Methylated cap formation by enzymes bound to nuclear informofer particles. Rat liver nuclear 30 S ribonucleoprotein particles containing pre-mRNA and nuclear sap proteins have been shown to modify in vitro the synthetic dinucleotide ppGpC in the presence of GTP and S-adenosyl-L-methionine (SAM) by the formation of a blocked and methylated (capped) structure 7(meG(5')ppp(5'-GmepC. In the absence of SAM the predominant reaction was GpppGpC. Our results indicate that the 30S ribonucleoprotein particles (informofers) as well as the proteins of the nuclear sap possess both guanylyltransferase, N7-, and 2-o-methyltransferase activities.


Changes in nonhistone chromosomal proteins in phytohemagglutininstimulated lymphocytes. Stimulation of bovine lymphocytes with phytohemagglutinin results in quantitative as well as qualitative changes in the nonhistone chromosomal proteins. Analysis of these proteins by hydroxyapatite chromatography and sodium dodecylsulfate polyacrylamide gel electrophoresis shows not only a selective increase in the amount of some nonhistone proteins but also a decrease of other nonhistone protein bands. This observation is compatible with the view that nonhistone proteins have an inhibitory as well as an activating function at the genome level.


[Effect of divalent copper ions on heat denaturation of DNA]. Using the thermal denaturation method the effect of bivalent copper of (4-10(-6)-10(-3)) M concentrations on the helix-coil transition of DNA was studied in the solution of Na+ concentrations 10(-3)-10(-1) M. Unlike the previous studies, this paper makes allowance for the effect of impurity ions present in DNA and deionized water. It has been shown that in the region of low Cu2+ and Na+ concentrations, thermal stability increases, the melting range extends and the denaturation curves become asymmetric. At concentrations more than approximately 3-10(-5) M Cu2+, melting temperature starts to fall, and the range reduces to 1-1.5 degrees at [Cu2+] greater than or equal to 2-10(-4) M. As [Cu2+] reaches these values, the denaturation curve asymmetry and melting range increase again, which is due to the inversion of the relative stability of AT- and GC-pairs. Employing experimental and phase-transition-theory data for homopolymers, the constants of Cu2+ binding with phosphates and DNA bases were calculated. The concentration dependence of the DNA denaturation parameters was shown to be governed by the superposition of binding Cu2+ with phosphates and nucleic acid bases.


[Molecular organization of the long-wave complexes of purple photosynthesizing bacteria. Effect of pronase on the B890 complex of Chromatium minutissium and Rhodopseudomonas palustris]. The pronase action on the long-wave complexes B890 from two different purple bacteria has been investigated. Differences in the kinetics of decrease of the reaction center photochemical activity of electron-donor activity of cytochromes and of destruction of Bx890 (875) forms have been discovered. Different rates of the proteolysis of RC proteins were revealed by SDS-gel-electrophoresis. The heavy protein of RC was the first to degrade. The photochemical transformations deltaA890(875) in B890 complexes was observed during formation of peptides with molecular weight about 17 000 from two other RC proteins. On the basis of obtained data the model of molecular organization of B890 complexes from purple bacteria is discussed.


[Character of the methylation and reassociation of wheat DNA fractions differing in their nucleotide composition]. The GC and AT fractions (GC content is 55.2 and 36.2 mole %, respectively) were isolated from wheat germ DNA by the thermal fractionation method (sequential thermal DNA denaturation followed by separation of denatured and undenatured DNA molecules by hydroxyapatitie chromatography). The amount of each of the two fractions isolated corresponds to about 25% of the total DNA. The 5-methylcytosine (m5C) content in the GC fraction (9.2 mole %) is 4.6 times higher than in the AT fraction. The DNA fractions isolated are very different in the level of methylation of cytosine residues (m5C/C+m5C ratio differs 3 times), in the amount of respective pyrimidine isostichs and in the renaturation kinetics. In contrast to the AT fraction, in the GC fraction the amount of dipyrimidine isostichs is higher than monopyrimidine ones. The AT and GC fractions isolated contain unique, moderately and highly reiterated nucleotide sequences. About 90% of the GC fraction is represented by reiterated sequences. The isolated (from the GC fraction) highly reiterated sequences (GC fraction I, Cot = 2.8 X 10(-2)) are very similar to the original GC fraction in the GC and m5C contents as well as in the amount of m5C in the respective pyrimidine isostichs. GC fraction I differs from the total GC fraction in a lower pyrimidine clustering degree. In total DNA and in GC and AT fractions m5C is found in mono- (34-40% of total m5C), di-(26-30%) and in all longer pyrimidine isostichs. It is suggested that in plants there exist many types of DNA sequences to be methylated as well as many respective DNA methylases.


[Genetics and genetic counselling in childhood epilepsy (author's transl)]. According to electroencephalographical studies on the pathogenesis of epilepsy a hereditary predisposition plays a greater role than believed before. It is far more frequent than the manifest disease. The phenomenon of cerebral excitability is influenced by different genetically determined, differently age- and sexdependent but amongst each other independent factors. When defining the risk of epilepsy for siblings and descendents in practice, one is forced to proceed from the statistical empirical value with all its uncertainty. During the past few years, the figures have become more exact for special types of epilepsy as absence-epilepsy, myoclonic astatic Petit mal, and Impulsiv-Petit mal. Details of these results and their consequences for genetic advice are discussed.


[Ratio of primidone to phenobarbital serum levels as a criterion in the assessment of anticonvulsive therapy with primidone (author's transl)]. Serum levels of primidone and phenobarbital were measured and showed a relatively constant ratio in patients under primidone monotherapy. In outpatients, however, this ratio was lower and the range of its values wider than in hospitalized children, and the difference was significant (1:2.05 or 1:2.95). The reason for this turned out to be irregular intake of the drug by the outpatients. The ratio of primidone to phenobarbital serum levels offers itself as a control of regularity of intake of primidone.


[Study of the acceptor portion of photosystem I according to the temperature relationships of P700 photoconversions]. The functioning of the acceptor part of photosystem I was studied by temperature dependence of time course of light induced absorbtion changes at 700 nm of digitonin chloroplast fragments, enriched by photosystem I. Partial irreversibility of P700 photooxidation at low temperatures and appearance of two components (rapid and slow) in the time course of P700+ dark reduction reflect the contribution of different acceptors in electron transport. Thermoinactivation of fragments incubation at acid pH or treatment by glutaraldehyde cause complete inhibition of irreversible P700 photooxidation and slow dark reduction of P700+ at -170 degrees. The slow component of P700+ reduction and irreversible photooxidation of P700 are ascribed to contribution of secondary ferredoxin acceptors. The accurence of rapid component of P700+ dark reduction in light induced signal of treated fragments indicate that this component is due to recombination of reduced primary acceptor and P700+. Because only one electron transport takes at -170 degrees, the occurence of rapid and slow components in dark decay kinetics of P700+ suggests, that secondary acceptors of some reaction centers are incapable to reduction at -170 degrees. The shape of temperature dependence curve of the slow P700+ reduction component is interpreted as an indication of the tunneling electron transport.


[Pharmacokinetic investigations on sisomicin in children (author's transl)]. Sisomicin is an aminoglycoside effective against gramnegative germs. The sensitiveness of coli, proteus, pseudomonas and klebsiella ranges from 0,1 to 0,4 mcg/ml. Germs with inhibition-values of up to 1 mcg/ml are certainly Sisomicin-sensitive. The side-effects of Sisomicin resemble those of other aminoglycosides, as for instance lesions of the VIIth cranial nerve and the kidney. Since aminoglycosides have a relatively small therapeutic range between toxicity and effective minimal-concentration, investigations are important especially in children. 66 children of different age groups received Sisomicin in doses of 3 mg/kg, 2 mg/kg and 1 mg/kg, and examined pharmacokineticly. Serum-levels were measured after 30 min 1, 2, and 4h, in some cases also after 6 and 8 h. In a separate group we determined the values after 5, 10, 15, 20, 30 and 40 min. The urinary output was controlled and the content of Sisomicin in meconium determined. Based on these results we recommend an individual, Sisomicin dosage for each age group. Clinically the Sisomicin proved to be well tolerated and effective antibioticum.


[Role of the ribose residue of substrates in reactions catalyzed by ribonuclease]. The rate constants and Km for the hydrolysis of the optically active nonglycosidic analogues of the CpA and C greater than p catalysed by RNase A and RNase BS-I were measured. The rate of hydrolysis of the model substrates in 10(5) and 10(3) slower that for the appropriate dinucleoside phosphate and nucleoside cyclophosphate. However, substitution of the relatively rigid ribofuranose ring with flexible alifatic chains is accompanied by little variation in binding constants. The analyses based on the single substrate system indicate that the observed difference in rate constants must be accounted for by a difference between the binding of the substrates in the transition state to the RNase active site. Consequently, the "rigidity" of the ribose rings in RNA leads to large decreases in the free energy of activation for the reactions catalysed by RNases.


[Transcription and the composition of chromatin isolated from rat liver cells after cortisone administration]. The effect of removal of various protein fractions on the patterns of transcription of the chromatin isolated from rat liver nuclei after cortisone administration has been studied. The RNA synthesized in vitro on the protein-depleted chromatin templates was investigated by competitive hybridization technique with the nuclear RNA synthesized in vivo. Extraction of chromatin with 0.7 M NaCl (removal of histone H1 and a part of loosely bound nonhistone proteins) did not interfere with the synthesis of the hormone-specific RNA population on chromatin templates. However, treatment of chromatin with 1.0 M NaCl fully eliminated the hormone-related pattern of transcription. Electrophoretic analysis demonstrated that the fractional composition of chromatin proteins is changed under the action of cortisone. An additional protein fraction specific for the hormone-activated chromatin with a lower electrophoretic mobility than H1 histone was found by electrophoresis at pH 2.7. Using the method of SDS electrophoresis, the additional subfraction of H1 histone was observed and the amount of protein located between H1 and H3 histones increase as the result of cortisone injection.


[Protein evolution rate and immunoglobulin induction]. The capacity of proteins to induce the synthesis of specific immunoglobulins was shown to be correlated with their evolution rate. This correlation can be understood in terms of the clonal-selectional theory. The characteristic correlation parameter is the number of differences in the amino acid sequences between the immunogenic protein and the homological protein of the immunized animal. The above correlation was traced most clearly for the evolutionary conservative proteins.


