surfaces, in contrast to the fibrilized surfaces, were very clean and free of thrombi at autopsy. The thromboembolization was not dependent on anticoagulation and platelet adhesiveness inhibitor in hearts with rough surfaces. Based on 20 experiments including 78- and 94-day TAH survivors (Avcothane and Biomer hearts), there is an indication of the need of a new ventricular design. The ultimate design should generate physiological pulse waves without turbulences or stagnation areas within the device.


Comparative study of in vitro flow characteristics between a human aortic valve and a designed aortic valve and six corresponding types of prosthetic heart valves. A model of a pulsatile cardiovascular system is described including an electronic control, a hydraulic driving unit, a volume storage, a peripheral resistance and measuring equipment. Six different artificial heart valves, a designed aortic valve (Aachen pockett valve II) and a human aortic valve have been tested in the outflow position of the pump. Three of them are presently being used in clinical applications. Measurements of pressure and volume flow have been obtained for different frequencies n, pump volumes Vp and time ratios between pressure and suction phase. From the experimental results a comparative evaluation was deducted for different working conditions. In comparison to natural human aortic valve (NK) large volume flow is verified by the Aachen pocket valve II (AT), the Gott-Dagget value (GD), the Starr-Edwards valve (SE) and the Lillehei-Kaster valve (LK). The Gott-Daggett valve has the smallest back flow volume. The Smeloff-Cutter and in particular the Wada-Cutter valve have the largest regurgitation. This is to be expected since the Cutter valves are purposely so designed that they do not close tightly in order to avoid blood sedimentation. The human aortic valve, the Gott-Daggett valve and the Aachen pocket valve demonstrate the most favourable opening-closing characteristics. The human aortic valve achieves a negligible pressure loss, followed by the Björk-Shiley and the Lillehei-Kaster valve.


Effect of low molecular dextran on total liver blood flow in hemorrhagic shock. Hemorrhage amounting to 40% of the calculated blood volume in dogs produced a fall in systemic blood pressure to a level of approximately 50 mm Hg. This was associated with a decline of total liver blood flow of about 60% of normal. Infusion of low molecular dextran (LMD) or saline of a volume, corresponding to 1/7 of the volume of blood taken out, increased the total liver blood flow. This increase was much more pronounced in the LMD group, maybe due to the ability of LMD to simultaneously increase systemic blood pressure, decrease blood viscosity and disaggregate red blood cells in the microcirculation.


An attempt to induce portal hypertension and esophageal varices in the rat. An attempt to induce portal hypertension using Ameroid constrictors and shunt operations is described. 1 week after the application of the Ameroid constrictor around the portal trunk, it was completely occluded and portal venous pressure was elevated to a level about twice of normal range. Angiographically, splenorenal collaterals and collaterals overbridging the Ameroid constrictor were observed in all examined rats. However, esophageal varices could not be found in any rat. In the second series of the experiment, an end-to-side cavoportal shunt was created before the application of the Ameroid constrictor. This operation model was devised to increase the portal venous flow. At the same time this operation should inhibit the development of splenorenal collaterals and as expected collaterals to the superior vena cava system developed instead. However, they were not located in the esophageal wall but retroperitoneally.


Exercise fitness, cardiac work and blood viscosity factors in patients and normals. A study of 41 cardiovascular patients and normals showed significant correlations between physical fitness (as expressed by a fitness index based on work output) and high shear rate blood viscosity (p less than 0.01); between the cardiac work expressed as double product (= myocardial oxygen demand) and aggregation of red cells (p less than 0.05); between the triple term of cardiac work (fitness index divided by double product) and high shear rate blood viscosity (p less than 0.005) or aggregation of red cells (p less than 0.05), in all cases correlations being negative i.e., higher cardiac work or higher fitness being related to low blood viscosity or lower aggregation of red cells. Significant differences were found between high-fitness and low-fitness groups, the high-fitness group showing from plasma viscosity (p less than 0.0005), lower fibrinogen level (p less than 0.05), and higher albumin/fibrinogen ratio (p less than 0.01).


The place of gastrin determination in ulcer surgery. This paper is concerned with the place of gastrin determination in ulcer surgery. Only the acid-stimulating properties of gastrin are considered. The role of the vagus in the gastrin response to a test meal was investigated in patients with duodenal ulcer. 50 patients were studied before and 3, 6, and 12 months after highly selective vagotomy without (25 patients) and with Wnagensteen-pyloroplasty (25 patients). Basal and stimulated gastrin concentration in serum, as determined by radioimmunoassay, were higher 3 months after the operation and 3h after the test meal gastrin levels were still 50% higher than the basal levels. No difference was found between the patients treated with highly selective vagotomy and the patients treates with HSV and additional pyloroplasty. 6 and 12 months after the operation a moderate decrease of gastrin secretion was observed, but basal as well as stimulated levels were still elevated after 12 months compared to the values before operation. Our results indicate that the pattern of gastrin secretion changes as time passes after highly selective vagotomy with or without additional pyloroplasty.


Modification of procine stress ulceration by methylprednisolone, vitaminA and methysergide treatment. Using a swine shock ulcer model, three pharmacological agents, methylprednisolone, vitamin A and methysergide were evaluated, as they protect gastric mucosa against acute ulceration. Following haemorrhagic shock (3 h duration; mean arterial pressure 40 mm Hg) nine of the ten control animals (90%) developed gastric ulceration. Of the six test animals treated with intravenous methylprednisolone during the shock, only one (17%) developed gastric lesions (p less than 0.02; x2 = 5.76). Of the ten test animals pretreated with massive doses of parenteral vitamin A, only three (30%) developed lesions (p less than 0.05; x2 = 5.21). In contrast to this, treatment with methysergide, a serotonin antagonist, did not significantly effect the ulceration rate, since four of the six test animals (67%) had gastric lesions. The results suggest that methylprednisolone and vitamin A do protect the gastric mucosa from experiment stress ulceration, but their mechanism of action remain obscure and further investigation is needed to judge their value in clinical use.


Insulin response and portal-peripheral insulin difference during the oral glucose tolerance test in patients after abdominal operations. Following abdominal surgery, insulin and glucose concentrations in the portal vein, and a peripheral vein are compared in patients during control periods and after oral administration of glucose. During the control period, the glucose concentrations are identical in both veins. After glucose loads with the prompt increase of portal glucose concentration the portal-peripheral difference also increases (p less than 0.01). During the control period the insulin concentration in the portal vein is double as compared to peripheral blood (p less than 0.005). After glucose load the increasing portal insulin as well as the peripheral and portal glucose correlate with the portal-peripheral insulin difference (p less than 0.001). Furthermore, there is a significant positive correlation between the peripheral glucose area as a parameter of glucose tolerance and the portal insulin area as a semiquantitative parameter of insulin secretory capacity (p less than 0.001). It can be concluded that in the early postoperative period in patients with a diminished oral glucose tolerance (large glucose areas) there is an even greater insulin response in comparison to patients with normal oral glucose tolerance. On the other hand, however, in those patients with diminished glucose tolerance, the insulin response is essentially delayed.


Metabolism in the hypothermically perfused kidney. Production and utilization of lactate and utilization of acetate in the dog kidney. The mechanism for the high lactate production during hypothermic kidney perfusion has not been clarified previously. The metabolism of lactate and acetate was studied in 23 dog kidneys during continuous hypothermic perfusion. The perfusions were performed in a Gambro machine with a perfusate based on human serum albumin. With a perfusate containing fatty acid extracted albumin, which was almost free of fatty acids, the glucose uptake of the kidney was more pronounced than during perfusion with a fatty acid-rich perfusate. The high glucose uptake under this perfusion condition was associated with a lower lactate production and a higher glucose oxidation rate. In perfusions with a perfusate containing lactate at a concentration of 2.5 mmol/l a considerable lactate uptake of the kidney was shown. By isotope dilution technique the production and uptake rate of lactate was estimated at 4.4 and 8.0 mumol/g kidney and day in two experiments. The labeled lactate carbon was recovered in CO2, and glucose in the perfusate indicating a continuous oxidation and gluconeogenesis. Acetate was used by the kidney both for oxidation and for gluconeogenesis. Addition of acetate to the ordinary fatty acid-rich perfusate caused an enhanced lactate production from the perfused kidney. The results indicate that the high lactate production during hypothermic perfusion of kidneys is mainly dependent on a metabolic blockade at the level of pyruvate dehydrogenase.


