Enterovirus infection in a semi-closed community. Infection with enteroviruses was studied over a 61-week period (during 1960-61) in a semi-closed child community in the Detention Home of the Allegheny County Juvenile Court in Pittsburgh, Pennsylvania. While most of the viruses isolated were known adeno- and enterovirus types, three apparently represent new enterovirus types or 'prime strains'. Viruses were isolated in all but 6 weeks of the 61-week study period from the gastro-intestinal tracts of 110 children out of a total population of 514 (21%); of these 110, 24 children (22%) excreted virus at the time of admission. The population averaged 37 children (more than half of whom were under 5 years of age), with a turnover of about nine per week. Spread of infection in this community on introduction of a new virus was demonstrated, with virus shedding of variable duration after infection. Thirteen of the 110 positive children (12%) showed mixed virus infections. During the entire study period, no clinical diarrheal illness was found associated with the viral infections detected.


Metronidazole bioassay with increased sensitivity. The bioassay of metronidazole using Clostridium butyricum incorporated in agar plates detected concentrations higher than 1.0 microgram/ml. Gentamicin in the sample did not affect the growth of the target organism or the inhibition by metronidazole. Penicillin in the sample could be eliminated by the incorporation of penicillinase in the agar or by using as the target organism a surface inoculum of the penicillin-resistant Bacteroides fragilis. Increasing duration and temperature of aerobic prediffusion before allowing the growth of the strictly anaerobic Cl. butyricum increased the diameters of inhibition by metronidazole, but did not affect the threshold of detectability. The incorporation of metronidazole in the agar increased the sensitivity of the assay ten- to 100-fold.


Prolonged survival in chronic lymphocytic leukemia: a case report. A patient with long-standing chronic lymphocytic leukemia with both humoral and cellular immunodeficiency had lymph node receptor evidence of a B lymphocyte disorder. He was also found to secrete the Epstein--Barr virus and, late in his illness, developed a markedly positive antinuclear antibody. Interrelationship of these findings may be important in the ultimate determination of the etiology and functional mechanisms in lymphocyte malignancies.


Interrelationship between oxygen consumption, superoxide anion and hydrogen peroxide formation in phagocytosing guinea pig polymorphonuclear leucocytes. The paper presents an experimental procedure for a simultaneous assay of oxygen consumption, O2- release and H2O2 accumulation at a very early stage of the respiratory burst that is induced by phagocytosis in guinea pig polymorphonuclear leucocytes. The main findings are as follows: (a) The oxygen consumption that is measurable does not correspond to all oxygen that is reduced. The relationship between the actual oxygen consumed and the amount that is reduced depends on the fate of the intermediate products O2- and H2O2. (b) O2- is measurable extracellularly by the reduction of cytochrome c. When cytochrome c oxidizes the extracellular O2-, molecular oxygen is formed. This fact is shown by a decrease of oxygen consumption. The molar ratio between the O2- detected and the oxygen given back is 1. (c) The amount of O2- released from the cells accounts for only a small part of oxygen actually reduced. (d) H2O2 is detectable only in the presence of NaN3. In this condition almost all oxygen consumed is recovered in the form of H2O2. The molar ratio O2/H2O2 is near unity. The amount of H2O2 derived from dismutation of O2- released is only an aliquot of the total H2O2 accumulated. Thus, most of H2O2 is derived from intracellular sources. (e) In the absence of inhibitors of H2O2 degrading reactions, no detectable accumulation of peroxide occurs. Under these conditions, the main part of H2O2 formed is degraded in almost equal amount by catalase and myeloperoxidase, while only a small aliquot is degraded by NaN3 insensitive reactions.