[Absorption spectrum and magnetic circular dichroism of heme-containing proteins in nonequilibrium states. I. Hemoglobin and its derivatives]. Absorption and magnetic circular dichroism spectra of nonequilibrium states of hemoglobin and its derivatives formed by reduction oxidased forms of hemoproteins by thermalysed electrons at 77 degrees K were studied. Mixtures of low spin and high spin ferroforms were observed for nonequilibrium hemoglobin and its complexes with inosithexaphosphate and fluorine. The content of the high spin form increasing as follows: hemoglobin, complex with inosithexaphosphate, complex with fluorine. Only low spin forms were found for cyanide and azide complexes of hemoglobin reduced at low temperature. The spectral differences of nonequilibrium low spin ferroforms were supposed to be due to the presence of different ligands in the coordination sphere of the heme iron. The alpha-band splitting was observed for the nonequilibrium imidazole complex of hemoglobin. This effect was explained by a lowe-ring of the active centre's symmetry. The temperature relaxation of all nonequilibrium systems was investigated.


Relation between plasma and red-cell electrolyte concentrations and digoxin levels in children. We determined alterations in plasma and red-cell electrolyte concentrations associated with digoxin administration in 11 children in heart failure, 24 nontoxic patients receiving maintenance digoxin and 11 children in whom digoxin toxicity developed. Twenty normal children served as controls. Digoxin therapy was associated with a mean (+/- S.E.M.) increase in red-cell sodium from a pretreatment level of 6.2 +/- 0.7 meq per liter to 11.9 +/- 1.2 meq per liter and a decrease in red-cell potassium from 105.4 +/- 1.4 to 99.5 +/- 1.9 meq per liter (P less than 0.001). The red-cell sodium levels of toxic patients exceeded those of nontoxic patients whereas the potassium concentrations were lower (P less than 0.001). Toxic patients manifested significantly higher ratios of red-cell sodium to red-cell potassium (0.213 +/- 0.003) than nontoxic patients (0.085 +/- 0.008; P less than 0.001). Changes in red-cell electrolytes are sensitive indicators of digoxin affects.


Oral contraceptives and birth defects.

Oral contraceptives and birth defects. We reviewed the birth certificates and hospital records of 7723 infants those mothers had reported using oral contraceptives. The overall frequency of malformation was 4.3 per cent for infants whose mothers terminated use of oral contraceptives shortly before conception, as compared with 3.3 per cent for infants whose mothers did not take oral conceptives diring the three years before conception. The 90 per cent confidence limits for the prevalence ratio were 1.0 and 1.7. No difference was apparent for major malformations. For specific malformations the most notable difference was for undescented testis, but this excess, like the overall excess, could be explained by sampling variability. Despite the slightly greater rate of minor malformations in the short-interval group, a reasonable interpretation of these data would be that oral contraceptives present no major teratogenic hazard.


Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute's retrospective Laetrile analysis. The National Cancer Institute, in response to widespread public interest, undertook a retrospective analysis of Laetrile treatment. Only cases thought to have shown objective benefit from Laetrile were solicited by mail request to 385,000 physicians and 70,000 other health professionals and by direct contact with pro-Laetrile groups. Although it is estimated that at least 70,000 Americans have used Laetrile, only 93 cases were submitted for evaluation. Twenty-six of these Laetrile cases had to be eliminated because of insufficient documentation, and an equal number of conventionally treated cases selected from the institute's files were added to the records to be analyzed. A panel of 12 oncologists, who had no knowledge of the actual treatments given, was then asked to evaluate the results of 160 courses of treatment (68 Laetrile, 68 chemotherapy, 24 "no treatment") in the abstracted records from 93 patients. The panel judged six Laetrile courses to have produced a response (two complete and four partial). These results allow no definite conclusions supporting the anti-cancer activity of Laetrile. The National Cancer Institute will use the data in deciding if further study is needed.


Low positioning of umbilical-artery catheters increases associated complications in newborn infants. We performed a randomized prospective study of the effect of placement position of umbilical-artery catheters on complication rates in high-risk newborn infants. A higher complication rate (31 of 40 vs. 13 of 33) (P less than 0.005) occurred in the group with the catheter tip at the third to fourth lumbar segment, as compared to those with the tip at the seventh to eighth thoracic segment, owing to more episodes of blanching and cyanosis of the extremities. There was no difference between groups in the rate of complications requiring catheter removal. Aortography revealed thrombosis in 21 of 23 patients studied, but there was no clinical evidence of impaired circulation. In retrospect, we found that, independently of catheter position, administration of antibiotics through the catheter was associated with an increased rate of complications (63 vs. 20 per cent). Umbilical-artery catheterization entails potential risks regardless of the position of the catheter; placement of the catheter with its tip at the seventh to eighth thoracic segment may be associated with fewer complications than at lower positions.


Lung cancer after employment in shipyards during World War II. A case-control study, undertaken to identify reasons for the exceptionally high rate of lung cancer among male residents of coastal Georgia, revealed a significantly increased risk associated with employment in area shipyards during World War II. The summary relative-risk estimate, adjusted for smoking, other occupations, age, race and county of residence was 1.6 (95 per cent confidence limits = 1.1 to 2.3). A synergistic relation was found between shipyard employment and cigarette smoking. These findings suggest that asbestos and possible other shipyard exposures during wartime employment account for part of the excess mortality from lung cancer in certain coastal areas of the United States.


Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria. We studied the components of the hepatic phenylalanine hydroxylating system in a child with phenylketonuria who showed substantial neurologic impairment despite early dietary control of elevated blood phenylalanine levels. Phenylalanine hydroxylase, dihydropteridine reductase and dihydrofolate reductase activities were normal. In contrast the level of hydroxylation cofactor, tetrahydrobiopterin, in liver was only 10 per cent of normal. In addition to this hepatic deficiency, serum and urinary levels of biopterin-like compounds were low, and the serum biopterin did not increase in response to a phenylalanine load as it does in normal and phenylketonuric subjects. The phenylalanine hydroxylase activity in this child, as determined by an in vivo tritium-release assay, was 2.3 per cent of the normal value. These results indicate that the child suffers from a variant form of phenylketonuria--a deficiency of a functional phenylalanine hydroxylating system secondary to a defect in biosynthesis of biopterin.


Growth and development in children with sickle-cell trait. A prospective study of matched pairs. To ascertain if sickle-cell trait (Hb AS) impairs physical growth and cognitive development, we prospectively investigated 50 matched pairs of black children. For each child with Hb AS, an Hb AA child was matched at birth for sex, birth date, birth weight, gestational age, five-minute Apgar score and socioeconomic status. Between the ages of three and five years, the members of each matched pair were evaluated, with one month of one another, by persons "blind" to the hemoglobin genotype. Twelve outcome measurements were obtained at evaluation: height, weight, head circumference, skin-fold thickness, cross-sectional area of arm muscle, bone age, five scores of the McCarthy Scales of Children's Abilities, and the Peabody Picture Vocabulary Test. There were no statistically significant differences in these measurements favoring the AA group. The results show that children with sickle-cell trait in this age group have no deficits in standard measurements of growth and development and emphasize the importance of rigorous methods when clinical groups are assembled and compared.


A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. We studied a six-month-old infant with severe megaloblastic anemia, coma and hyperpigmentation of the extremities. He was found to have methylmalonic aciduria (79 mumol per milligram of creatinine) and homocystinuria (0.85 mumol per milligram of creatinine). Additional biochemical abnormalities included cystathioninuria, glycinuria, methylcitric aciduria, 3-hydroxypropionic aciduria and formic aciduria. The concentration of vitamin B12 in the serum was 20 pg per milliliter. This severe nutritional deficiency was a consequence of inadequate intake, for the infant was exclusively breast-fed by a strictly vegetarian mother who manifested methylmalonic aciduria. Our observations emphasize the importance of educating strict vegetarians about the deficiency of vitamin B12 in their diets and the importance of vitamin B12 supplementation.


Effect of fetal monitoring on neonatal death rates. We analyzed data from 15,846 live-born infants to assess the effect of electronic fetal monitoring on neonatal death rates. The crude neonatal death rate was 1.7 times higher in unmonitored infants than in those monitored. Adjusting for inherent risk and changes in mortality rates and monitoring rates during the years of the study lowered the relative risk to 1.4 (95 per cent confidence interval, 0.85 to 2.45). The estimated yield from monitoring decreased as the inherent risk of the baby declined. Thus, in the highest-risk group 109 lives might be saved for every thousand babies monitored. In the lowest risk group (babies at term with no risk factors) the neonatal death rate is around one per thousand. The absolute benefit for this large group could therefore not exceed one life saved for every thousand babies monitored.


The autopsy: its decline and a suggestion for its revival. The hospital autopsy rate in the United States dropped from 41 per cent in 1964 to 22 per cent in 1975. This reduction is attributable to a declining interest for many reasons by clinicians, surgeons, pathologists, families of the deceased and hospital administrators and hospital accreditors. Various advances in medicine and surgery in recent years have not replaced the value of the autopsy; indeed they have increased the potential information to be gained from it. For interest in autopsies to be revived among physicians and surgeons, pathologists must provide more expert information from the autopsy. To provide the type of information sought from autopsies by physicians and surgeons, the training of pathologists must be altered so that there can be more specialization in anatomic pathology and more subspecialization in the various organ systems, as in internal medicine. In addition, the means of communication between anatomic pathologists and clinicians needs altering so that important clinical questions are recognized by pathologists, and the answers sought and promptly, understandably and diplomatically communicated to physicians and surgeons. Moreover, the large body of information obtained in recent years from autopsies alone needs to be better recognized by clinicians so that they may better understand the value of these examinations.


Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. The role of glucagon in diabetes was studied in four patients with juvenile-type diabetes during continuous insulin infusion and a diet containing 150 g per day of carbohydrate. During insulin alone, plasma glucagon, measured at two-hour intervals, averaged 182 +/- 34 pg per milliliter, glucose 269 +/- 11 mg per deciliter, glucose excretion 52 +/- 8 g per 24 hours, ketone excretion 1.3 +/- 0.3 mmol per 24 hours, and urea nitrogen 12 +/- 2 g per 24 hours (mean +/- S.E.M.). Somatostatin (2 mg per day) lowered glucagon to 60 +/- 13 pg per milliliter, glucose to 111 +/- 17 mg per deciliter, glucose excretion to 1 +/- 0.7 g per 24 hours, ketone excretion to 0.5 +/- 0.2 mmol per 24 hours and urea nitrogen excretion to 8 +/- 2 g per 24 hours. Replacement of glucagon raised glucagon to 272 +/- 30 pg per milliliter, glucose to 202 +/- 20 mg per deciliter, glucose excretion to 14 +/- 7 g per 24 hours, ketone excretion to 0.8 mmol per 24 hours and urea nitrogen excretion to 11 +/- 2 g per 24 hours. In a subsequent study, similar improvement occurred on a diet of 30 g of carbohydrate daily, when absorption of dietary glucose was negligible. Hyperglucagonemia has an important role in diabetes; its correction reduces diabetic abnormalities to or toward normal.


Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. We examined the relation of carcinoembryonic antigen levels to time, site and extent of recurrence in 358 patients with colorectal cancer. The recurrence rate was higher in patients with Dukes' B and Dukes' C lesions who had preoperative levels higher than 5 ng per milliliter. There was a linear inverse correlation between preoperative levels and estimated mean time to recurrence in patients with Dukes' B and C lesions, ranging from 30 months for a level of 2 to 9.8 months for a level of 70 ng per milliliter. In patients with Dukes' C lesions the median time to recurrence was 13 months if preoperative levels were higher than 5 ng per milliliter, and 28 months if they were lower. Preoperative carcinoembryonic antigen levels in patients with resectable Dukes' B and C cancer provided an additional criterion for allocating these patients to groups at high or low risk for recurrence.


Neoplastic transformation induced by a direct perturbation of DNA. Treatment of Syrian hamster embryo cells with 5-bromodeoxyuridine followed by near ultraviolet irradiation results in neoplastic transformation of these cells. This demonstrates that a direct perturbation of DNA is sufficient to initiate neoplastic transformation.


Selfish genes, evolutionary games, and the adaptiveness of behaviour. The science of sociobiology, which began in principle with the work of Fisher and Haldane and has more recently been developed by Hamilton, Maynard Smith, Trivers, Wilson and others, has been the centre of both scientific and political controversy. Dr Parker discusses the strengths and weaknesses of the approach, and illustrates that behaviour can be adapted in a complex way in conformity with sociobiological theory.


Sensory neurones recognise defined pathways in Drosophila central nervous system. An analysis of the central projection of various sensory neurones in the homoeotic mutant bithorax postbithorax, and in flies where an adult nerve had been experimentally misrouted, reveals that neurones are able to develop a normal projection even if they enter the central nervous system at an unusual place.


Electrophoretic movement and localisation of acetylcholine receptors in the embryonic muscle cell membrane. A steady electric field of 30 mV across a single embryonic muscle cell produces accumulation of acetylcholine receptors toward one pole of the cell within 1 h. The movement is electrophoretic in nature and the accumulation results in the formation of stable, metabolically independent receptor aggregates.


The role of the electrogenic sodium pump in the potassium relaxation of the rabbit ear artery. 1. The mechanism of the potassium-induced relaxation of contracted vascular smooth muscle has been studied in helical strips of rabbit ear artery by recording isometric tension and membrane potential. The arteries were stimulated with a standard concentration of 2 x10(-8) M noradrenaline producing about 20% of the maximal contractile response to noradrenaline. 2. At K+ concentrations between 1.2 and 20.0 mM, a positive correlation was found between [K+]0 and the contractile response to noradrenaline, i.e. increasing [K+]0 enhanced the effect of noradrenaline. However, when noradrenaline was added after a 10 min exposure to reduced [K+]0 (1.2 mM) and [K+]0 was then increased to 5.9 mM after the tension had reached a plateau, a relaxation of about 50% occurred instead of the expected increase in tension. The relaxation was preceded by a membrane hyperpolarization of about 8 mV. 3. A biphasic change of both membrane potential and tension resulted when, after exposure of arterial strips to 1.2 mM K+ and stimulation with noradrenaline, [K+]0 was increased to 20.0 mM: hyperpolarization and relaxation developed faster than at 5.9 mM K+, but after 1 min the hyperpolarization changed to a depolarization followed by an increase in tension. 4. Ca2+-free solution and D 600 (an inhibitor of Ca2+ transmembrane flux) diminished, but did not abolish, the tension response to noradrenaline; in the presence of D 600, the hyperpolarization upon increasing [K+]0 after a previous exposure to 1.2 mM K+ was not affected, but a relaxation no longer occurred. 5. It is concluded that a) electrogenic ion transport causes the hyperpolarization that occurs when [K+]0 is increased after a period of exposure to low [K+]0; b) the hyperpolarization leads to relaxation by blocking the influx of extracellular Ca2+, but does not affect that component of the contractile response which is due to the release of intracellular Ca2+.


Comparison of the thermoregulatory responses to intracerebroventricularly injected dopamine and noradrenaline in the sheep. The thermoregulatory effects of dopamine (DA), given by intracerebroventricular (i.c.v.) injection to sheep, have been examined and compared with those of i.c.v. noradrenaline (NA). At ambient temperatures (Ta) of 20 degrees and 30 degrees C both DA (200 nmol . kg-1) and NA (100 nmol . kg-1) induced constriction of the ear vessels, a decrease in respiratory frequency and an increase in rectal temperature (Tr). At Ta of 10 degrees and 0 degrees C both substances caused a decrease in heat production and a fall in Tr. The DA receptor blocker spiroperone (30 nmol . kg-1, i.c.v.), which itself had a vasodilatatory effect at 20 degrees C Ta, blocked the peripheral vasoconstriction and slightly attenuated the rise in Tr normally caused by i.c.v. DA or NA at this Ta, but did not eliminate the suppression of respiratory frequency. During i.c.v. infusion, at 20 degrees C Ta, with the DA-beta-hydroxylase inhibitor FLA-63, the effect of i.c.v. DA on Tr was attenuated, while that of NA was enhanced. These results suggest that in sheep central thermoregulatory system there are DA receptors which stimulate the pathway that controls peripheral vasomotor tone. The inhibitory effect of NA and DA on heat production and evaporative heat loss is probably mediated by noradrenergic receptors, which can also be activated by DA both directly and after its conversion to NA.


A compartmental model for hepatic transport of taurocholic acid in isolated perfused rat liver. In order to characterize the transport of bile acids through the liver and to study the influence of drugs on these processes, a kinetic model for hepatobiliary transport of taurocholic acid (TC) using the isolated perfused liver was developed. After the system was brought to a steady state by infusing TC at a constant rate, a tracer dose of 14C-TC was injected into the medium. The medium disappearance of 14C-TC followed a first-order kinetic with a single rate constant. The plot of the biliary secretion rate of radioactivity versus time revealed a curve composed of at least three exponential components. From the described results and the present knowledge of hepatobiliary transport of bile acids we proposed a three compartment model, composed of a perfusion medium compartment and two liver compartments. Parameters calculated from the model constants agreed well with model-independent estimations. The influence of bromosulfophthalein (BSP) on the kinetic parameters was studied to compare the result with the known effect of BSP on hepatic transport of taurocholic acid. BSP decreased the constant describing the fractional transfer of taurocholic acid from medium into the liver, which is in agreement with the inhibition of hepatic uptake of taurocholic acid by BSP. Thus a three compartment model may adequately define the hepatobiliary transport of taurocholic acid in the isolated perfused rat liver.


Binding of benzo(a)pyrene metabolites to cellular DNA in perfused rat lungs. The influence of pretreatment with monooxygenase inducers on total irreversible binding of metabolically activated [3H]-benzo(a)pyrene to cellular DNA and the formation of benzo(a)pyrene metabolite-deoxyribonucleoside adducts after cytochrome P-448 induction was studied in perfused rat lungs. Pretreatment with the cytochrome P-448 inducer beta-naphthoflavone increasing binding by a factor of 23. In lungs of induced animals, 0.45 pmoles of benzo(a)pyrene equivalents were bound per mg DNA. Binding to RNA and to protein was also considerably induced by beta-naphthoflavone. Phenobarbital treatment did not significantly increase binding to cellular macromolecules of rat lung. Analysis of hydrolyzed DNA of lungs from beta-naphthoflavone-treated rats by Sephadex LH 20 chromatography revealed the formation of at least two nucleoside adducts with metabolically activated benzo(a)pyrene one of which is probably due to modification of the DNA with a benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide and the other to modification of DNA with secondary metabolites of benzo(a)pyrene phenols.


[Dynamics of neuronal reactions during elaboration of a conditioned defensive reflex to sound]. When elaborating and realizing defensive conditioned reflexes in cat cortex areas 3 and 4 series of phases was distinguished in the neuronal reactions: initial response, short-lasting depression of activity, early and late after-discharges, activation after sound cessation. The initial response arose or was augmented during the beginning of the reflex elaboration (initial 5-15 stimuli combinations). After-discharges were relatively stabilized to the 20th-40th combinations. Conditioned motor reactions occurred 100-400 ms after the onset of the sound. Movements usually coincided with early after-discharges of cortical neurons during both real conditioned reflexes and initial period of trace reflexes. Differential neuronal reactions were elaborated with the same efficacy as positive ones. The conditoional stimulus reinforcement plays an important role not only in increasing neuronal excitability (which is significant for acquiring polysensory properties), but also in modifying after-discharges.


[Responses of pulvinar neurons in cats to presentation of moving visual stimuli]. Responses of 114 pulvinar neurons to stimulation by moving light spots were studied. Most neurons (79) displayed background activity, the mean frequency of discharges being about 10-25 imp/s. 35 neurons showed no background activity, 41 neurons responded only to the movement of black stimuli, the rest being excited either by black or by light stimulus. The neurons were divided into two groups: those sensitive to the movement direction and those responding to two opposite directions of the movement by the equal numbers of discharges. A small number of neurons was observed responding to two opposite directions by regular bursts of spikes differently distributed in time (multimodal responses). Some neurons changed their nondirectional responses to the direction-sensitive ones after modifying the dimensions of the light spot.


[Functional organization of the tecto-thalamic link of the transcollicular afferent channel of the visual analyzer]. The distribution of the evoked potentials in pulvinar, lateralis posterior, posterior, suprageniculate and dorsolateral nuclei of the thalamus was studied on anesthetized cats after electric stimulation of the optic tract and the surface layers of the superior colliculus. It is found that the functional projections of the superior colliculus and the optic tract to the posterior thalamus differ from each other. A suggestion is made that the transcollicular afferent channel of the visual system is not reduced during evolution.