Skeletal muscle metabolites as possible indicators of imminent death in acute hemorrhage. The extent to which changes in tissue energy metabolism correspond to the severity of a hemorrhagic shock condition has been studied. In cats, 50% of the blood volume was withdrawn within 10 min, resulting in a fatal outcome within 3h (range from 45 min to 3 h). Skeletal muscle and blood samples were taken prior to the hemorrhagic and in the agonal phase or after 2 h in compensated bled animals. Tissue levels of ATP, CrP, G-6-P, lactate and glucose as well as blood levels of glucose, lactate and pyruvate were determined enzymatically. The results showed no depletion of phosphagen levels in the agonal phase, while glycolytic metabolites, lactate in particular, demonstrated a close correlation to circulatory deterioration and imminent death.


Wound healing. Comparison of healing rates of burn wounds and of excisional wounds. The process of healing of skin excisions and skin burns of equal sizes has been compared in rabbits. Excisions heal definitely quicker than burns, despite the fact that the part of the skin exposed to the burning agent does not undergo necrosis. Small excisional wounds heal more rapidly than larger ones but the healing rate of burn wounds in our series was independent of their size. Secondary excision of the burned tissue accelerates the healing process. Thus the healing time of burn wounds seems to depend more on clearing the wounds of the necrotic tissue than on the mere repair of the skin loss.


Motility depressed intestinal propulsion following selective jejunal myotomy in the rat. The effect of segmentary sectioning of the proximal jejunal tunica muscularis on intestinal propulsion was studied in the rat. Care was taken to avoid damage to the mucosa. In no instance was perforation or occlusion of the intestine observed. Myotomy was followed by a significant slackening of the passage of a test meal during the first 15 min after feeding, while the total transit time was virtually unchanged. Sectioning the musculature of the intestinal wall is shown to be responsible for retardation of bowel passage.


Bone mass in maintenance haemodialysis. Prospective study with sequential biopsies. The change of bone mass during maintenance haemodialysis was studied in 20 patients. Iliac crest biopsies were obtained at a 9 - 16 months interval. Two biopsies were taken in order to give an independent estimate of the sampling error. 22 individuals in the same age group without skeletal disease who died from traffic accidents or from violent deaths were used as controls. Undecalcified sections of bone (Masson-Goldner-stain) were evaluated by micromorphometry. At the beginning of the study osteosclerosis (i.e. volumetric density of bone above x +/- 2 SD in control patients) was found in 14 out of 20 patients. Volumetric density of bone only increased in one of the patients during the observation period. A significant decrease of volumetric density of bone was found in 5 out of 20 patients. This could be attributed to prolonged immobilisation in two cases and to inadequate protein- and calorie-intake in two cases. No predisposing factor could be found in the fifth case. It is concluded that loss of spongy bone mass (osteopenia) is not an invariable result of haemodialysis.


Activity of erythropoietin and renin in renal venous blood of hypertensive patients. Plasma activities of renin and erythropoietin were determined in the renal veins of the right and left kidneys of hypertensive patients. The patients were divided into the following groups either according to the origin of the hypertension (group 1: control for essential hypertension, group 2: renovascular hypertension) or according to the hormone levels (group 3: renin activity exceeding 10 ng/litre in at least one of the renal veins and group 4: erythropoietin activity higher than 4% 59Fe incorporation in at least one of the renal veins). In groups 1, 2 and 3 a statistically significant difference in renin activity was found between the kidney with the higher renin activity and that with the lower activity. However, in group 4, the side, which showed elevated erythropoietin values also had higher renin activity as compared to the essential hypertensive group. Erythropoietin activity probably does not parallel the increased renin activity found in renovascular hypertension or in some cases of non-renovascular hypertension. However, in several cases of renal vascular alterations, both systems can be activated simultaneously.


Influence of bile acids upon biliary cholesterol and phospholipid secretion in the dog. The relationship between taurocholate or taurochenodeoxycholate secretion and cholesterol and phospholipid secretion in bile was studied in anaesthetized dogs infused with graded doses of these bile acids. Cholesterol output was linearly related to bile acid output during both taurocholate and taurochenodeoxycholate infusions. On the average 1.45 nmol and 4.70 nmol of cholesterol were secreted per mumol of taurocholate or taurochenodeoxycholate respectively (P less than 0.001). A linear relationship was also observed between phospholipid secretion rate and taurocholate or taurochenodeoxycholate secretion rates. However, the amounts of phospholipid secreted per mumol of taurocholate or taurochenodeoxycholate (respectively 0.10 and 0.15 mumol) were not significantly different. Thus, bile was less saturated with cholesterol during taurocholate infusions than during taurochenodeoxycholate infusions. These results are consistent with the hypothesis that micelle formation by bile acids is a major determinant of cholesterol and phospholipid secretion in the dog.


Removal of exogenous plasma triglycerides in forearm muscle and subcutaneous tissue of hyper-and normotriglyceridaemic men. Absolute arterio-venous removal and fractional removal of blood-borne exogenous triglyceride particles by skeletal and subcutaneous tissues were determined in eight normotriglyceridaemic and six hypertriglyceridaemic men. Estimations were made by simultaneously sampling blood from catheters inserted into a brachial artery, and in the distal direction, into a superficial and deep vein, draining subcutaneous tissue and skeletal muscle respectively. During the infusion of the fat emulsion IntralipidR for 3 hours steady arterial concentrations of exogenous TG particles were found, indicating first order kinetics. In all subjects absolute arterio-venous and fractional removal of triglycerides were about twice as high in skeletal muscle as in subcutaneous tissue. In skeletal muscle the fractional removal and absolute removal were significantly higher in normotriglyceridaemic than in hypertriglyceridaemic subjects (p less than 0.001). No decrease in removal with time was observed, which would have suggested saturation of removal sites. Mean fractional removal in skeletal muscle was significantly correlated with the k2 value determined by an intravenous fat tolerance test before the infusion study (r = 0.61, p less than 0.05). In subcutaneous tissue fractional removal was also significantly higher in normotriglyceridaemic subjects (p less than 0.05). The results suggest that in both skeletal muscle and subcutaneous tissue the removal system is impaired in hypertriglyceridaemic subjects. This finding supports the concept that a decreased elimination capacity in these tissues may partly account for triglyceride elevation in hypertriglyceridaemic subjects.


The effects of prostaglandin E1 and sodium meclofenamate on blood pressure in renal hypertensive rats. Conflicting evidence exists regarding the ability of PGE1 to normalize blood pressure in renal hypertensive rats. We performed experiments to determine the effect of PGE1 (15 mug/kg i.p. daily for 3 weeks) in renal hypertensive Wistars and found no significant change in systolic pressure. A higher dose (150 mug/kg i.p.) lowered pressure after 14 days of treatment, but not back to control levels. Further investigations are required to establish the mechanism whereby PGE1 evokes this fall. To test the hypothesis that endogenous prostaglandins have a hypotensive function in renal hypertension, experiments were performed using sodium meclofenamate to inhibit prostaglandin biosynthesis. In chronic hypertensive rats the drug had no significant effect, while in the acute phase of renal hypertension there was a dose-dependent inhibition of the pressure rise. The possibility is suggested that prostaglandins may initiate or sustain the acute phase of renal hypertension in rats.


Effects of levomepromazine, chlorpromazine and their sulfoxides on isolated rat atria. The effects of levomepromazine, chlorpromazine and their sulfoxides were studied on spontaneously beating and on electrically driven rat atria in vitro. Levomepromazine, chlorpromazine and levomepromazine sulfoxide produced a dose-dependent decrease in the work index of spontaneously beating atria and in the contractile force of electrically driven atria, while chlorpromazine sulfoxide was relatively inactive in these respects. At higher concentrations, levomepromazine sulfoxide caused a pronounced increase in the threshold for electrical stimulation and the effective refractory period. Compared to chlorpromazine, levomepromazine looses less of its cardio-depressive effect through sulfoxidation.