Some newly characterized collagenases from procaryotes and lower eucaryotes. Chemical and enzymatic properties of four collagenases newly isolated from anaerobic Clostridium histolyticum, aerobic Achromobacter iophagus, and from two lower eucaryotes, the fungus Entomophthora coronata and the insect Hypoderma lineatum are reviewed. The problems of their biosynthesis and precursors, namely the effect of induction of collagenase and neutral proteinase in Achromobacter by their macromolecular substrates are discussed. The two bacterial collagenases are Zn-metallo-enzymes; the highly purified Clostridium collagenase contains cyst(e)ine, serine phosphate and tryptophan additionally to amino acids reported previously. Achromobacter collagenase has the highest specific activity of all collagenases; it yields by autolysis enzymatically active degraded forms. The active dimer is composed of two identical subunits of molecular weight 35,000. Similarities between Achromobacter collagenase, thermolysin and Bacillus subtilis neutral proteinase in molecular weight, amino acid composition, and amino acids important for the active sites are discussed. The two collagenases from low eucaryotes are serine proteinases; Hypoderma collagenase is homologous to the trypsin family in the amino terminal sequence. The initial cleavage of native collagen by highly purified bacterial collagenases occurs in the central helical part of the alpha chains and not progressively from the amino terminal end. One of the two initial cleavages produced by Achromobacter collagenase is situated in the region cleaved specifically by vertebrate collagenases, but with different bond specificity. The same is true for the insect collagenase. Entomophthora collagenase is a proteinase of broad specificity which also cleaves collagen in its helical parts. All four collagenases also degrade other proteins according to their bond specificity.


Differential synthesis of lens proteins in the presence of m7G(5')pppG and cleavage product m7GMP in an embryonic chick lens cell lysate. The effect of m7GMP release from m7GMP-containing mRNA cap sequence m7GpppG by the embryonic chick lens m7GpppN-pyrophosphatase activity on the synthesis of lens proteins was examined in a newly developed homologous translation system derived from 15-day embryonic chick lenses. The synthesis of total lens polypeptides and delta-crystallin polypeptides, the major translation product, was inhibited 84% and 88%, respectively, by 0.5 mM m7GpppG; m7GMP (0.5 mM) inhibited total synthesis by 63% but was 33% less inhibitory toward delta-crystallin synthesis; GpppG and GMP were not inhibitors, m7GpppG inhibited met-tRNAfmet incorporation into 80S initiation complexes.


[Light-dependent paramagnetic center in photosystem 2 of higher plants]. In subchloroplast fragments of photosystem II from Vicia faba, free from P700 contamination, a free-radical ESR signal (singlet of 9 G peak-to-peak line-width, g approximately 2,0025) appears under illumination in presence of silicomolybdate as electron acceptor. Using ESR-active electron donors and acceptors as well as conventional redox reagents Hill activity of preparations has been evaluated under different conditions. Evidences are presented that the light-induced dark-reversible silicomolybdate-dependent ESR signal is of the same origin as photobleaching centered at 680 nm which has been earlier interpreted as a result of P680 center of photosystem II oxydation. The relaxation properties of this paramagnetic center as measured by microwave power saturation are different from that of P700+-center in photosystem I.


[Mechanism of coupling of ion transport and ATP hydrolysis in the Na-pump]. A generalized scheme of the reaction pathways during activation of the Na,K-ATPase by sodium and potassium ions and a relevant molecular model of the Na-pump are proposed. The model suggests light and heavy enzyme subunits possessing cavities with ion exchange sites. The cavities are of limited size and can contain only 3 sodium or 2 potassium ions. Free energy of ATP hydrolysis is expended on the formation of a special transient nonequilibrium enzyme conformation. In this conformation ion exchange between the subunit cavities becames possible. Na-pump operates as an enthropy machine: the ion movement across the membrane is provided by thermal oscillations of the subunits.


[Study of the dynamics of water-protein systems by the technic of gamma-resonance spectroscopy]. The possibility of using gamma resonance spectroscopy (GRS) for studying the dynamics of water-protein systems is shown in the present work. The experiments were carried out on an albumin-water system. The results obtained are compared with those obtained by the spin label method under the same conditions. The different behaviour of Fe ions which are firmly- and weakly-related with the protein matrix allows to separate the mobility of the whole protein macromolecule and also the mobility of its subunits.