[Statistical study of the impulse activity of posterior hypothalamic neurons in the presence of local changes in its temperature]. Distribution of the intervals between spikes of 50 neurons in the posterior hypothalamus were studied in 17 unanesthetized rabbits. Three main types of the interspike-interval distribution were found in the thermoneutral zone: 1) unimodal, mode 2-4 ms; 2) unimodal, mode 16-512 ms; 3) bimodal, modes 2-10 ms and 64-512 ms (the posterior hypothalamus temperature was 39.1 +/- 0.02 degrees C). When the posterior hypothalamus temperature was increased or decreased (by 0.5-1.5 degrees C), changes in the initial interspike-interval distributions were observed in 11 neurons. The changes disappeared when the thermal stimuli were removed; 6 neurons (of 11) altered the mean firing rates too when the posterior hypothalamus temperature was changed.


[Lamellar structure of the dorsal cochlear nucleus in rats]. The lamellar ultrastructure of the dorsal cochlear nucleus (DCN) was studied in frontal ultrathin wide sections of the nucleus which were placed on lead aprons and included all the nucleus layers. The electron-microscopic description of the different cell types and distribution of the axonal terminals are presented. Large branchy axonal terminals (6-8micron) with small spherical synaptic vesicles 40-50 nm in diameter, small terminals (1-3 micron) with spherical synaptic vesicles (45-60 nm) and thin unmyelinated axons prevail in the surface and middle layers of the neuropile as compared to the deep layer. The number of the myelinated axons and large oval terminals 4-6 micron in diameter with central distribution of mitochondria and neurofilaments as well as with spherical synaptic vesicles 50-60 nm in diameter increased from the middle layer to the deep one. The number of granular cells was larger in the surface and middle layers than in the deep one. The functional significance of each terminal type is discussed.


[Responses of cat cerebellar cortex neurons to stimulation of the caudate nucleus, globus pallidus and substantia nigra]. Impulsive responses (IR) of the Purkinje cells (PC) and other units of the cerebellar cortex in the paramedian lobules, lobulus simplex and tuber vermis were evoked by stimulation of nucleus caudatus (NC) in cats under chloraloze-nembutal narcosis. The phasic IR as simple discharges (due to mossy fibre activation) were exhibited mainly with a latency of 5-12 and 14-20 ms; a latency of the compound responses ) due to climbing fibre PC activation) was equal to 5-6, 9-22 ms and more. There were differences in rhythmic reproduction of the responses depending on their latency. The recruitment responses were found during a 4-6/s NC stimulation. There was an inhibitory pause as an obligatory component of the tonic neuronal responses. Reactions of the same types (phasic and tonic) as in the case of the NC stimulation, but differing in unit's quantitative distribution according to the latency appeared in the globus pallidus (GP) stimulation. The minimal latency was 4 ms. Recruitment was observed as well. The substantia nigra (SN) stimulation evoked PC responses, activated by the climbing fibres with a stable latency (8.5 +/- 0.3 ms). SN, GP, n. inferior olive as well as thalamic nuclei are considered to play a definite role in realizing caudate-cerebellar connections, both oligosynaptic and polysynaptic.


[Action potentials of cat masseter muscle motor neurons evoked by stimulation of low-frequency infraorbital nerve afferents]. The responses of masseter motoneurons evoked by stimulation of the low-threshold infraorbital afferents by different number of stimuli were investigated in cats under chloralose-nembutal anesthesia. It is shown that 3-4 succesive stimuli (1.2 of threshold) evoked action potentials in masseter motoneurons if their frequency was above 300/s. Stimulation of the infraorbital nerve by paired stimuli produced action potentials in these motoneurons when the interval between the stimuli was 1.3-4.0 ms. With longer intervals only facilitation of the second EPSP was observed, the degree of facilitation varying from 0.2 to 1.0. A conclusion is made that the masseter motoneurons discharges can be produced by activation of the infraorbital nerve. A -fibres probably connected to rapidly adapting receptors of the vibrissae.


[Comparative analysis of the morphologic and physiologic characteristics of nodes of Ranvier]. The intravital light microscopic study of the Ranvier node and paranodal structure was carried out in the isolated nerve fibres of Rana ridibunda. For the same fibres the electro-physiological characteristics obtained by the voltage-clamp method were compared with morphological ones. Definite correlations were found between the reduction of Na+ and K+ permeability constants and the degree of the paranodal myeline damage. The leakage conductance variations of the fibres under study did not exceed the normal range. High vulnerability of sodium and potassium systems seems to reflect a more complicated molecular organization of the electrically excitable Na+ and K+ channels as compared to nonexcitable leakage pathways. Essential changes of the Na+ channels properties caused by batrachotoxin were not accompanied by a visible alteration of the paranodal structure. The data obtained are discussed from the view point of modern ideas of the nature of axoglial relationships in myelinated nerve fibres.


[Quantitative description of a slowly inactivating barium current through the somatic membrane of mollusk neurons]. The slow-inactivating barium current was recorded under voltage clamp conditions from identified neurons of the snail Helix pomatia. Experimental data were analyzed using the Hodgkin-Huxley equations. The dependence of the steady-state value of the inactivation variable on membrane potential was obtained. Slow-inactivating barium current was found to be proportional to the third power of the activation variable. The time constant of activation is strongly dependent upon the membrane potential.


[Cortico- and rubrofugal influences on interneurons of the superior cervical segments of the cat spinal cord]. Stimulation of the medullary pyramids and contra- and ipsilateral red nuclei produced short latent EPSPs in interneurons of the lateral part of Rexed's laminae V--VII of the C1--C3 segments of the cat spinal cord. Stimulation of the first and second cervical dorsal roots was not effective in exciting of these neurons. It is supposed that these interneurons represent a relatively specialized group which form, apparently, disynaptic cortico- and/or rubro-motoneuronal pathways.


[Horseradish peroxidase labeled sources of the spinobulbar and spinothalamic fiber systems of the cat brain]. A dense accumulation of horseradish peroxidase (HRP) positive neurons was found after bulbar HRP injections in the ipsilateral dorsal grey matter and in the intermediate zone on both sides. After thalamic injections the labelled neurons were located bilaterally in the ventral part of the intermediate zone. A conclusion is made that cells of the origin of the spinobulbar and spinothalamic tracts are located in the dorsal horn and in the intermediate zone of the spinal cord.


[Periodic changes in primary afferent depolarization during fictitious locomotion in thalamic cats]. Dorsal root and cord dorsum potentials were recorded in lumbar segments L6, L7 during fictitious locomotion of thalamic immobilized cats. Negative waves in the dorsal root potential and respectively positive waves in the cord dorsum potential appeared during periodic discharges in the ankle flexor nerve. The conclusion is made that central locomotor generator activity modulates the level of primary afferent depolarization.


Effects of tumor cell culture supernatants on macrophages. It is proved that supernatants of various tumor cell cultures, as well as cell-free ascitic fluid and sera from tumor bearing animals induce the detachment of macrophages from glass, the loss of their ability to form pseudopodia, the inhibition of their migration and the permeability alteration of their membranes. The cytotoxic effect is not produced by normal tissues, excepting placenta. The effect of tumor cell culture supernatants depends on the characteristic evolution time of each tumor; irradiation diminishes this effect. The involvement of macrophages in immune surveillance and response makes the results interesting for the tumor-host immune relation.


The suitability of different quantitative methods for determination of the cytotoxic activity of agents in cell cultures. Studies related to the measurement of growth inhibition of HeLa cells by 6-Thioguanine (TG) and Vermiculine (V) have been described. Control and treated cell populations were enumerated as uniform suspensions of whole cells, prepared by standard treatment with trypsin. Determination of cell number, measurements of protein, DNA and RNA as well as of glucose consumption from the culture medium were made throughout the treatment with the studied drugs. It was apparent that the total cell number in control cultures was directly proportional to the total cell protein or nucleic acids. However, in both treated cultures the relationship between these parameters was disturbed as consequences to unbalanced growth which was an integral part of the cytotoxic reaction of the studied agents. From the results presented it followed that only the direct cell enumeration was suitable for the detection of agents' cytotoxicity.


5-Hydroxy-6-methoxy-2-indolylcarboxylic and 6-hydroxy-5-methoxy-2-indolylcarboxylic acids in the urine of hamsters with melanotic melanoma. The isomeric metabolites, 5-hydroxy-6-methoxy-2-indolylcarboxylic and 6-hydroxy-5-methoxy-2-indolylcarboxylic acids have been identified in the urine of hamsters bearing transplantable melanotic melanoma. Their identification was carried out by spectral and chromatographic comparison of the two isomers isolated from urine with the same compounds achieved synthetically.


Quantitative parameters of melanomas differentiation. Melanin concentration which represents one of biochemical parameters expressing the degree of pigment cell differentiation was studied by new gravimetric procedure in human, Bomirski hamster, Harding-Passey mouse and horse melanomas and also in several non-tumor pigment tissues. In amelanotic varieties of human and hamster melanomas relatively high melanin level was discovered. This finding (together with known electron microscopic evidence of pre-melanosomes presence in some amelanotic melanomas) suggests that the term "amelanotic" is not correct. Comparison of melanin content between melanomas and normal pigment tissues clearly demonstrates in quantitative way that as for melanomas their proliferation does not decrease the degree of their biochemical differentiation.


The cell-mediated immunity in patients with malignant melanoma. Cellular immunity in 22 patients with malignant melanoma and the blocking effect of their sera was followed by means of the leukocyte migration inhibition test. The migration of peripheral leukocytes from malignant melanoma patients was significantly inhibited in the presence of malignant melanoma antigen in 50% of examined patients and only in 2 cases in controls. The blocking activity of serum on migration inhibition was observed in 3 melanoma patients. From the results of the tests performed related to the two-years-course of the disease the conclusion may be drawn that the prognosis in patients with proved cellular hypersensitivity to malignant melanoma antigen is more favorable than in anergic individuals.


Prognostic factors in gastric carcinoma. One hundred and thirty eight gastric carcinomas were studied histologically with special reference to the morphology of the tumor, its surrounding tissues and the regional lymph nodes. A special search was focused on the morphologic manifestations of possible host factors in association with gastric carcinoma. The most prominent findings were as follows: 1. The nuclear grade of the tumor was positively correlated with the 5-year survival rate of the patients. 2. The content of tumor-derived mucus was not a prognostic determinant. 3. The intensity of the stromal lymphocyte and plasma cell reactions did not affect the prognosis but was inversely related to the frequency of nodal metastases. 4. Sinus histiocytosis and nodal mast cell reactions were an important determinant of whether nodal metastases appear or not. 5. An active paracortical area of the lymph node was almost incompatible with the appearance of nodal metastases.


Myoinositol--a uremic neurotoxin?