Turnover of acid dopamine metabolites in striatal and mesolimbic tissue of the rat brain. The subject of this study was the disappearance of 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the brain of rats treated with pargyline and pargyline in combination with tropolone. The DOPAC decline was exponential after pargyline treatment, while the HVA decline became a first order elimination when in addition to monoamine oxidase, catechol-O-methyl transferase was also inhibited. The turnover of the metabolites was calculated by multiplying the steady state level by the fractional rate constant (k). The DOPAC turnover was found to be 23.3 nmol/g/h in the corpus striatum and 22.6 nmol/g/h in the mesolimbic structures. The HVA turnover was 11.2 nmol/g/h in the corpus striatum and 6.7 nmol/g/h in the mesolimbic structures. The data showed that under control conditions DOPAC is only partially O-methylated to HVA, while the formation of HVA via the methoxytyramine pathway is unlikely. DOPAC turnover therefore probably approximates dopamine turnover.


Distribution and occurrence of amphetamine and p-hydroxyamphetamine in tissues of the rat after injection of d-amphetamine sulfate. The distribution of amphetamine and the formation and distribution of its principal metabolite p-hydroxyamphetamine after the injection of relatively small amounts of d-amphetamine was examined in the rat. Amphetamine entered all organs readily and was rapidly eliminated. p-Hydroxyamphetamine was rapidly synthesised and it is suggested that substrate inhibition of hepatic hydroxylating enzymes occurs. In the brain, amphetamine was homogeneously distributed between the seven brain regions examined whereas p-hydroxyamphetamine was predominantly concentrated in the striatum.


The masking role of the sodium pump and chloride ions on the effect of carbachol in- and outside the endplate region of rat diaphragm muscle. The effect of carbachol (10(-3)M) on the membrane potential of rat diaphragm muscle fibres near and remote from the endplate has been investigated by means of a microelectrode technique. In the endplate region a rather slow depolarization was observed followed by spontaneous repolarization. Outside the endplate region similar, but smaller, responses could be measured. In a muscle part separated from the endplate zone, carbachol had no depolarizing effect. Inhibition of the sodium pump by ouabain (10(-4)M) or potassium-free medium not changing the membrane potential itself, allowed carbachol to exert a depolarizing effect on this endplate-free membrane, while in endplate-free regions continuous with the endplate-zone the depolarizations already observed were enhanced. In low chloride solutions carbachol also had a depolarizing effect on endplate-free muscle membrane. It is concluded from these experiments that a direct effect of cholinergic drugs on endplate-free muscle membrane of rat diaphragm is counteracted by the sodium pump in combination with passive chloride movements. The results are discussed in the context of known receptor densities and chloride effects.


Effects of anesthetics and septal lesions and stimulation on 3H-acetylcholine formation in rat hippocampus. The rate of 3H-acetylcholine (ACh) formation from i.v. injected 3H-choline was studied in the rat hippocampus after various treatments which alter the activity of cholinergic septal hippocampal neurons. Administration of pentobarbital and placement of acute septal lesion reduced the formation of 3H-ACh but did not change 3H-choline content. Chloral hydrate administration reduced the formation of 3H-ACh and also increased 3H-choline content. The chloral hydrate induced increase in 3H-choline occurred also in animals with chronic septal lesions. Electrical stimulation of the septum caused an increase in both 3H-ACh and 3/-choline. Chronic septal lesion caused a reduction in both radioactive and endogenous ACh, but did not affect radioactive or endogenous choline. These findings suggest that there are multiple pools of choline in the brain and that the precursor pool for ACh synthesis is difficult to measure. Overall, the parameter that best correlated with cholinergic activity was the level of 3H-ACh. Possible mechanisms, for this finding are discussed.


Inhibition by ethanol of noradrenaline output from peripheral sympathetic nerves: possible interaction of ethanol with neuronal receptors. The sympathetic nerve terminals of the isolated rabbit heart perfused with Tyrode solution were used to study the action of ethanol on the noradrenaline uptake and release. The uptake of exogenous noradrenaline (10 ng/ml) into the sympathetic nerve endings, the noradrenaline output evoked by raising the concentration of potassium ions in the perfusion fluid, and the release in response to electrical stimulation of the nerve axons were inhibited only by lethal concentrations of the alcohol; the concentrations which caused 50% inhibition (IC50) amounted to 760 mM, 830mM, and 1150 mM respectively. However, ethanol at concentrations compatible with moderate intoxication reduced the noradrenaline release in response to activation of the nicotine receptors on the nerve terminals by dimethylphenylpiperazine; the threshold concentration was 36 mM and the IC50 was 129 mM. It is suggested that this effect is due to hydrophobic interaction of the alcohol with receptor proteins, thus inhibiting stimulus formation.


A new probe for heterogeneity in muscarinic receptors: 2-methyl-spiro-(1, 3-dioxolane-4, 3')-quinuclidine. The title compound (MSDQ) is a new muscarinic agonist related to 3-acetoxyquinuclidine (3-AcQ) but also of a highly rigid structure. In view of this, it may constitute a probe for the detection of heterogeneity among muscarinic receptors. Indeed, equipotent molar ratios (EPMR) for ACh, 3-AcQ and MSDQ were as follows: guinea pig ileum, 1 : 14 : 240; vasodepressor effect in the cat, 1 : 6 : 188. But EPMR for 3-AcQ and MSDQ as stimulants of the superior cervical ganglion in the cat were 1 : 1 and for the induction of tremors in mice, 9 : 5. No such subtle differences in receptor specificity were detected when the probe used was the 2, 2-diphenyl analogue (DiPSDQ) of MSDQ which was a powerful competitive antagonist in all systems, more potent than atropine, but with a CNS/PNS activity of 1.1 compared to 26 for atropine. In view of this, the use of potent antagonists as probes for muscarinic receptor heterogeneity is questionable.


Alteration of tumor growth by aspirin and indomethacin: studies with two transplantable tumors in mouse. Oral daily administration of aspirin or indomethacin retarded growth of experimental tumors in mouse. Aspirin treatment, 150 mg/kg twice daily, inhibited growth of a transplantable mast-cell ascites tumor (P815) by 39-43% (p less than 0.001) and of a s.c. transplanted Lewis lung carcinoma by 52% (p less than 0.025) without adversely affecting body growth. The total serotonin, histamine and histidine decarboxylase content of the ascites tumor was also reduced as was the urinary excretion of the amines. Treatment with 3 and 5 mg/kg indomethacin resulted in 40% (p less than 0.01) and 80% (p less than 0.001) reduction, respectively, in ascites tumor growth. With the higher dose of indomethacin, no tumor was observed in half of the animals inoculated with tumor, although signs of indomethacin toxicity (reduced body growth, gastric lesion) was evident in the animals.


Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system. Clonidine (30 mug/kg, i.v.) reduced centrally evoked electrodermal responses (EDR) following stimulation of reactive loci in the hypothalamus and medulla. The responses were most depressed following low frequency stimulation. Similar results were observed on the EDR evoked by stimulation of the cervical cord in the spinal cat. Little effect was seen following peripheral nerve stimulation. These results demonstrate that clonidine depresses the reactivity of this sympathetic-cholinergic system at all central levels including the cervical cord.


Effects of chlorprothixene isomers on platelet 5-hydroxytryptamine receptors: evidence for different 5-hydroxytryptamine conformations at uptake and stimulatory sites. The thioxanthene neuroleptic, cis-chlorprothixene, was approximately 200 times more potent than its transisomer as an inhibitor of the aggregation of human blood platelets induced by 5-hydroxytryptamine (5HT). Against the active uptake of 5HT by these cells, however, trans-chlorprothixene was twice as inhibitory as its cisisomer, and this inhibition was found to be competitive. It is suggested that 5HT adopts different conformations for binding to its two platelet receptors.