Reproductive capacity and dominant lethal mutations in female guinea-pigs and Djungarian hamsters following X-rays or chemical mutagens. The reproductive capacity and induction of dominant lethal mutations in adult female guinea-pigs and Djungarian hamsters were tested following treatment with 400 rad X-rays, 1.6 mg/kg triethylenemelamine (TEM) or 75 mg/kg isopropylmethanesulphonate (IPMS). A fairly high level of dominant lethals were observed in female guinea-pigs mated at the first oestrus after irradiation (23.4 +/- 6.4%) with a lower yield at 3 months (9.6 +/- 8.2%). Neither of the chemicals caused any significant induction of dominant lethals at either mating time. In the reproductive capacity experiments, the mean litter size of irradiated female guinea-pigs was reduced for about 12 months and this was especially marked in the first 6 months following treatment. Neither of the chemicals caused any significant differences in early litter sizes but there was a noticeable reduction in the litter sizes of TEM-treated females in the 18--24 month interval. With Djungarian hamsters a marked effect of X-rays on reproductive capacity was apparent. After 400 rad a smaller proportion of irradiated females littered in the first 25-day interval than after the other treatments, and no irradiated females produced more than one litter. Neither of the chemicals caused such a drastic reduction in fertility but TEM-treated females produced fewer litters and became sterile at an earlier age than control or IPMS-treated females. With IPMS, the number of litters produced was similar to the controls. Both chemicals caused a significant reduction in litter-size but further work is needed to establish whether this was due to induction of dominant lethals. No translocations were observed in the sons of treated female guinea-pigs or hamsters, but the numbers of animals studied were too small for any conclusions to be drawn.


[Conformational mobility and functional activity of photosynthetic reaction centers of Rhodopseudomonas sphaeroides]. In pigment-protein complexes of photosynthetic reaction centres (RC's), extracted from chromatophore membranes of Rps. sphaeroides with sodium dodecylsulphate, functional activity and intramolecular mobility were studied as a function of temperature and hydration by use of the technique of optical absorbance and ESR spectroscopy. Over the studied temperature range from +20 to -120 degrees C and at a relative humidity (P/Ps) from 0.9 to 0.1, there observed a close interrelationship between reversible kinetic changes of direct and backward redox-reactions of the photo-reduced endogeneous acceptor of quinone nature and the effective parameter of the correlation time of the rotational diffusion of the hydrophobic spin probe as well as of spin labels chemically bound to SH- and COOH-groups of amino acid residues of the RC's protein. The findings support the view that the conformational dynamics in the RC controls the effectiveness of the primary processes of stabilization of photochemically separated charges.


Identification of human glandular kallikrein in the beta cell of the pancreas. To determine the cellular localization of glandular kallikrein in the human pancreas, immunohistochemical studies were performed with a monospecific antibody against the antigenically identical urinary kallikrein (urokallikrein). The localization of glandular pancreatic kallikrein to the beta cells of the islets was the same as that of insulin in normal human pancreas and in two islet-cell tumors. When beta cells were lacking in islet-cell tumors or in the pancreas of a patient with juvenile-onset diabetes, kallikrein antigen was not detectable. Anti-urokallikrein absorbed with purified urinary or pancreatic kallikrein no longer identified a pancreatic antigen, whereas absorption with insulin had no effect. The beta-cell localization of human pancreatic kallikrein, an endopeptidase that, in concert with carboxypeptidase B, converts bovine proinsulin to a polypeptide with the electrophoretic mobility of insulin, suggests that pancreatic kallikrein may be involved in the physiologic activation of proinsulin.


Myasthenia gravis: a personal view of pathogenesis and mechanism, part 2. A review of our current knowledge of the etiology and pathogenesis of myasthenia gravis is presented, with particular emphasis on the immunological aspects of the disease. Part 1, published in the January/February issue of MUSCLE & NERVE, dealt with the clinical and genetic features of myasthenia gravis which led to the autoimmune theory of the etiology of the disease. Part 2, which appears in this issue, provides a review of the dysfunction of physiology, pharmacology, and structure of the neuromuscular junction in myasthenia gravis, and the part played by the autoimmune process.


Sural nerve conduction study in the rat: a new technique for studying experimental neuropathies. An electrophysiologic technique for studying sensory fibers in the rat sural nerve is described. The conduction velocity of the sural nerve in rats is much slower than in humans, probably because of lack of large myelinated nerve fibers in rats. An experimental neuropathy (induced by hexachlorophene) that predominantly causes a myelin disorder produced a slowing of sural nerve conduction velocity and a potential of normal amplitude and duration. An experimental neuropathy (induced by zinc pyrithione) that primarily causes axonal degeneration produced a sensory potential of lower amplitude and shorter duration that had a normal conduction velocity.


Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections. A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuprressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. There preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, antithymocyte globulin appears to increase the severity of infection from cytomegalovirus among these patients.


Lumbar plexus neuropathy resulting from retroperitoneal hemorrhage. A case of lumbar plexus neuropathy occurring in the setting of heparin therapy is reported. Documentation of the site of a retroperitoneal hematoma by CT scan was made prior to the full clinical evolution of lumbar plexus neuropathy resulting from a psoas-muscle hematoma. Two patterns of retroperitoneal bleeding and their respective clinical manifestations are discussed. Early diagnosis of these syndromes may allow for intervention before neurologic compromise is established.


Peripheral neuropathy in lead-intoxicated sickle cell patients. Peripheral neuropathy and hypertension caused by lead intoxication are reported in two children with sickle cell anemia. One child had generalized weakness in the initial occurrence and distal paralysis during a relapse two years later. The second child had foot and wrist drop. Both had slow peripheral nerve conduction velocities during the episodes. Chelation therapy was successful and resulted in a return of strength (over a period of several months) and a normalization of the blood pressures. Children with sickle cell anemia who are subjected to lead intoxication appear to be predisposed to peripheral nerve damage.


Ringworm of the African hedgehog (Erinaceus albiventris) in the Ivory Coast due to Arthroderma benhamiae. Isolates of the conidial state of Arthroderma behnhamiae (+ mating strain) were obtained from dry, scaly lesions on the ears of 3 hedgehogs in the Ivory Coast. This is a new record for this country.


Local aggregation of hormone-receptor complexes is required for activation by epidermal growth factor. An analogue of epidermal growth factor (EGF) which is virtually devoid of biological activity retains receptor binding activity but cannot form cell surface clusters or patches. Bivalent anti-EGF antibodies restore both bioactivity and patch formation. The sensitivity of fibroblasts to native EGF can also be enhanced greatly by these antibodies, especially in hormone-resistant cell lines.


Cell-surface antigens induced by RNA tumour viruses. Host animals show an immune response to the surface of cells infected with RNA tumour viruses. An element of this response is due to expression of viral structural antigens, but the major part is due to virus-induced cell-surface antigens (CSAs). This article compares the properties of CSAs of the avian, murine and feline retrovirus systems.


Effect of posture on the plasma concentrations of aldosterone in hypertension and primary hyperaldosteronism. Measurement of plasma aldosterone concentrations (PAC) at 8 a.m. and after 4 h in the upright posture can further assist in identifying the adrenal pathologic lesion in patients with primary aldosteronism. Increases in PAC are associated with hyperplasia, and decreases with adenoma. Normal increases in response to upright posture are observed in patients with essential hypertension with normal or reduced renin concentration.


Neural control of renal tubular sodium reabsorption. Renal adrenergic nerves are in contact with the basement membranes of tubule cells and, when these nerves are stimulated or ablated, proximal tubular reabsorption of sodium is increased or decreased, respectively. Renal adrenergic nerve activity appears to be regulated by low-pressure cardiopulmonary receptors and high-pressure arterial baroreceptors in response to changes in blood volume. Thus, a decrease in blood volume or in effective circulating blood volume leads to an increase in renal nerve activity, release of norepinephrine, alpha-adrenergic stimulation and increased tubular reabsorption of sodium, whereas an increase in blood volume leads to a decrease in renal nerve activity, a decreased release of norepinephrine, an increased release of dopamine, possible beta-adrenergic stimulation and a decreased tubular reabsorption of sodium.


Cortisol secretion after hemorrhage: multiple mechanisms. Multiple mechanisms appear to be involved in mediation of increased secretion of cortisol after hemorrhage. Signals from cardiovascular receptors are transmitted to the hypothalamus through ascending neural pathways to release ACTH. Angiotensin II stimulates release of ACTH by an action on the median eminence, but does not stimulate adrenal secretion of cortisol directly. However, secretion of cortisol can increase rapidly after hemorrhage without changes in ACTH. Common afferent pathways probably mediate all these mechanisms.