Myoinositol--a uremic neurotoxin? In 28 patients predialysis plasma myoinositol was significantly elevated to 10.8 +/- 2.5 versus 0.75 +/- 0.15 mg/100 ml in normals (mean +/- 1 SD), and was weakly correlated with plasma creatinine concentrations (r = 0.42, p less than 0.05). Dialysis decreased plasma myoinositol concentrations to 3.5 +/- 1.1 mg/100 ml. In 16 patients studied more extensively plasma myoinositol was similarly elevated to 10.6 +/- 3.4 mg/100 ml, and spinal fluid myoinositol was increased to 9.4 +/- 2.3 mg/100 ml (versus 2.7 +/- 0.7 in normals, p less than 0.001). Nerve conduction velocities were reduced in 15 and EEG tracings were abnormal in 12 of the 16 patients. However, neither spinal fluid nor plasma myoinositol showed any correlation with nerve conduction velocities or EEG changes (r = 0.05-0.20, NS) Myoinositol is one of the substances retained in renal insufficiency but no indication was found that it is a toxin causing uremic neurological disturbances.


Studies of cell-mediated immunity in human glomerulonephritis by macrophage migration inhibition test. Using the macrophage migration inhibition test (MIT), a total of 113 patients with various renal diseases, namely glomerulonephritis (GN), were studied for evidence of cell-mediated immunity to various soluble antigens prepared. The positive rate of MIT in the presence of streptococcal antigen, glomerular basement membrane antigen, renal tubular epithelial antigen and heat-aggregated IgG antigen was 15, 23, 16 and 15%, respectively. Out of 15 positive patients who were able to be evaluated with those four antigens, 9 cases exhibited cellular hypersensitivity to two or more antigens at the same time. These findings suggest that there is an abnormal cellular response to certain antigen or widespread cell-mediated hypersensitivity to a variety of antigens in certain forms of human GN.


Spontaneous rupture of tendons. A complication of hemodialyzed patients treated for renal failure. Rupture of ten major tendons occurred in 7 out of a total of 50 renal patients treated by chronic hemodialysis, in two renal units. The rupture occurred spontaneously without any special strain. Rupture was complete in five tendons and imcomplete in the other five. In 2 cases, rupture occurred simultaneously in both quadriceps tendons. In 1 case a single quadriceps and a triceps brachii tendon were affected together. In 3 cases one quadriceps tendon was affected and in the last case, one triceps  brachii tendon alone was ruptured. All the patients suffered from long-standing renal disease with severe secondary hyperparathyroidism. We are anable to explain the high incidence (15%) of this complication in our area. No local factors were found in our study.


Changes in structure and function of rat kidney slices produced by low sodium. The effects of a low Na medium on PAH transport, renal morphology, and acetate stimulation of PAH transport have been studied. Low Na inhibits PAH uptake and induces vacuolar formation in tubular cells. Both processes are reversible by reincubating in a high Na medium. Vacuolization appears temperature dependent being much greater at 37 than at 25 degrees C. Acetate uptake consists of a passive and an active component, neither of which is sodium dependent. Acetate stimulation of PAH uptake does, however, require Na. This latter observation suggests that Na may act by altering cell metabolism.


Kinetic characteristics of the glutamate uptake into normal astrocytes in cultures. Kinetics for uptake and release of glutamate were measured in normal, i.e., nontransformed, astrocytes in cultures obtained from the dissociated, cortex-enriched superficial parts of the brain hemispheres of newborn DBA mice. The uptake kinetics indicated a minor, unsaturable component together with an intense uptake following Michaelis-Menten kinetics. The Km (50 micrometer) was reasonably comparable to the corresponding values in brain slices and in other glial preparations. The Vmax (58.8 nmol min-1 mg-1 protein) was, however, much higher than that observed in glial cell lines or peripheral satellite cells, and also considerably higher than that generally reported for brain slices. The release of glutamate was much smaller than the uptake, and only little affected by an increase of the external glutamate concentration, suggesting a net accumulation of glutamate rather than a homoexchange. Such an intense accumulation of glutamate into normal astrocytes may play a major role in brain metabolism and may help keep the extracellular glutamate concentration below excitatory levels.


Effect of neurotoxic divalent cations on the activity of the intrinsic nerve ending membrane-associated sialidase of bovine brain. Exposure to Hg2+ below 10 micrometer destroys synaptosomal membrane-associated sialidase of bovine brain in situ. Inhibition by Cu2+ occurs only at relatively higher concentrations, and is demonstrable after the synaptosomal membrane preparation has been presaturated with Cu2+ . Pb2+ does not inhibit enzymatic activity. Hg2+ does not exert a significant effect on the free energy of association of monomeric brain gangliosides into aggregates, or on the stability of the aggregate forms, as estimated by ultracentrifugal analysis of the ion-independent moment of ganglioside micelles as a function of concentration. Hg2+ inhibits synaptic membrane sialidase acting both in situ on the native sialocompounds in the membrane, or on exogenous ganglioside. Kinetic analyses of the exogenous activity in membranes exposed to Hg2+ reveal lowered Vmax values but no substantial change in Km for synaptosomal membrane gangliosides. These findings suggest that the powerful inhibitory effect exerted by Hg2+ on nerve ending membrane sialidase is enzyme directed, not substrate directed. It may be postulated that part of the neurotoxic effect of low levels of Hg2+ stems from an interference with synaptic metabolism by the destruction of membrane-associated sialidase. This enzyme can serve the purpose of modulation of synaptic negative charge density by releasing bound, strongly anionic, sialic acid from highly concentrated sialocompounds in the membrane.


Influence of taurine dosage on cobalt epilepsy in mice. The present work addresses itself to answering several questions in relations to the antiepileptic action of taurine (see "Introduction"). For this purpose, cobalt epileptic mice, treated with isoosmolar saline or not treated, was compared with groups of mice that had received doses of taurine varying between 1.0 and 10.0 mg/kg. Whereas all the taurine doses employed effectively reduced seizure incidence, with 10.0 mg/kg giving the best results, none of these doses had ameliorated the amino acid abnormalities in the cortex after two days of treatment in comparison with the group that had received isoosmolar saline. On the contrary, the largest amino acid abnormalities occurred in the group of mice (10.0 mg/kg) that had improved the most clinically. We conclude that the acute antiseizure action of taurine, and its effect on restoring normal amino acid patterns in the cortex, represent two separate properties of taurine.


Effect of insulin-induced epileptic seizures on neutral glycolipids of rabbit cerebral cortex. The neutral glycolipids of rabbit central cortex were analyzed during epileptic seizures produced by insulin or pentetrazol injection. The two agents gave similar results. A decrease of glycolipid content occurred in the cortex and in the neuronal fraction during seizures. The normal glycolipid level was restored during the recovery phase.


Some properties of phenylethanolamine-N-methyltransferase of rat brain. Phenylethanolamine-N-methyltransferase (PNMT, EC 2.1.1.28) was partially purified from rat brain. Brain homogenates were subjected to ultracentrifugation, salt fractionation, and gel filtration on Sephadex G-100. To compare the rat brain PNMT with that of adrenals, the same procedure was carried out with rat adrenal homogenates. The brain enzyme was eluted from Sephadex as a single fraction with a molecular weight of 26,900, while the enzyme from adrenals under the same conditions appeared in two fractions with molecular weights of 38,700 and 108,500. The brain fraction separated on Sephadex G-100 was active on phenylethanolamine substrates and inactive on indoleamine and phenylethylamine substrates. Products of the enzyme reaction were identified by bidimensional thin-layer chromatography as N-methyl derivatives of the corresponding amines. Kinetic studies showed that the type of inhibition of PNMT from rat brain and rat adrenals by SK&F 7698 was the same as described for PNMT from rabbit adrenals. Also, when normetanephrine and S-adenosyl-L-methionine were used as substrates, the apparent Km values found with PNMT from rat adrenals and rat brain were similar.


Biopterin. III. Purification and characterization of enzymes involved in the cerebral synthesis of 7,8-dihydrobiopterin. Three specific enzymes are involved in the cerebral synthesis of 7,8-dihydrobiopterin from GTP. These were isolated, purified, and characterized. The first enzyme, also catalyzing the rate-limiting step, is GTP-cyclohydrolase A-I or Mg2+-dependent A-II, which hydrolyze the GTP to the specific product 2-amino-6-(5-triphosphoribosyl)-amino-5-or-6-formamido-6-hydroxypyrimidine (FPyd-P3). FPyd-P3 is cyclized by a synthetase to D-erythro-7,8-dihydroneopterintriphosphate (NPTH2-P3). The new enzyme, D-erythro-7,8-dihydroneopterintriphosphate synthetase (enzyme B) is a basic protein of 9177 daltons containing three free SH groups, isoleucyl-seryl- as N- and valyl-glutamyl- as C-terminals. This enzyme of 69 amino acid residues from rat and 68 residues (one less aspartic acid) from guinea pig brain contains no hydroxyproline, methionine, or tryptophan. The enzyme from rat brain will gradually convert its product NPTH2-P3 to BH2, wherease the enzyme from guinea pig brain lacks this property. 2,4-amino-6-hydroxypyrimidine and dFPyd-P3 are effective inhibitors of this enzyme. The synthesis of BH2 from NPTH2-P3, but not from 7,8-dihydroneopterin, is catalyzed by L-erythro-7,8-dihydrobiopterin synthetase (enzyme C), which was purified to electrophoretic purity. This enzyme does not require pyridine nucleotides of Mc2+ for its catalysis.


[Neurologic disorders in acute intermittent porphyria]. In a material of 28 patients with acute intermittent porphyria and 2 with mixed porphyria neurological disturbances occurring in acute attach and the degree of their persistence during remission were analysed. The obtained results indicate that the symptoms of acute attach are neurogenic. In the acute phase of the disease a reversible disturbance of function develops in the first place in the nerve fibres with acetylcholine-type of impulse transmission. Clinically detectable permanent signs of polyneuropathy were observed only in some cases with most severe and prolonged acute attack.


[Symptoms preceding rupture of subarachnoid aneurysms: an analysis]. In a group of 281 cases of subarachnoid haemorrhages including 105 cases of intracranial aneurysms confirmed on autopsy or by angiography the authors analyse the symptoms preceding subarachnoid haemorrhage and suggesting presence of aneurysm. The most frequent symptom suggesting presence of intracranial aneurysm were headaches, especially associated with other symptoms such as dizziness, nausea, paraesthesiae of extremities, visual disturbances. A careful analysis of these symptoms and early radiological examination may help in establishing the diagnosis of aneurysm before its rupture.