The positive inotropic and chronotropic actions of some amino acids and their effects in mobilizing noradrenaline. The effects of methionine, cysteine and serine on the rate and strength of contractions of isolated Langendorff preparations of perfused dog heart and on spontaneous release of catecholamine (CA) from these hearts were investigated. These neutral amino acids increased the amplitude of ventricular contractions. Methionine and cysteine also stimulated the ventricular rate. They induced release of noradrenaline (NA) from the isolated heart. Their inotropic and chronotropic effects were significantly inhibited by pretreatment of the heart with propranolol.


Cardiovascular responses to acute hypoxia in dogs pretreated with benserazide and L-DOPA. In the control dogs, hypoxia induced different hemodynamic modifications (i.e. an increase of arterial blood pressure, heart rate, cardiac output, regional blood flow) which seem to be related to a release of epinephrine. Pretreatment with benserazide (20 mg/kg i.v.) and L-Dopa (50 mg/kg i.p.) either lessened or completely suppressed any sign of sympathetic stimulation. These results suggest that chemoreceptors are centrally inhibited as had been previously proved for baroreceptors.


Recovery of central respiratory function following anticholinesterase intoxication. Spontaneous recovery of central respiratory function was studied in anesthetized guinea pigs intoxicated with pinacolyl methylphosphonofluoridate (Soman) or isopropyl methylphosphonofluoridate (Sarin). I.v adiministration of either agent produced an immediate disruption phrenic nerve activiity and resulting ventilatory failure. Animals were maintained on artifical respiration until spontaneous functional recovery was complete, as evidenced by the re-establishment of synchronized burst activity on the phrenic nerve and return of tracheal airflow. This usually occurred within 1 h. Animals were sacrificed at predetermined intervals after intoxication, and the brainstem homogenates were analyzed for AChE activity. Results showed no significant return of AChE activity after 1 h, although functional recovery of respiration was complete within this time. Additional doses of the agents were administered at various times after recovery from the respiratory blockade. Following spontaneous restoration of ventilatory function, subsequent injections of the organophosphorus compounds failed to reinstate central respiratory paralysis, although they further depressed brainstem AChE levels. These data suggest that spontaneous recovery of central respiratory function after intoxication with Soman or Sarin may not be related to the return of AChE activity.


Des-Asp1-angiotensin I: a metabolite of angiotensin I in the perfused feline adrenal. The administration of radioactive angiotensin I to the retrogradely perfused feline adrenal gland caused a brisk discharge of catecholamines. Recovery of the labelled decapeptide and metabolites in the adrenal effluent fluid was complete in 5 min. Radioimmunoassay of this perfusate revealed that most of the peptide remained as angiotensin I, but chromatographic and electrophoretic evaluation indicated that  greater than 68% of the peptide had been metabolized to des-asp1 -angiotensin I. The absence of des-asp1  -angiotensin II, angiotensin II or his-3H-leu in adrenal effluent fluid suggested minimal dipeptidyl carboxypeptidase activity in this preparation. In addition, the profile of angiotensin I metabolites from the perfused adrenal was not altered by treatment with a converting enzyme inhibitor B. jararaca nonapeptide. The des-asp1-angiotensin I peptide was a very weak secretagogue in the adrenal medulla. If metabolism of the decapeptide to the nonapeptide occurs in the medulla, this may represent a pathway to limit the secretory action of angiotensin I. These results suggest a high degree of adrenal aminopeptidase activity which may be primarily localized in the adrenal cortex.


Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatments in the rat. Tolerance and physical dependence induced by chronic treatments with depressant drugs has been proposed as being due to denervation or disuse supersensitivity in the central nervous system. To illustrate this hypothesis, tolerance to barbiturates and the sensitivity to central cholinergic stimulation were recorded in the same male rats. Tolerance to barbiturates was recorded with a hexobarbital threshold. The dose needed to obtain an EEG criterion was measured. Sensitivity in central cholinergic structures was recorded by a temperature threshold method. A subthreshold dose of pilocarpine (3.5 mg/kg) was given s.c. together with 1.0 mg/kg methylscopolamine i.p. An increase in sensitivity to pilocarpine was recorded as a decrease in body temperature. In the abstinence period after 42 weeks of oral treatment with barbital, tolerance was recorded with the hexobarbital threshold method. The tolerance had two peaks, one after the end of the treatment and one approximately 3 weeks later. An increased sensitivity to pilocarpine was also recorded in the abstinence period. It had the same biphasic time pattern as the tolerance. Cholinergic neurones are thus probably involved in the changes induced by chronic barbital treatment. The denervation supersensitivity hypothesis of tolerance was not refuted by the present experiments.


A study of muscarinic receptor heterogeneity with weak antagonists. A study of heterogeneity among muscarinic receptors was carried out with new rigid molecules, comprising structures in the fused quinuclidine-valerolactone, quinuclidine-cyclohexenone, quinuclidine-cyclohexanone and quinuclidine-cyclohexane derivatives. These are structurally related to the potent muscarinic agent, 3-acetoxyquinuclidine but substantially different from in it conformation. All proved to antagonize acetylcholine-like activity, but to a different extent in different systems. The equipotent molar ratio with respect to atropine (as 1) was: isolated guinea pig ileum, 10,000-1,000; salivary gland (mouse), 1,000-100; superior cervical ganglion (cat), 100-10; CNS (mouse), approximately 10. It is suggested that the rigid structure induces a three-point constrained fit in the receptor (onium group, hydrophobic moiety and carbonyl group), but that not all muscarinic receptors are capable of responding equally. In this case, receptor specificity of the drug is a direct consequence of its graded departure from the preferred conformation of acetycholine and, therefore, is necessarily associated with partial loss of potency.


Radioimmunoassay for the simultaneous determination of morphine and codeine. Antiserum against morphine was produced in rabbits immunized with morphine hapten conjugated to bovine serum albumin. The carrier protein was conjugated to the nitrogen atom of the opiate alkaloid in order to make the phenolic hydroxy group on C3 and the alcoholic group on C6 as determinant groups. The antibody does not recognize codeine or the major metabolite of morphine, 3-O-monoglucuronide. This antibody was used in conjunction with an antibody prepared against 3-O-carboxymethylmorphine to develop a radioimmunoassay which can measure codeine in the presence of morphine. The assay was used to follow both the plasma and brain levels of codeine and its biotransformation to morphine. Codeine when administered at a dose of 5 mg/kg i.v. showed a biphasic plasma decay curve the first phase of which had a +1/2 of 26 min. Peak concentrations of morphine were detected in the plasma following that dose of codeine at 0.5 h. 30 min after the injection of 20 mg/kg i.p. codeine, the brain levels of morphine were only 2% that of codeine. Thereafter, the brain levels of morphine slowly declined.


Influence of chloride and sodium pump activity on carbachol- and acetylaholine-induced depolarizations in denervated rat diphragm. The effect was measured of low chloride medium and ouabain on carbachol- and acetylcholine-induced depolarizations in denervated rat diaphragm. Membrane potentials were measured in rat diaphragm muscle fibers 10-14 days after denervation. Depolarizations induced by carbachol and acetycholine were increased when the extracellular chloride concentration was diminished from 110 to 40 or 10 mM. Sodium pump inhibition by ouabain (10(-4) M) dramatically enhanced the carbachol depolarizations. In 40 mM Cl- solutions, dose-response relations were determineed with ACh in the absence of presence of dTc. For ACh a pD2 value of 5.2 was found; the pA2 value for dTC appeared to be about 6.4. Therefore, the binding properties of the post-denervational receptors do not appear to be influenced by the chloride gradient. It was concluded that drug-induced depolarizations of the denervated rat diaphragm are short-circuited by chloride ions and counteracted by sodium pumping.


Steroid anaesthesia (Althesin - CT 1341) and dorsal horn cell activities in feline spinal cord. The effects of steroid anaesthesia (Althesin -CT 1341) on dorsal horn cells (laminae 4 and 5) were studied by extracellular recordings in the spinal cat. I.v. administration of Althesin (0.2 ml/kg) strongly depressed the spontaneous and evoked activities of both types of cells. No differences were found between cells activated by noxious or innocuous stimuli. These results emphasize the fact that the transmission of afferent messages is depressed by various anaesthetics at the level of the first synapses in the CNS. The depressive effects on lamina 5 cells could explain in part the analgesic effects of Althesin.