Growth characteristics in patients with Bartter's syndrome. Studies on the growth and development of patients with Bartter's syndrome indicate that severe growth retardation occurs during infancy and early childhood. Delayed adolescent growth spurt has occurred in all patients studied thus far who had manifested the syndrome during infancy. Normal stature is eventually attained. Mental development ranges from normal to brain damage and dysfunction; however, the majority of patients show some degree of mental retardation. The coexistence of Leigh's encephalopathy with Bartter's syndrome in one patient and the finding of severe motor and congnitive retardation with communicating hydrocephalus in another indicate that the prognosis of mental development in some cases of Bartter's syndrome is guarded. Particular attention should be given to maintaining normal nutritional status in all patients, particularly during infancy and early childhood.


Nephrogenous cyclic AMP as a parathyroid function test. In man, the total amount of cyclic AMP (cAMP) excreted in urine is derived from (a) the filtered load of the nucleotide and (b) cAMP formed de novo in the kidney (nephrogenous cAMP, NcAMP). NcAMP is the only pool of the nucleotide easily quantified in vivo and appears to provide a specific index of the effects of circulating, active parathyroid hormone. Elevated values for NcAMP (4.64 +/- 1.95 nmol/100 ml GF, mean +/- SD) were found in 90% or more of 115 patients with primary hyperparathyroidism, and low values (0.31 +/- 0.16 nmol/100 ml GF, mean +/- SD) were noted in 41 individuals with absent or suppressed parathyroid function. When properly expressed (as a function of glomerular filtration rate), results for the total cAMP excretion provided similar findings. The measurement of NcAMP provides a sensitive index of parathyroid function over the entire range of parathyroid activity and has proven to be an optimal method for assessing parathyroid suppressibility in response to intravenous or oral calcium administration. These techniques, the 'calcium injection test' and the 'oral calcium tolerance test', are useful in evaluation a number of subtle disorders of calcium metabolism.


Kidney stones: various forms and treatment. Calcium urolithasis is not a homogeneous entity, but is a result of many etiologies, with different physicochemical and physiological backgrounds. This diversity of presentation requires an appreciation of specific diagnostic criteria, and a selection of an appropriate treatment regimen for each cause.


Control of aldosterone secretion.

Control of aldosterone secretion. This paper reviews the control of aldosterone secretion, including the role played by hepatic metabolic clearance, ACTH, and the renin-angiotensin system, and the interrelationships of aldosterone secretion with sodium and potassium metabolism. The physiological modulations of aldosterone secretion by the upright posture, progesterone, estriol and estradiol are also discussed.


Different effects of K+ and Ca++ on alpha-MSH and ACTH release from superfused neurointermediate lobe of the rat hypophysis. The effects of K+-enhanced and Ca++-free media on alpha-MSH and adrenocorticotropic hormone (ACTH) release from superfused neurointermediate lobe (NIL) were studied in the same experiments. High K+ caused reversible and repeatable inhibition of alpha-MSH release and stimulation of ACTH release, Removal of Ca++ impaired the effect of K+, irreversibly for alpha-MSH and reversibly for ACTH. The existence of both melanotrophic and corticotrophic cells within the intermediate lobe (IL) of rat hypophysis could account for the different effects of ionic modifications on in vitro alpha-MSH and ACTH release.


Inhibition of adrenocorticotrophin secretion during deprivation-induced eating and drinking in rats. Rats that were maintained on a 23-h food and water deprivation schedule (food and water available between 09:00 and 10:00 h) for 21 days, and whose blood was sampled at various times following initiation of ingestion showed a decrease in plasma adrenocorticotrophin (ACTH) concurrent with dropping plasma levels of corticosterone (COR). This drop occurred from elevated levels of these hormones, most likely due to altered circadian patterns of pituitary-adrenal activity as a result of the rhythm-entraining properties of the feeding schedule. This inhibition of secretion of ACTH is interpreted as reflecting the inhibitory effect of a central nervous system mechanism that can affect ACTH secretion independently of corticosteroid negative feedback.