[Modified acupuncture in the treatment of pain]. The authors report the results of treatment with a modification of acupuncture associated with chemical stimulation in 144 patients with painful radicular syndromes and headaches. In 57 cases sciatic pains were present, in 21 cases shoulder pains, in 20 migraine and in 46 vasomotor headaches. Permanent disappearance of pain, that is disappearance of pain during the procedure and lack of recurrence within several successive days, was obtained in about 40% of cases of radicular syndromes and in 62% of cases of headaches, early disappearance of pain for 3 to 48 hours after the procedure was obtained in 14% of radicular syndromes and nearly 26% headaches, while improvement, that is reduction of pain intensity, was achieved in 29.5% of radicular pains and 3% of headaches, while in 15.3% of cases of radicular syndromes and 9% of cases of headaches no improvement was observed. Both vasomotor headaches and neuralgias belong to the group of nervous system diseases in which pain is the basic and sole symptom, while treatment includes its removal. In these cases acupuncture is a valuable analgesic method. The presently reported results agree with those in the literature on the use of classical acupuncture and its modifications. It is worth stressing that insertion of needles into the traditional points used in classical acupuncture is without any greater importance was shown by the presently reported experiences (various points were used in the same case) as well as by the reports of other authors. The modification of acupuncture with addition of chemical stimulation has been tried by the authors for 4 years. A weak stimulus resulting from insertion of the needle and irritation of the nerve endings with concentrated sodium chloride acts similarly as mechanical or electrical irritation. The method is simple and completely safe.


[Type of pain, personality traits and effectiveness of modified acupuncture]. In 50 patients with headaches and 50 with radicular pains pain sensitivity and pain tolerance as well as personality traits (Eysenck and Cattell questionnaire) were determined and a modification of acupuncture (with additional chemical stimulation) was used for treatment. The results of treatment were compared with personality traits. Differences were found in the personality traits between patients with paroxysmal headaches and patients with radicular pains. No statistically significant correlation was found, on the other hand, between the results of treatment and personality traits. The obtained results were best in the group of patients with paroxysmal headaches (permanent analgesic effect obtained in 70% of cases). The results of treatment obtained in the group of patients with continuous headaches and with radicular pains were similar. In patients with a lower threshold of pain sensitivity a higher proportion of permanent disappearance of pain was observed after treatment, and this observation may be useful for establishing indications to this therapy. Lack of any influence of personality traits on the result of this modified acupuncture may suggest that the basic analgesic action of these procedure is at lower levels of the nervous system and that it causes blockade of inflow of pain stimuli.


[Evoked cortical somatosensory potentials in painful cervicobrachial radicular syndromes]. The authors determined the subjective, objective and maximal pain threshold by means of electrical stimulation in two groups of subjects. Group I comprised healthy subjects, group II patients with right-sided radicular cervicobrachial pains. The method applied by the authors for objective determination of pain threshold with evoked cortical somatosensory potential differentiated both groups which suggests its practical usefulness in clinical practice and expertise.


[Evaluation of the bioavailability of Polfa phenytoin tablets]. Bioavailability of Phenytoin "Polfa" tablets was studied in comparison with Epanutin "Parke-Davis" capsules. It was found that the relative degree of bioavailability of Phenytoin in relation to Epanutin as a standard is 70,7 +/- 6,3% (SD). The cause of worse bioavailability of Phenytoin "Polfa" are differences in pharmaceutical forms of both preparations. The necessity to increase an average dose of Phenytoin "Polfa" tablets is suggested to gain optimal concentration of diphenyl-hydantoin in serum, in therapeutic range.


[Pizotifen (Sandomigran) used in the treatment of parkinsonian tremor (preliminary communication)]. On the basis of the concepts connecting parkinsonian tremor with reduced amount of serotonin in the striatum and in the light of the hypothesis of an agonistic action of pizotifen in relation to serotonin a trial was undertaken to reduce parkinsonian tremor in 12 patients administering Sandomigran in daily doses of 1.5 mg. A significant reduction of tremor was achieved in two-thirds of these patients. No side effects or increased intensity of other parkinsonian signs were observed.


[Diagnostic value of radioisotope cisternography in low-pressure hydrocephalus syndrome]. In the light of pneumoencephalographic investigations and radioisotope scinticysternography carried out in 22 patients with clinical manifestations suggesting the syndrome of Hakim the authors analyse the diagnostic usefulness of both methods. In all cases PEG demonstrated dilatation of the ventricular system, in 10 cases radioisotope cisternography showed abnormal passage of the cerebrospinal fluid, and in 8 of these cases ventricular reflux was found lasting at least 24 hours, while in 2 other cases absorption of the cerebrospinal fluid was impaired. On the basis of this material the authors believe that in cases of presence of ventricular reflux this investigation is very important for undertaking the decision of surgical treatment, besides that, the authors think that despite normal scintigraphic pattern in early stage of the disease the investigation should be repeated after from 10 to 20 months, since clinical symptoms may precede disturbances of cerebrospinal fluid passage detectable in cisternographic investigation.


[Rheoencephalographic and electroencephalographic changes in congenital heart defects]. The authors carried out rheoencephalographic, electrocardiographic, electroencephalographic, laboratory and radiological investigations in 30 patients with valvular heart diseases in different stages of circulatory failure. In the analysis of EEG and REG tracings the degree of changes, their character and location were taken into account. The analysis of REG tracings included evaluation of their symmetry, amplitude, area of waves and synchronism of changes in the record. On the basis of these results and correlations found between them the authors have reached the following conclusions: 1. The morphological features of REG tracings depend on the character of arrhythmia, value of arterial blood pressure and efficiency of venous circulation. 2. In 26 patients REG investigations demonstrated presence of generalized changes varying in intensity. 3. In 8 patients focal changes were present. 4. With increasing intensity of circulatory failure EEG and REG changes also increase in intensity. 5. EEG changes with abolition of reactions, scant morphological features and considerable decrease of amplitude may be the passive type of reaction to hypoxia.


[Blood clotting disorders in cases of encephalomalacia]. In a group of 22 patients with foci of brain softening certain blood clotting factor were determined at different stages of the disease. The control group consisted of 16 healthy subjects. Shortening of the prothrombin time was observed after 4 weeks in the group of patients as compared with the control group. The fibrinolytic activity was higher in the plasma on the 4th day of the disease and a fall of plasma fibrinolytic activity after 4 weeks to normal values was observed.


[Clinical value of lumbar tap in the diagnosis of obliteration of vertebral canal by intraspinal tumors]. The author analyses the clinical data and pathological manifestations in 29 cases of intraspinal tumours in which the results of preoperative lumbar tap were equivocal or excluded presence of vertebral canal obliteration. On the other hand, myelography showed presence of complete or incomplete contrast stop at the level of the tumour, despite misleading information of the diagnostic lumbar tap.


[Scintigraphic studies in stroke].

[Scintigraphic studies in stroke]. The authors report the results of scintigraphic investigations in 70 patients treated for brain strokes. The diagnostic and prognostic values of these investigations were estimated. It was observed that ischaemic foci were present most frequently in the area of vascularization of the middle cerebral artery. The intensity of neurological signs was correlated with the size of the pathological focus in the cerebral scintiscan. A close relationship was observed between improvement in the neurological status of the patients and regression of pathological changes in control scintigrams.


[Familial form of myasthenia].

[Familial form of myasthenia]. In 2 daughters of healthy parents severe myasthenia with involvement of the eye muscles, bulbar muscles and extremities developed at the age of 20 and 28 years. In both patients persistent thymus was demonstrated. The authors suggest that familial occurrence of myasthenia does not seem to be coincidental; there may be a relationship with genetically determined HL-A system.


[Large aneurysm of the middle cerebral artery]. Seven surgical cases of large aneurysms (over 10 mm in diameter) are described. In 5 cases the neck of the aneurysm was closed, in 2 the aneurysmal sac was excised. Large aneurysms of the middle cerebral artery cause great difficulties in surgical closure of their necks with routinely used clips. Late results of treatment were very good in 5 cases.


[Case of giant aneurysm of the basilar artery]. The authors report a case of a giant aneurysm of the basilar artery of the brain diagnosed accidentally on autopsy. Slowly progressive syndrome of bulbar involvement began after craniocerebral trauma. Of considerable interest was the misleading result of pneumoencephalography which showed a normal pattern of basal cisterns. In the light of results of positive-contrast ventriculography an inoperable expanding lesion of the anterior part of the brain stem with associated hydrocephalus was diagnosed and symptomatic treatment was started inserting a Pudenz-Heyer valve. Despite normalization of intracranial pressure the patient died. Vertebral angiography would not have permitted the aneurysm to be diagnosed intravitally since its lumen was filled with clots.


[A microsurgery operation for lumbar disc herniation (author's transl)]. An application of operating microscope for lumbar disc herniation surgery may reduce surgical trauma as compared to non-microsurgical procedure. This can be done very easily by monosegmental approach and employing of the improved optical conditions. This procedure implies better differentiation of anatomical structures and therefore also gentler manipulation of nerve root and dural sac. This procedure can be led to (1) much less bleeding, (2) much less (little) damage of muscle and nerve, (3) less local complication due to postoperative muscular insufficiency, (4) short period of the hospitalization and (5) easiler having postoperative rehabilitation.


[Cystic craniopharyngioma extending down into the upper cervical spinal canal (author's transl)]. A case of craniopharyngioma with a large cyst extending through the posterior fossa down into the upper cervical spinal canal was reported. The patient is a 14-year-old female who was operated on for the first time in 1970, because of a suprasellar calcified mass. Histological examination verified craniopharyngioma of adamantinomatous type. Since then, she had been operated three times because of deterioration of visual acuity. She was admitted for the fifth time in January, 1977, complaining of severe neck pain radiating bilaterally to the shoulders. Radiological examination demonstrated, besides the suprasellar tumor, a huge mass extending along the clivus down to the level of C3 of spinal canal. Anteroposterior diameter of bony spinal canal evidently enlarged in upper cervical region. Interpedicular distance also widened markedly in the same region. Laminae of C1-C3 vertebrae were abnormally stretched and the spinal cord was compressed posteriorly by the tumor. Suboccipital craniectomy verified a cystic tumor in the region of foramen magnum and cervical spinal canal. The medulla oblongata was pushed backward by the tumor. The cystic tumor was evacuated and the capsule of the tumor was partly resected, which was histologically verified as craniopharyngioma of squamous type. The patient was relieved from the neck pain after operation and discharged in April 1977.