Effects of apomorphine and of pimozide on renin secretion in the anaesthetized dog. This paper presents the results of a study of the receptors involved in renin hypersecretion induced by dopamine. Apomorphine induces renin hypersecretion without significantly modifying the renal blood flow. This renin hypersecretion is inhibited by haloperidol. However, pimozide, a selective dopaminolytic agent, is incapable of inhibiting the renin hypersecretion induced by dopamine. These results provide supplementary evidence for the existence of renal dopaminergic receptors which would appear to differ from the central dopaminergic receptors.


Effects of acute administration of delta9-tetrahydrocannabinol on pulmonary hemodynamics of anesthetized dogs. I.v. administration of delta9-THC (2.5 mg/kg) To anesthetized dogs resulted in a decrease in heart rate, pulmonary blood flow (PBF), and a significant increase in pulmonary artery pressure (PAP) and total pulmonary vascular resistance (PVR). The increase in PVR to delta9-THC was significantly reduced by cardiac pacing, and was virtually abolished either by bilateral vagotomy or by pretreatment with hexamethonium. The data indicated the delta9-THC induced elevation of PVR was mediated via reflexogenic mechanisms involving afferent vagi and efferent autonomic pathways.


L-alpha-amino-beta-chloropropionic acid hydroxamide: an inhibitor of GABA-lapha-oxoglutarate aminotrarsferase. The intramuscular administration of L-alpha-amino-beta-chloropropinonic acid hydroxamide (2 mmol/kg) to mice strongly inhibited the activity of GABA-T, but not GAD, in the brain of the animals. Adminstration of the compound 3 h prior to isonicotinic acid hydrazide treatment significantly delayed the onset of seizures induced by the hydrazide.


Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats. Bilateral electrolytic lesion of the area of the nucleus tractus solitarii (NTS) in rats produced a sustained increase in blood pressure and reduced the hypotensive response to a single dose of clonidine (30 mug/kg, i.v.). The same dose of clonidine evoked a much larger drop in blood pressure in another group of rats in which an equialent increase in blood pressure was produced by bilateral section of the vagosympathetic trunks and occlusion of both carotid arteries. It is concluded that the dorsal part of the medulla oblongata in the area of NTS is an important link in the hypotensive action of clonidine.


Inhibitory effect of a caerulein-like peptide on human gastric secretion. A synthetic heptapeptide corresponding to the C-terminal heptapeptide of caerulein but characterized by a nor-leucyl residue replacing the methyonyl residue of caerulein, when given by i.v. infusion (2 mug/kg/h), inhibited by 70-80% pentagastrin (4 mug/kg/h)-stimulated gastric secretion...


Clozapine: reduction of the initial dopamine turnover increase by repeated treatment. The levels of homovarillic acid and 3,4-dihydroxyphenylacetic acid in rat c. striatum after acute and 10 day administration of clozapine (30 and 100 mg/kg p.o.), thioridazine (100 mg/kg p.o.), haloperidol (1 mg/kg p.o.), and chlorpromazine (30 mg/kg p.o.), were estimated. With clozapine and haloperidol, the mesolimbic area was also investigated. With all these neuroleptics, the levels of both dopamine metabolites were reduced after a 10 day treatment as compared to acute administration, sometimes almost to control values. With clozapine, however, such a reduction occurred only with the higher dose of 100 mg/kg p.o., acting for a period longer than 24 h. This tolerance phenomenon was also observed with clozapine and haloperidol in the mesolimbic area. We conclude that clozapine is not qualitatively different from classical neuroleptics with respect to development of biochemical tolerance.


Dehydrobenzperidol and disopyramide in A-V conduction. The effects on A-V conduction of dehydrobenzperidol (Droperidol) 0.35 and 1.0 mg/kg i.v.) and disopyramide (1, 5 and 10 mg/kg i.v.) were tested in anesthetized, open chest and paced dogs. His's bundle electrograms were recorded by means of a catheter electrode or by a sutured electrode-bearing plaque in the A-V nodal region. Droperidol at the lower dose did not modify conduction time, while 1.0 mg/kg (3 times the usual clinical dose), prolonged atrial-His conduction without modifying H-V interval. Disopyramide 1 mg/kg caused a non-significant decrease in atrial-His concuction time, while in doses of 5 and 10 mg/kg it prolonged both conduction times (S-H and H-V), due to a predominant direct depressant effect, which is opposite to the atropinic actions of the drug.


5-Hydroxytryptamine as a sensitizer of somatic nociceptors for pain-producing substances. Experiments were performed on loosely restrained, conscious dogs in the femoral artery of which a chronic catheter was implanted. All substances were administered through the catheter and vocalization responses to them were used as a principal measure of nociception. In 10 experiments done on 7 dogs, after a single injection of 3 or 10 mumol of 5-hydroxytryptamine, threshold doses (about 0.5 mumol) of acetylcholine for vocalization produced vocalization responses comparable with those to about 3 times threshold doses. In 5 experiments on 5 dogs, after 10 mumol of 5-hydroxytryptamine, threshold doses (about 0.3 nmol) of bradykinin for vocalization produced vocalization responses comparable with those to about twice threshold doses. These doses of 5-hydroxytryptamine produced small vocalization responses in only 3 of the 12 dogs. These results indicate that 5-hydroxytryptamine, although almost devoid of the activity producing noceceptive responses, sensitizes somatic nociceptors for pain-producing substances.


Nicotine-induced weight loss in rats without an effect on appetite. Rats were administered 0.8 mg/kg nicotine (as base) i.p. 2 or 3 times a day for 5 weeks, and their mean body weights were observed to be significantly lower than those of control groups administered 0.9% saline on a similar regimen. The reduction in body weight after chronic nicotine administration proved highly replicable and was produced in the absence of a significant decrease in food consumption. Upon cessation of nicotine administration, the mean body weights of the rats returned to control group levels. Administration of phenylbenzoquinone, an agent that stimulated sensory pain receptors, failed to produce a similar decrease in body weight. Likewise, pretreatment with cholinergic blocking drugs, mecamylamine and hexamethonium did not antagonize the nicotine-induced decrease in body weight. Application of these results to the human smoking habit and possible mechanisms of actions are discussed.


Dog platelets fail to aggregate when they form aggregating substances upon stimulation with arachidonic acid. Dog platelets are refractory to aggregation by arachidonic acid (AA) but generate an unstable activity that aggregates rabbit platelets. Formation of this activity is inhibited by indomethacin, by the peroxide scavenging enzyme catalase, by two chelating agents that bind Cu+ and Cu2+ ions, by the -SH agent dithiothreitol and is stimulated by cysteine. Agitation of dog platelets is followed by spontaneous aggregation and uncovers aggregation by AA, which is blocked by indomethacin. Neither indomethacin nor apyrase prevent spontaneous aggregation, ruling out both activation of prostaglandin synthetase and leakage of ADP as possible explanations. Complexation of plasma Ca2+ by citrate as an explanation for refractoriness to AA was ruled out by replacing citrate with heparin. Dog platelets are also refractory to PGH2 formed from AA by the cyclo oxygenase component of prostaglandin synthetase. Aggregation of rabbit platelets by PGH2 is not inhibited by indomethacin, by catalase, by dithiothreitol or by metal chelating agents and is not potentiated by cysteine. This confirms that the reagents act before PGH2 is formed. Aggregating activity generated by dog platelets is probably due to an unstable lipoperoxide whose generation involves mechanisms similar to those responsible for aggregation of rabbit platelets, since similar antagonists block both processes.