Anticonvulsant and anesthetic barbiturates: different postsynaptic actions in cultured mammalian neurons. Mammalian spinal cord neurons were grown in dissociated cell culture and used to study the effects of the anticonvulsant barbiturates phenobarbital and mephobarbital, and the anesthetic barbiturates pentobarbital, secobarbital, and 1,3-dimethyl-butylethyl barbituric acid on amino acid responses and neuronal membrane properties. All barbiturates augmented responses to GABA and diminished glutamate (GLU) responses, but the anesthetic barbiturates were more potent. The anesthetic barbiturates directly depressed excitability by increasing membrane conductance, an effect reversed by the GABA antagonists picrotoxin and penicillin. Anticonvulsant barbiturates, however, had only minimal GABA-mimetic inhibitory action at high doses. Modulation of synaptic events mediated by GABA and GLU might contribute to barbiturate anticonvulsant activity; and direct GABA-mimetic inhibition, combined with similar modulation of synaptic transmission, might underlie barbiturate anesthesia.


Neurologic disturbances in Paget disease of bone: response to calcitonin. The neurologic manifestations of Paget disease and the therapeutic effect of calcitonin were studied in 49 patients. Twenty-four patients (49%) had neurologic disorders involving cranial nerves other than the auditory system, brainstem, spinal cord, or spinal roots and nerves. Eighteen of the 24 patients (75%) showed significant subjective or objective improvement after calcitonin treatment. The effect of calcitonin treatment on spinal cord compression was dramatic in three of six patients. The observations made of these patients support previous data suggesting that the neurologic signs and symptoms of Paget disease have their pathogenesis in both mechanical impingement and vascular distortion. The importance of early detection of neurologic signs and symptoms is emphasized, since prompt treatment with calcitonin may prevent severe complications.


Cholinergic dysautonomia and Eaton-Lambert syndrome. Cholinergic autonomic function was abnormal in a 47-year-old woman with Eaton-Lambert syndrome (ELS), not associated with carcinoma. Pupillary constriction to light and accommodation, sweating, lacrimation, and salivation were all affected. There was no evidence of Sjogren syndrome or botulinum intoxication. The defect of acetylcholine release from presynaptic terminals in the Eaton-Lambert syndrome may not be restricted to the neuromuscular junction of skeletal muscle.


Perhexiline maleate and peripheral neuropathy. Peripheral neuropathy has been noted as a complication of therapy with perhexiline maleate, a drug widely used in France (and in clinical trials in the United States) for the prophylactic treatment of angina pectoris. In 24 patients with this complication, the marked slowing of motor nerve conduction velocity and the electromyographic changes imply mainly a demyelinating disorder. Improvement was noted with cessation of therapy. In a few cases the presence of active denervation signified a poor prognosis, with only slight improvement. The underlying mechanism causing the neuropathy is not yet fully known, although some evidence indicates that it may be a lipid storage process.


[Survival and therapy of multiple myeloma. Apropos of 56 observed cases]. 56 cases of myeloma observed since 1956 are reviewed and it is noted that course, prognosis and survival have changed in relation to the improvement in diagnostic procedures and therapeutic aids. The recent introduction of polychemotherapeutic approaches based on theoretical considerations has not yet been fully vetted in the clinic although a higher percentage of remissions compared to that obtained by monochemotherapy would seem to be confirmed. Personal experience with a new polychemotherapeutic schema in advanced myeloma resistant to monochemotherapy + prednisone is reported.


[Case studies of the histological characterization of primary tumors of the testis]. One hundred-ninety nine cases of testicular tumours, of which 189 (94,9%) germ cell tumours, have been studied by histological methods. Seminoma with its two subtypes (anaplastic and spermatocytic) is the most frequent tumour (110 cases i.e. 55,2%), followed by embryonal carcinoma (30 cases: 15,3%), teratocarcinoma (25 cases: 13,2%), teratoma (12 cases: 6,3%) and choriocarcinoma (5 cases: 2,6%). Tumours showing more than one histologic pattern are frequent. The distinctive histologic features have studied, with emphasis of those useful for diagnostic and prognostic purposes. The ages mostly involved by various tumours are stressed. The rarest tumours are briefly described. Histologic data suggest that germinal tumours are originated by the same primordial germ cell which is able to develop various degrees of differentiation. Histologic and histogenetic features of limphomas and tumours of specialized gonadal stroma are also discussed.