[A case of cervical extradural neurinoma with vertebral artery occlusion (author's transl)]?1.H. A case of cervical extradural neurinoma with total occlusion of the right vertebral artery is reported. The patient was a 22-year-old man who had suffered slowly progressive tetraparesis for 8 years. Neurological examination demonstrated spastic tetraparesis, muscle atrophy of the trunk and four extremities, and hypalgesia corresponding to C2, 3 and 4 dermatomes. Plain radiogram of the cervical spine revealed a large bony defect on the right side of C2 and C3 vertebrae and enlargement of the intervertebral foramen of the right C2-3. Vertebral angiogram showed a reticular tumor stain in the area of the bony defect mentioned above and an occlusion of the right vertebral artery at the level of the inferior border of the C2 vertebra. It's feeding arteries were radicular arteries. The tumor was located extradurally and excised successfully. Histology showed a typical neurinoma. Referring to the reported cases, vertebral angiography has been rarely performed and there were only three cases including our cases in which total occlusion of the vertebral artery was demonstrated.


[On the surgical treatment of cerebellar infarction (author's transl)]. Recently we have experienced two cases of acute uncomplicated cerebellar infarction which had been surgically treated. Onset of the disease in both cases was an attack of vertigo with nausea and vomiting, followed by the signs of an expanding lesion in the posterior fossa. There were thirty-one surgically treated cases and only six were fatal so far as we have reviewed cases reported in the literature. The clinical pictures of cerebellar vascular accident are typical in most cases and those of cerebellar infarction are similar to those of cerebellar hemorrhage. These two are frequently indistinguishable on the clinical as well as angiographic grounds, however, CT-scan may be of great value in the differential diagnosis. It is important to realize the cerebellar infarction is also a surgical lesion and not to spend valuable time in differentiating cerebellar infarction from cerebellar hemorrhage. Low mortality rate and low morbidity in cerebellar infarction adequately treated surgically confirm importance for early exploration.


[Three cases of the dermoid and epidermoid tumors in the 4th ventricle (author's transl)]. Two cases with epidermoid and one case with dermoid in the 4th ventricle were treated in our clinic during the last one year. The clinical findings in these three cases were described, and dermoid and epidermoid tumors in the 4th ventricle were discussed dealing with the incidence and the characteristic features of the findings in CT scanning. The correct diagnosis of both epidermoid and dermoid in the 4th ventricle was done by CT-scanning which showed an irregular low density area of EMI No. -4 approximately 12 in the posterior fossa without any contrast media enhancement. The low density lesion could be differentiated by both angiogram and ventriculogram from arachnoid cyst, ependymoma, cystic astrocytoma and cystic hemangioblastoma in the 4th ventricle. Total removal of the tumor was performed on 2 cases, and a part of the tumor capsule attached to the medulla oblongata was left in the other case. All patients returned to their own job after operation.


Study of axonal dystrophy. I. Pathology of the neuropil of the gracile and the cuneate nuclei in ageing and old rats: a stereological study. The changes with age in the neuropil of the gracile and the cuneate nuclei of rats were studied using stereological techniques, in relation to the occurrence of axonal dystrophy. The following were found: (1) significant difference in the volume fraction of presynaptic boutons between the gracile and the cuneate nuclei throughout the whole life span (17% and 13% respectively at 100 days of age); (2) progressive decrease in the volume fraction (34% decrease in the gracile nucleus between 100 and 800 days of age) and in the numerical density of presynaptic boutons, the decline being evident as soon as the animals reached maturity and before axonal dystrophy became manifest; (3) significant differences in the volume fractions of dendrites and of nerve cell bodies between the two nuclei throughout the whole life span of the animals, both being greater in the cuneate than in the gracile nucleus; an age-related decrease in the volume fraction of dendrites was also suspected in the gracile nucleus; (4) progressive increase in the volume fraction of fibrous astrocytic processes (from 3% at 100 days to 10.5% at 800 days in the gracile nucleus); (5) the above described age-related changes of presynaptic boutons and fibrous astrocytic processes were significant only in the gracile nucleus, not in the cuneate. The loss of boutons in ageing gracile nuclei was partially reflected in the appearance of degenerating nerve fibres in ageing gracile tract in the rostral cervical cord. Involutional loss of boutons and dystrophic formation of spheroids both appear and progress closely related in time and space. It was suggested that this set of changes can be understood as one integrated whole in which axonal dystrophy may represent only one side of the coin. The question of the causal mechanisms of axonal dystrophy still remains unanswered.


Glial outgrowth and central-type myelination of regenerating axons in spinal nerve roots following transection and suture: light and electron microscopic study in the pig. Glial bundles growing out of the spinal cord were observed in spinal nerve roots in the pig after their section and surgical repair. The heterotopic occurrence of glial cells, most of which were identified as astrocytes, was more frequent and more pronounced in dorsal than in ventral roots. Several of the glial bundles contained regenerated myelinated axons. These were probably myelinated by cells which showed the typical cytological criteria for oligodendrocytes and the mode of myelination was clearly of central type. It was concluded that the glial outgrowth is induced by degeneration and regeneration of axons passing the central-peripheral transition zone.


Histoenzymology of the developing rat spinal cord. Using histochemical methods the activity of acetycholinesterase, acid phosphatase and various dehydrogenases was investigated in the developing rat spinal cord. At the ninth embryonic day (E9) only the activity of the lactate dehydrogenase slow-moving isoenzymes was prominent in spinal neurons. Between E13 and E15 an increase was observed in the activity of most of the dehydrogenases and of acid phosphatase in motoneurons and posterior root ganglion cells. Between E15 and E17 acetylcholinesterase activity increased markedly. On E17 and E20, this enzyme was also detectable in anterior and posterior roots and in neurons of the intermediate grey matter. On E20, although all grey matter neurons were cytologically fully differentiated, their enzymatic content was found to be still incomplete. The prominent acid phosphatase reaction within laminae I and II, which is characteristic of the adult rat, was absent in the fetal spinal cord. These findings indicate that the spinal cord metabolism is predominantly anaerobic during the first two-thirds of gestation. The histoenzymological maturation of grey-matter neurons is delayed in comparison to their cytological differentiation. Furthermore, the ontogenesis of motoneuronal acetylcholinesterase activity correlates well with the development of motor activities in the rat fetus.


Prognostic factors in ruptured aneurysms of the circle of Willis: the significance of systemic hypertension. The incidence of essential hypertension has been retrospectively studied in a group of sixty-four fatal cases of ruptured berry aneurysm, and compared with a non-fatal group. Hypertension is more frequent in the fatal group, and is associated with a higher incidence of multiple aneurysms, a smaller size of aneurysm at rupture and a poorer survival after two haemorrhages when comparison is made with normotensive patients. The possible role of hypertension in the development and rupture of aneurysms is discussed, and it is concluded that it may contribute to both. Following rupture it carries a poor prognosis with a resulting over emphasis of its significance in autopsy series. Possible mechanisms for this effect include diffuse vascular disease, and an increased liability to oedema or spasm following rupture of an aneurysm.


Observations on remyelination in the rabbit spinal cord following demyelination induced by lysolecithin. The extent and type of remyelination that occurred following demyelination induced by intraspinal injection of small volumes of lysolecithin was examined in 24 rabbits. Unlike the rat and cat following this procedure remyelination is not complete even after 6 months' survival and little Schwann cell invasion occurs. The cellular environment around remyelinated and persistently demyelinated axons differed. Remyelination was associated with a good astrocytic presence and removal of myelin debris, while persistently demyelinated axons were surrounded by myelin debris and a poor astrocytic presence. It was conluded that the environment around the demyelinated axon influences oligodendrocyte remyelination.


Arrest of myelination and demyelination in rabbit retina induced by herpes simplex virus infection. Herpes simplex virus was injected into the vitreous of suckling and adult rabbits. In the suckling rabbits the infection caused an arrested myelination of the strip. Further, the infected strips showed degenerative changes with splitting and distension of myelin sheaths which then disintegrated. Ultrastructurally, herpes simplex virus particles were found in both oligodendroglial cells and in astrocytes in the bundles. No increase in intraocular pressure was recorded during the inflammation. The infection spread along optic pathways to the opposite side. Inflammatory cells appeared at the surface and infiltrated the degenerating strip. Especially in the contralateral eye, an extensive inflammatory cell infiltration was seen among bundles of nerve fibres which showed partly well-preserved myelin and partly with signs of demyelination reminiscent of the picture of experimental allergic encephalomyelitis in the epiretinal strip.


Growth hormone response to hypoglycemia under gamma-hydroxybutyrate narco-analgesia in the rat. Plasma immuno-reactive growth-hormone (RIA-GH) concentrations were investigated under in vivo continuous blood glucose (BG) monitoring after administration of gamma-hydroxybutyrate (GHB) as well as during spontaneous or insulin-induced hypoglycemia. During the narco-analgesia by GHB a marked secretory episode is consistently observed. This secretion peak is not accurately time related with GHB administration and seems to fade off in aging animals. Strictly controlled hypoglycemia elicits a consistent and specific GH release. In contrast deep hypoglycemic levels resulting in a state of metabolic stress inhibit GH secretion. Our results suggest that previous data on the GH regulation pattern during hypoglycemia may depend upon the anesthetic used and/or nonspecific stress responses following deep hypoglycemia. The above mentioned experimental conditions indicate that GH metabolic regulation is not fundamentally different in rodents and primates.


In vitro nuclear 3H-hydrocortisone binding in the hypothalamus of the pig. Hypothalamic cell nuclear uptake and binding of 3H-hydrocortisone (3H-HC)-receptor complexes were studied in a cell-free system. Greater net concentrations of radioactivity were found in the 0.4 M KCl non-extractable fraction (sediment) in the first 20 min of incubation and in the 0.4 M KCl extractable fraction (supernatant) from 30 to 60 min. Incubation in low ionic strength medium favored localization of radioactivity in the supernatant, whereas high ionic strength promoted greated localization in the sediment. Specific binding in the supernatant was non-saturable, but reached a plateau in the sediment at about 5 X 10(-8)M 3H-HC. The observed value of Kd for binding in the nuclear sediment was 4.88 X 10(9)M-1 and the maximum number of binding sites was 8.8 femtomoles/mg DNA. RNA polymerase activity increased by 59% in the presence of hormone-receptors over that in the presence of free hormone in buffer.