Different chronotropic and inotropic effects of pentobarbital in the blood-perfused, isolated dog atrium. The isolated right atrium of the dog heart was perfused with arterial blood introduced from a carotid artery of a support dog. The selective administration of pentobarbital into the cannulated sinus node artery induced a negative inotropic effect without any significant change in chronotropism at relatively small doses. At higher doses, pentobarbital caused both negative chronotropic and inotropic effects. Even at that time, the negative chronotropic response to pentobarbital was much less than the negative inotropic response. Accordingly, pentobarbital could show a dissociation of electrical and mechanical activity in this preparation. On the other hand, either verapamil or manganese caused a negative chronotropic effect at the threshold dose for inducing a negative inotropic effect. It is suggested that the mode of cardiac action of pentobarbital may differ from calcium antagonists such as manganese or verapamil, although pentobarbital-induced effects may be associated with an impaired removal of calcium ion.


Reduction by indomethacin of furosemide effects in the rabbit. The effects of furosemide on urine flow, sodium and potassium excretion and on plasma renin activity (PRA) were studied in anesthetized rabbits with and without pretreatment with indomethacin 5 mg/kg. Furosemide caused a 10-fold increase in urine flow and in sodium excretion, and a 2-3 fold increase in PRA. Pretreatment with the prostaglandin synthesis inhibitor, indomethacin, reduced the effects of furosemide on diuresis and on electrolyte excretion by over 80% (p less than 0.01) and PRA did not increase over the initial level. The results suggest that the effects of furosemide on PRA and on urinary sodium excretion may be related to the intrarenal activation of the prostaglandin system.


Binding of 14C-imipramine by pigmented and non-pigmented tissues. When pigmented and non-pigmented rabbit irides were incubated with various concentrations of 14C-imipramine at equilibrium (120 min), the accumulation of the drug by the pigmented iris was 1.5 times as great as that by the non-pigmented iris. The accumulated drug is lost from both types of irides in a complex fashion. However, even after 120 min of washing, the differences in accumulation remain nearly constant. When accumulation of the drug in the non-pigmented iris was analyzed by discontinuous sucrose density gradient, it was observed that the drug was bound mainly by the low density sucrose fractions where the synaptosomes separate. On the contrary, in the pigmented iris approximately 70% of the drug was found in the melanin-containing fraction. The homogenate from the substantia nigra accumulated 1.5 times more than that from the human brain cortex. The affinity of the drug for bovine iris melanin granules and the synthetic L-dopa melanin was 9.9 X 10(5) M-1 and 3.8 X 10(3) M-1, respectively. On the rabbit iris sphincter muscles, imipramine was evaluated for antimuscarinic effects. The apparent dissociation constants, KB values, for the antagonist in the non-pigmented and pigmented iris were 1.7 X 10(-7) M and 3.8 X 10(-6) M, respectively. The low antimuscarinic activity in the pigmented iris is attributed to the loss of the drug to the pigment. On this basis, relevancy of the drug binding by pigmented tissues to the effects of this tricyclic drug is discussed.


The effect of local anaesthetics on the vasoconstrictor response of the isolated perfused artery to adrenaline and noradrenaline. The vascular response to intraluminally and extraluminally administered catecholamines mixed in combination with local anaesthetics has been studied using the isolated perfused rabbit ear artery as the model system. Potentiation of the vascular response to extraluminal adrenaline was observed when prilocaine, lignocaine or cocaine were combined in low concentrations with the vasoconstrictor. No potentiation of the vascular response to extraluminally administered noradrenaline could be demonstrated in the presence of prilocaine or lignocaine. Further, no potentiation to either catecholamine was found if the artery had been denervated or the drugs were applied intraluminally. Possible mechanisms for the potentiation of extraluminally applied adrenaline are discussed.


The interaction of delta9-tetrahydrocannabinol with cholinomimetic drugs in an agonist-antagonist paradigm. In rabbits, i.v. delta9-tetrahydrocannabinol (delta9-THC) at 0.5 mg/kg was challenged with i.v. arecoline (0.025 mg/kg), nicotine (0.02 mg/kg) or physostigmine (PHYSO, 0.05 mg/kg), and observations were made on quantified EEG and behavior. The cholinomimetics effectively reversed the cortical and hippocampal EEG alterations induced by delta9-THC. Arecoline and PHYSO temporarily reversed the behavioral-sedative effects of delta9-THC whereas the combination of delta9-THC with nicotine produced behavioral collapse preceded by behavioral disturbance.


Depression of rat cerebral cortical neurones by H1 and H2 histamine receptor agonists. Histamine (H) and H1 agonists 2-pyridylethylamine (PEA) and 2-methylhistamine (2-MH) produced a greater depression of the corticospinal and unidentified rat cerebral cortical neurones than did 4-methylhistamine (4-MH), an H2 agonist. Mepyramine antagonized the effects of 2-MH, PEA and H, and partially antagonized the depression induced by 4-MH. Metiamide and cimetidine, H2 antagonists, blocked 4-MH and H but not 2-MH- and PEA-induced depression. These results indicate that H-induced depression of cortical neurones involves activation of H1 and H2 receptors.


Regional rat brain levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid: concurrent fluorometric measurement and influence of drugs. A concurrent semi-automatic fluorometric assay technique for 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), is described. The method is based on a rapid manually performed isolation of DOPAC and HVA on small columns of Sephadex G-10 followed by an automated fluorometric detection with a continuous flow system. DOPAC and HVA were measured in the corpus striatum, nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after treatment with amphetamine, apomorphine, clozapine, haloperidol, morphine, oxotremorine, pargyline, probenecid, sulpiride and thioridazine. Clozapine, morphine, sulpiride and oxotremorine induced the most pronounced rise of DA metabolites in the nucleus accumbens. Probenecid produced a DOPAC accumulation in the nucleus accumbens. Striking differences were observed between the DOPAC/HVA ratios in the different structures of control animals. The concurrent assay enables a rapid screening of the action of drugs in regional DA metabolism.


Action of clonidine on the baroreceptor pathway and medullary sites mediating vagal bradycardia. In anaesthetized dogs, clonidine (10 mug/kg i.v.) increased the spontaneous firing of the carotid sinus nerve and decreased blood pressure and heart rate. After transection of the spinal cord, clonidine decreased heart rate and this bradycardia was abolished by selective baroreceptor denervation. Clonidine (1 mug/kg) injected into the vertebral artery of anaesthetized dogs, pretreated with a beta-adrenoceptor blocking agent (S 2395: 50 mug/kg i.v.) potentiated the bradycardia induced by stimulation of the carotid sinus nerve but did not change the hypotension and bradycardia produced by stimulation of the nucleus tractus solitarius or of the nucleus ambiguus. In anaesthetized cats with bilateral destruction of nuclei tractus solitarii, clonidine (10 mug/kg i.v.) decreased blood pressure and heart rate. Clonidine (2 mug/kg), injected into the vertebral artery of anaesthetized dogs pretreated with a beta-adrenergic blocking agent (S 2395: 50 mug/kg i.v.) or guanethidine, induced a bradycardia but the discharges of the carotid sinus nerve were not increased. Selective baroreceptor denervation abolished this bradycardia. In conclusion, these experiments provide direct evidence that the central facilitory effect of clonidine on baroreceptor impulses play a role in the bradycardic effect of the drug. This facilitation is likely localized in the nucleus tractus solitarius at the first synapse of baroreceptor fibres. The vagally mediated bradycardia can be explained by an increase in baroreceptor discharges and by the central facilitation of baroreceptor impulses. The site of the hypotensive effect of clonidine did not seem to be localized in the nucleus tractus solitarius.


Discriminative pentobarbital stimulus in rats immediately after intravenous administration. Rats with chronically implanted venous cannulas were trained to make differential active or passive shock-avoidance responses in a 2-compartment box at 15 sec after i.v. adminstration of pentobarbital (5 mg/kg) or saline. The discriminative pentobarbital stimulus persisted for several min after adminstration. The pentobarbital response also was elicited in tests at 15 sec after i.v. injection of chlordiazepoxide (2.5 and 5 mg/kg) or alcohol (500 mg/kg). Subsequent training at 10 min after i.p. injection of pentobarbital (10 mg/kg), followed by tests after i.p. administration of other drugs, indicated that the discriminative drug stimulus is qualitatively similar with this different route and time interval. A general preference for the passive over the active response developed only in the second stage of training, during i.p. injections.


Studies relating morphine hypothermia with serotonin reuptake in the rat hypothalamus. Experiments were conducted to determine if the acute hypothermia elicited by morphine in the rat resulted from morphine-induced inhibition of serotonin reuptake into hypothalamic nerve-endings. The acute hypothermia elicited by morphine (30 mg/kg, s.c.) was reversed by pretreatment with naloxone (10 mg/kg, s.c.), a narcotic antagonist, which alone did not alter body temperature. In vitro uptake of serotonin into synaptosomes prepared from rat hypothalamus was inhibited 53% by the addition of morphine (7 X 10(-4) M) and 53.9% by naloxone (1 X 10(-3) M). Simultaneous addition of both drugs in these same concentrations further inhibited synaptosomal serotonin uptake 77.8%. Uptake of serotonin uptake into synaptosomes isolated from rats injected with morphine (30 mg/kg, s.c.) was not altered as compared to controls. These data suggest that the acute hypothermic acition in morphine in the rat is not related to an inhibition of the serotonin reuptake mechanism in hypothalamic nerve-endings.


Effects of zinc chloride on gastric secretion and ulcer formation in pylorus-occluded rats. The effects of 10-day pretreatment with i.p. injections of zinc chloride, 16 mg/kg, on gastric secretion and on gastric ulceration induced by stress or by acid accumulation were examined in pylorus-occluded rats. Zinc chloride pretreatment significantly reduced the volume of gastric secretion and the total acid output as well as the incidence of gastric ulcers induced either by stress or by acid accumulation. The findings support the idea zinc compounds may be useful in the treatment of gastric ulcers.


The effect of tricyclic antidepressants and neuroleptics on the peripheral and central action of norepinephrine in reserpine-treated mice. The effect of exogenous norepinephrine on the ptosis induced by reserpine and its modification by tricyclic antidepressants and neuroleptics were studied in reserpine-pretreated mice. S.c injection of norepinephrine (0.3-5 mg/kg) reversed dose-dependently the ptosis induced by reserpine. The maximal effect was obtained 15 min after norepinephrine administration. Tricyclic antidepressants (2.5 and 5 mg/kg i.p.) potentiated the effect of norepinephrine. In contrast neuroleptics (1 and 5 mg/kg i.p.) antagonized it. Intracerebral injection of norepinephrine (5-20 mug) also reversed dose-dependently the ptosis induced by reserpine, and the maximal effect was obtained within 5 min. Tricyclic antidepressants potentiated the effect of norepinephrine, but neuroleptics antagonized it. Among tricyclic antidepressants, the potentiating action of secondary amines was stronger than that of tertiary amines. Chlorpromazine blocked the action of norepinephrine more strongly than did the same dose of haloperidol.


Effect of antihypertensive therapy on lysine incorporation into vascular protein of the spontaneously hypertensive rat. Young spontaneously hypertensive rats (SHR) were either treated with hydralazine or hexamethonium or splanchnicotomized, so that the development of hypertension was effectively arrested for two weeks. The rate of incorporation of 3H-lysine into non-collagenous proteins in vivo of the heart, aorta and mesenteric arteries was determined in the treated SHR, as well as control SHR and normal Wistar/Kyoto (WK) rats. The lysine incorporation into the non-collagenous protein of mesenteric arteries was increased in 8-week-old SHR as compared with WK rats. Teh elevated lysine incorporation in the SHR was abolished by treatment with hexamethonium or by splanchnicotomy, but was not affected by treatment with hydralazine. It is suggested that sympathetic innervation is important fot the increased synthesis of vascular non-collagenous protein during the early hypertensive phase in the SHR.


Loss of an adrenergic effect in swiss mice. The effect of adrenaline on the amount of blood eosinophils (eosinophilia) which had been found in Swiss mice in earlier experiments was lost after a few generations. The hyperglycemic response to adrenaline had not been changed. Sensitivities to noradrenaline and adrenaline were as found earlier, but the sensitivity to isoprenaline was reduced. The reduction of beta-adrenergic responsiveness suggests variations in biochemical parameters of mice or the appearance of mice genetically less responsive to beta-adrenergic drugs in only a few generations.


Enkephalin: a potential modulator of noradrenaline release in rat brain. In slices of rat occipital cortex preincubated with 3H-noradrenaline, methioine-enkephalin diminished the overflow of tritium evoked by electrical field stimulation or by 20 mM potassium. The effect was not modified by phentolamine, but was antagonized by naloxone. Giver alone, naloxone slightly increased the potassium-evoked overflow. It is concluded that enkephalin reduces transmitter release from cerebrocortical noradrenergic nerve endings. One-function of endogenous opiate receptor ligands may be presynaptic inhibition of central noradrenergic transmission.


[Analysis of digoxin by a radio-immunologic]. A more accurate knowledge of the effects of cardiotonic heterosides can be gained using radiocompetition. The present investigation aimed at: -comparing two commercial kits, the usual quality criteria being applied; -estimating cross-reaction between the immune systems and the endogenous as well as exogenous structural analogues; -establishing the therapeutical or toxic levels in man.


[Determination of acetylator phenotype of isoniazid by superimposed sinusodial tension polarography]. Alternative current polarography has been applied to specific determination of INH and acetyl-isoniazide in serum and urine. Determinations can be achieved directly on diluted urines. The method allows measure of pharmacocinetic parameters and determination of acetylation phenotype following I.V. administration of the drug.


[Evoluation of biologic balance as a function of radiologic status in a population living in a endemic fluoride zone of southern Algeria]. Chronic fluoride intoxication in subjects living in an endemic South Algerian zone: El Oued (drinking water fluor: 3 to 5 mg/l), provokes some blood and urinary levels modifications, when compared to normals living in Algiers (drinking water fluor: 0,6 mg/l). These modifications are the more often present in stade 0 (normal radiologic aspect) and do not increase with radiological evolution (stades I, II, III). Fluoremy and fluorury increase. Phosphocalcic metabolism is altered. Tubular reabsorption coefficient, particularly, decreases strongly. Using renal functional exploration, a pretty soon tubular failure is founded, which preceeds glomerular failure. Blood levels of certain products and enzymes are studied.


[Irritant power of the principle chlorinated aliphatic solvents on the skin and ocular mucosa of the rabbit]. A study was carried out in the rabbit in order to compare the cutaneous and ocular mucosa irritant powers of the principal aliphatic chloride solvents and of pure hexachlorobutadiene. Using Draize's method, that of the official technique for the assessment of cosmetic products and the interpretation of Kay and Calandra, a study was made of the effects of a single application or instillation of the common aliphatic chloride solvents. Macroscopic observations were followed by histological examination of the lesions and their course. With the exception of trichloro trifluoro-1,2,3-ethane, these substances are primary irritants but their effects on rabbit skin and ocular mucosa differ.


[Poisoning by anorexigenics. Information from the data bank of the Anti-Poison Center of Marseille (1973)]. Using the data bank developed by the Computer Service of the Lyon Hospitals, the Anti-Poisons Centre of Marseille presents an initial study of intoxications by appetite suppressants. The work was complemented by a simultaneous study using conventional manual techniques. An epidemiologic review of 1973 and an approximate assessment of toxic doses in the adult and child were possible. They should be of particular use in answering telephone enquiries at anti-poison centres.


[Role of the laboratory in the diagnosis and treatment of lead poisoning]. A case of therapeutic lead poisoning in a six-week old child is reported, this aetiology being very common in paediatrics. The role of the laboratory in treatment is described, the latter having involved the addition of disodium calcitetracemate to the peritoneal dialysis fluid.


On the mechanism of erythropoietin-induced differentiation. XIV. The apparent effect of etiocholanolone on initiation of erythropoiesis. Etiocholanolone, when tested in normal mice or in mice that have been out of an hypoxic atmosphere for only a few days, stimulates erythropoiesis, but appears to have no effect on erythropoiesis when tested in plethoric mice that have very low residual red cell formation. The steroid, similarly, stimulates hemoglobin synthesis by marrow cells in culture if they are from normal mice, but has no effect on cells from transfused mice. Out data suggest that 5 beta-H androstane and pregnane derivatives do not have a primary action on the induction of erythropoiesis, but act on cells that are already differentiated.