The effect of 5-bromodeoxyuridine on remyelination in the peripheral nervous system of the mouse. The thymidine analogue, 5-bromodeoxyuridine (BrdU), has been used in an attempt to manipulate experimentally the proliferative response of the Schwann cell population that follows induction of segmental demyelination in the peripheral nervous system. It was found that in the presence of BrdU, a significant number of Schwann cells displayed a susceptibility to the agent, in that they could be 'held' in the pro-myelinated state. It is suggested that there is some regulatory transition requiring the priming of the Schwann cell genome for myelination that occurs before the remyelinating phase of repair can be started, but after the establishment of the Schwann cell/axon relationship.


The cervical cord in multiple sclerosis. The spinal cords were examined in eighteen cases of multiple sclerosis, with special attention to the cervical enlargement. It was found that (1) lesions in the cervical cord are about twice as common as at lower levels, (2) in this region there is a striking preponderance of fan-shaped lesions in the lateral columns. It is argued that both these findings are explicable on the theory that mechanical stresses play a part in determining the site of lesions; that such stresses are commonly transmitted to the cord via the denticulate ligaments during flexion of the spine; and that many of the lesions are attributable to vascular leakages due to tension in the denticulate ligaments. It is concluded that in patients with multiple sclerosis neck flexion is dangerous--especially in cases where Lhermitte's sign has occurred.


Catecholaminergic regulation of TSH and growth hormone release in ovariectomized and ovariectomized, steroid-primed rats. Third ventricular injection of dopamine (DA), Piribedil (ET-495), a DA receptor stimulator, norepinephrine (NE), epinephrine (E) and systemic administration of larger doses of DA and the receptor stimulant, apomorphine (APM), were used to evaluate their role in the regulation of TSH and GH secretion in ovariectomized (OVX) as well as ovariectomized, estrogen-progesterone treated (OEP) rats. Intraventricular or i.p. injection of DA or its agonists, ET-495, and APM, caused a lowering of plasma TSH and an elevation of plasma GH concentration in OVX as well as in OEP rats. In contrast, intraventricular injection of NE or E increased plasma TSH and GH concentration. On the basis of these results it is concluded that the central dopaminergic system is inhibitory to TSH secretion, as reflected in our exeriments by the significant reduction of TSH levels. On the other hand, the noradrenergic and adrenergic system has a stimulatory role on the release of TRH as evidenced by the increase in plasma TSH levels. Activation of dopaminergic, noradrenergic and adrenergic systems appears to promote release by hypothalamic GH releasing hormone as reflected in the enhanced concentration of plasma GH, but the precise physiological role of these biogenic amines in modulating the release of TSH and GH hormone remains to be elucidated.


Buckthorn neuropathy: effects of intraneural injection of Karwinskia humboldtiana toxins. Ingestion of the endocarp of the coyotillo fruit, Karwinskia humboldtiana, a shrub of the buckthorn family, causes "Buckthorn neuropathy" in man and animals. Two neurotoxic compounds T496 and T544 were isolated from the endocarp and each toxin was dissolved in sesame oil and injected into the sciatic nerve of rats. The nerves were subsequently examined by teasing and as sections by light and electron microscopy. During the first 3--4 days after injection, oil droplets, probably containing toxin, were observed in the cytoplasm of Schwann cells with intact myelin sheaths. Clinical signs of weakness in the limb first appeared at 5--6 days and were accompanied by segmental demyelination mainly of the larger fibres. These observations suggest that the toxins have a primary action on Schwann cell metabolism. The results of local injection of purified toxins are discussed in relation to reports of nerve damage in animals following oral administration of the endocarp where intramyelin vacuole formation and segmental demyelination are prominent features.


Evidence for the involvement of dopaminergic neurons in the pregnancy block effect. Impairment of eggs implantation by exposure to alien male during early stages of pregnancy can be completely prevented by blockade of the dopaminergic neurons of the central nervous system (CNS) or by increase of the prolactin (Prl) level in pregnant female mice. Stimulation of serotoninergic neurons delayed the phenomenal effect. Blockade of serotoninergic neurons or treatment by ergocriptine on the 2nd and 3rd day of pregnancy inhibited eggs implantation. These results indicate that Prl release in female mice during the time of implantation is under dopaminergic and serotoninergic control, but phenomenal effect is transmitted by dopaminergic system.


The effect of exposure to ether on prolactin secretion and the half-life of endogenous prolactin in normal and castrated male rats. Normal and castrated male rats implanted with permanent right atrial cannulae were used, and sequential blood samples were taken every 2 min through the cannula. When the rats, both normal and castrated, were exposed to ether for 2 min, the prolactin (Prl) concentration in plasma was immediately and dramatically elevated. During 40 min of continuous ether anesthesia, plasma Prl concentration was not sustained. After the initial 'surge' of Prl secretion, which lasted about 15 min, the concentration returned to normal levels. Following the peak of the Prl 'surge', Prl disappeared from the circulation with a calculated half-life of 7 min (mean value: 6.9 min; confidence interval: 6.3-7.7).


Pathogenesis of longitudinal splitting of muscle fibres in neurogenic disorders and in polymyositis. Longitudinal splitting of muscle fibres has been studied in the biopsies of eighteen patients with neurogenic disorders, and of twenty with polymyositis. In neurogenic disorders splitting predominantly affects hypertrophied fibres, and is probably due to mechanical overload induced by normal loads imposed on a weakened muscle. A similar phenomenon occurs in hypertrophied fibres in chronic polymyositis. However, in acute, or active polymyositis an appearance resembling fibre splitting can result from sequestration of necrotic segments within a fibre and also from regeneration occurring within intact sarcolemmal tubes after segmental sub-endomysial necrosis. These different processes, which can be distinguished by light and ultrastructural criteria, are important compensatory factors in neuromuscular disorders.


Pattern of adenohypophyseal hormone changes in male rats following chronic stress. To delineate the pattern of adenohypophyseal hormone secretion following chronic stress, adult male rats were exposed daily to 6 h of cold, forced exercise or immobilization for 3, 6, 10, 15, 28 or 42 consecutive days. Groups of these animals were sacrificed at the end of the last stress sessions, and plasma growth hormone (GH), luteinizing hormone (LH), prolactin (Prl) and follicle-stimulating hormone (FSH) levels were measured by radioimmunoassay (RIA). Irresspective of the different stimuli used, long-term stress induced a morphologic and hormonal response characterized by decreased ponderal growth, adrenal enlargement, thymus involution and significant diminutions in GH, Prl and LH levels with no modifications in FSH titers. The magnitude and duration of these changes varied with the severity of the stressors.


Late endocrine effects of administering monosodium glutamate to neonatal rats. Rats were injected with monosodium 1-glutamate (MSG) daily for the 1st 5 days of life and allowed to mature. This is known to cause selective destruction of neurons in the retina and in the arcuate nucleus of the hypothalamus. The adult animals had a significant increase in body fat without an increase in weight, a marked reduction in pituitary, thyroid, adrenal, gonadal and prostate weights. Pituitary, hypothalamic and serum thyrotropin (TSH) were significantly reduced in the males. Serum growth hormone (GH) was markedly reduced in both sexes and the serum prolactin (Prl) was increased significantly in females. FSH did not appear to be abnormal and the LH may have been increased in the males. Serum T4 was significantly reduced in females. The fertility of the females was normal, but treated males mated with normal females showed a marked reduction in fertility and, although the litter sizes of the offspring were normal, the birth weights of the pups of both sexes were significantly reduced. These persistent alterations in neuroendocrine function indicate that lesions produced by neonatal MSG treatment provide a convenient model for studying hypothalamic function.


Studies on the color-change mechanism in a fresh-water teleost, Nandus nandus (Ham.). II. Hormonal control. The chromatic spinal sectioning (mostly at 3rd, 3/4th and 4th vertebral levels) produced the maximal darkening in the fish. This darkening persisted in the fish on a black background, but a slow and gradual paling occurred in the operated animals when placed over a white background. These animals reached the maximum paling in 168 h as compared to the unoperated ones where similar state of paling was attained in a comparatively shorter period (3 to 5 h). The distinct difference in the results in respect of the rates of paling in the operated (melanophores under hormonal control only) and unoperated animals clearly suggests the involvement of a pituitary-borne melanophore-aggregating hormone (MAH) in the chromatic control mechanism of the fish Nandus nandus.


The effect of ovarian steroids on hypothalamic 5-hydroxytryptamine neuronal activity. The effect of ovarian steroids on the concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the anterior hypothalamus, as well as on the total decline of 5-HIAA levels after the administration of the monoamine oxidase (MAO) inhibitor pargyline, was studied in ovariectomized (OVX) rats at different times of the day. The concentration of 5-HT and 5-HIAA and the total decline of 5-HIAA levels were higher in the morning than in the afternoon in OVX rats. Three days after the injection of 20 microgram estradiol benzoate (EB), the concentration of 5-HT and its metabolite were reduced in the morning but not in the afternoon, resulting in a disappearance of the daily changes. The total decline of 5-HIAA levels after pargyline was significantly reduced by EB administration only in the morning. The injection of 2 mg progesterone (P) into OVX EB-primed rats restored all parameters to the levels present in OVX rats. These findings suggest that ovarian steroids have a modulatory action on the activity of hypothalamic serotonin-containing neurons.


Pars intermedia electrical potentials: changes in spike frequency induced by regulatory factors of melanocyte stimulating hormone (MSH) secretion. Spontaneous action potentials recorded from pars intermedia (PI) cells of frog pituitaries are correlated with spontaneous melanophore stimulating hormone (MSH) secretion from that gland. Those agents known to induce hormone release (e.g., serotonin, isoproterenol) increase the rate of electrical activity, whereas those which inhibit secretion (e.g., norepinephrine, dopamine, GABA) reduce the frequency of spikes. MSH secretion appears to involve cellular depolarization while inhibition of release is associated with cell membrane polarization.


Autoradiographic localization of androgen-concentrating cells in the brain of the male domestic fowl. Cells in the male fowl brain which accumulate radioactivity following 3H testosterone (T) administration were identified by autoradiography. Labelled cells were found principally in hypothalamic, limbic and midbrain structures. Marked uptake was observed in the preoptic area (POA) and in the anterior and posterior hypothalamus. There was also a significant amount of labelling in the archistriatum (ARCH), particularly in the nucleus taeniae (Tn), and in the lateral septum. In the midbrain, substantial uptake of labelled hormone was found in the nucleus intercollicularis (ICo). The pattern of accumulation of T in the male fowl was comparable to that for sex hormone uptake in vertebrates in general. Furthermore, accumulation was generally found in areas known to be concerned with sex hormone-dependent functions.