Nonbursal origin of humoral immunity: immune capacity and cytomorphological changes in chickens bursectomized as 52- to 64-hours-old embryos. Chickens sham-bursectomized as 52- to 64-hours-old embryos (SBx), chickens bursectomized at hatching (NeoBx) and chickens from which the bursal primordium was removed at 52-64 h of embryonation (EBx) were immunized with guinea pig red blood cells when 21 days old. Following the second injection of antigen, EBx chickens were found to elaborate ME-sensitive and ME-resistant hemagglutinins, to produce direct and indirect plaque-forming cells, and to contain lymphocytes bearing a specific bursa (Bu) antigen. These immune properties were more often expressed in sham-bursectomized and neonatally bursectomized chickens. Cytomorphological changes in the spleen, bone marrow and cecal tonsil of EBx chickens were typical for birds lacking the bursa. The number of lymphocytes and plasma cells in the bone marrow and liver of SBx, NeoBx and EBx chickens was very low. These results suggest that a very early embryonic bursectomy of chickens does not abolish humoral immunity completely and does not prevent the differentiation of Bu antigen-bearing lymphocytes.


Galactolipid fatty acids in brain of pyridoxine-deficient young rats. The non-hydroxy fatty acids of the galactolipid fraction of brain lipids of pyridoxine-deficient rats have been analyzed. The results suggest an impairment in the pathway for the synthesis of very long chain fatty acids in the brain of pyridoxine-deficient rats.


[Quantitative ultrastructural study of the perikaryon of the Purkinje cell and of the adjacent area in normal and hypothyroid rats aged 21 days]. The effects of neonatal hypothyroidism on synaptic organization, glial surrounding and cytoplasmic structures of the Purkinje cell perikaryon of the 21 days old rat were studied by electron microscopy. Hypothyroidism decreases the size of the perikaryon but does not change the nucleo-cytoplasmic ratio of the cell. At 21 days the axonal endings that make synapse on the Purkinje cell perikaryon, already show the adult morphological features and hypothyroidism does not change these. The general synaptic density on the Purkinje perikaryon is not significantly altered, but the cells of hypothyroid animals still recieve 1/3 of their axo-somatic synapses on somatic spines, whereas euthyroid animals have practically no synapses on somatic spines. Hypothyroidism leads the disappearance of the synchronism which normally exists between the translocation or resorption of the Purkinje cell somatic spines and the establishment of the basket cell synapses. The basket cell axons of the normal animals form synapses only on the smooth surfaces of the Purkinje cell perikaryon while they also establish it on the somatic spines of the hypothyroid animals. The density of the axon terminals of basket cells is decreased, while that of the endings of Purkinje cell axon collaterals and of climbing fibers are increased. Hypothyroidism produces an increase in the size of the glial sheath around the Purkinje perikaryon. It does not alter the proportion of the cytoplasmic area occupied by mitochondria, but in thyroid deficiency there is an increase in the numbers of mitochondria which are reduced in average size. The Golgi apparatus is only slightly affected. Thyroid defiency does not alter the density of the cytoplasmic agreggates of free ribosomes but there is a decrease in density of the ergastoplasm and a disorganization of the Nissl bodies.


Direct neural connection from the medial preoptic area to the hypothalamic arcuate nucleus of the rat. Direct neural connections from the medial preoptic area (MPOA) to the arcuate nucleus were studied on light and electron microscope level by a multistep experimental procedure. The hypothalamic deafferentation technique of Halász and Pupp (1965) was used in itself or was combined with electrolytic lesions. In order to eliminate all fibers of more rostral source traversing the medial preoptic area an extended rostral preoptic deafferentation was made, and a survival time of at least 3 weeks was chosen to allow for the complete disappearance of the degenerated fragments from the arcuate nucleus. In the main experimental group the medial preoptic area was destroyed by an electrolytic lesion 3 or more weeks following such rostral preoptic deafferentations. In these animals degenerated fibers and terminals certainly of preoptic origin were found distributed bilaterally, with a predominance on the side of the lesion. - These data suggest that axons originating from medial preoptic neurons terminate in the arcuate nucleus, thus constituting a preoptico-tuberal pathway.


Cat retinal ganglion cells projecting to the superior colliculus as shown by the horseradish peroxidase method. 1. Cat retinal ganglion cells projecting to the superior colliculus (SC) were detected in flat whole-mounts of Nissl-stained retinas by means of unilateral intracollicular injections of horseradish peroxidase (HRP). 2. With the purpose of drawing a comparison between HRP-labeled ganglion cells and the remaining population of unlabeled ganglion cells, the latter were classified according to their perikaryal characteristics into three groups: large, medium and small ganglion cells. Measurements of perikaryal sizes of ganglion cells distributed from the central area to the periphery of the retina showed that large cells ranged from 20 to 44 mum, medium cells from 15 to 30 mum and small cells from 8 to 17 mum. 3. Peroxidase-labeled retinal ganglion cells (HRP-cells) occurred among representatives of each of the three groups into which retinal ganglion cells had been classified. Small HRP-cells clearly constituted the majority of the HRP-cell population. When the injection site was restricted to the superior colliculus, medium HRP-cells as large as 19 mum were only occasionally observed, the 15 to 18 mum range being predominant over the medium cell population. 4. Medium HRP-cells larger than 20 mum were a common finding only when the injection site involved the pretectal nuclei and were never observed when the injection site was restricted to superior colliculus. 5. Possibility of a correspondence between the large, medium and small HRP-cells of the present study with, respectively, the physiological types Y-, X- and W- of cat retinal ganglion cells is discussed.


Transcerebellar inhibitory interaction between the bilateral vestibular nuclei and its modulation by cerebellocortical activity. In decerebrate, unanesthetized cats, the brain stem was longitudinally cut at the midline from its dorsal to ventral surface with the cerebellum kept intact, eliminating neural interactions between the bilateral vestibular nuclei through the brain stem. Extracellular spike potentials of vestibular type I neurons identified by horizontal rotation were distinctly inhibited by contralateral vestibular nerve stimulation. This crossed inhibition was abolished by removal of the medial part of the cerebellum, indicating that the inhibition was mediated through the cerebellum. Neither aspiration of the flocculus on the recording side nor intravenous administration of picrotoxin eliminated transcerebellar crossed inhibition, suggesting that it is mediated through the cerebellar nuclei. When the fastigial, interposite and dentate nuclei were stimulated, inhibition of vestibular type I neurons was produced only from the contralateral fastigal nucleus. Cerebellocortical stimulation which inhibited fastigial type I neurons suppressed transcerebellar crossed inhibition. Effective sites for suppression of transcerebellar crossed inhibition were localized to lobules VI and VIIa in the vermal cortex on the side of labyrinthine stimulation. Intracellular recordings were made from type I neurons in the medial vestibular nucleus. Stimulation of the contralateral vestibular nerve and the contralateral fastigial nucleus produced IPSPs in these neurons with the shortest latency of 3.8 msec and 1.8 msec, respectively. The difference between these two latency values approximates the shortest latency of spike initiation of fastigial type I neurons in response to vestibular nerve stimulation. It is postulated that transcerebellar crossed inhibition is mediated through the fastigial nucleus on the side of labyrinthine stimulation.


Effects of tectal slits on the anomalous corticotectal fibres. Following cortical lesion and a mid-saggital cut through the tectum in newborn albino rats, the remaining intact cortex was seen to project bilaterally to the superior colliculus with anomalous fibres running across the mid-line to the contralateral superior colliculus. In animals lesioned at day 5 postnatally and later, the anomalous fibres were mostly deflected by the scar tissue resulting from the tectal injury. In animals lesioned within the first 2 days after birth, a good proportion of the anomalous fibres coursed through the scar tissue. In all animals studied except one the pattern of terminations of the anomalous fibres was in agreement with the observations of Leong and Lund.