24-hour patterns of blood sugar, plasma insulin and free fatty acids in patients with primary endogenous hyperlipoproteinemia on isocaloric diets containing 30, 40 and 79 cal% carbohydrates. 10 patients with primary, endogenous hypertriglyceridemia (type IV hyperlipoproteinemia) underwent three different isocaloric dietary regimes of 10 days duration each. The diets contained either 30, 43 or 79% of calories as carbohydrate with 20% of calories from protein. Analyses of insulin, blood sugar and free fatty acids were conducted on the last day of each dietary period, at frequent intervals. There were no differences in either fasting or diurnal blood sugars with the different diets. Insulin levels were positively correlated with the amount of carbohydrate in the diet and there was an inverse correlation between the carbohydrate contents of the diets and circulating free fatty acid levels during waking hours. Since glucose tolerance is maintained, and diurnal plasma lipid levels are lowest with the low fat regime, such diets may be advantageously used for patients with endogenous hypertriglyceridemia.


Endometrial pathology and estrogens.

Endometrial pathology and estrogens. Endometrial biopsies were obtained from 46 hypogonadal patients (44 with gonadal dysgenesis; 2 panhypopituitary) who were receiving estrogen-progestogen therapy. Endometrial abnormalities occurred only in patients receiving a total lifetime conjugated estrogen dose of greater than or equal to 2500 mg and who had received estrogen treatment for a period longer than 4.2 years. The biopsy outcome was significantly related (P less than 0.01) to the estrogen dose at time of biopsy and to the total lifetime dose (P less than 0.05). The progestational drugs administered did not protect against development of endometrial abnormalities. None of the abnormal endometrial patterns were associated with abnormal vaginal bleeding.


Benign gestational trophoblastic disease metastatic to pleura: unusual cause of hemothorax. A unique case of hemothorax caused by proven pleural involvement with benign gestational trophoblastic disease and anticoagulation is presented. The pulmonary manifestations of gestational trophoblastic disease are reviewed. It is stressed that these may be associated with histologically benign as well as frankly malignant disease, and that the clinician must be alert for them in managing all patients with known or suspected gestational trophoblastic disease.


Heterologous mixed müllerian tumor confined to an endometrial polyp. Mixed müllerian tumors of the uterus, which have been divided into homologous and heterologous types, are considered neoplasms of high malignant potential. In the heterologous variety, the presence of rhabdomyosarcoma has been associated with an especially poor prognosis. We report the first case of a heterologous, malignant mixed mesodermal tumor (adenocarcinoma, stromal sarcoma, and rhabdomyosarcoma) confined to an endometrial polyp. The patient, treated by surgery only, remains clinically free of disease 11 years later. Mixed müllerian tumors of limited extent may not be associated with the dismal prognosis that usually accompanies such lesions.


Preliminary characterization of viruses isolated from cases of epididymitis and vaginitis in cattle. Twelve slow-growing virus isolates propagated in tissue culture from cattle with epididymitis and vaginitis were identified as herpes viruses by virtue of their biological, physicochemical and morphological characteristics. None of the 12 virus strains proved to be serologically related to the infectious pustular vulvo-vaginitis-infectious bovine rhinotracheitis (IPV-IBR) virus, but a further 3 strains included in this study were identical with IPV-IBR virus. Three of the slow-growing virus strains caused a mild anterior vaginitis when deposited in the vagina of heifers. A pool of 10 slow-growing viruses plus a strain of IPV-IBR virus produced anterior and posterior vaginitis in a heifer. the results are discussed in the light of the original description of vaginitis in the "epivag" syndrome.


Non-Hodgkin's lymphoma of the hard palate. In the past decades many changes have taken place in the classification of lymphoreticular malignancies. At present two main groups are recognized--Hodgkin's lymphomas and non-Hodgkin's lymphomas. Hodgkin's lymphomas rarely affect the oral cavity. The mouth, especially the soft tissues, is somewhat more frequently involved in cases of non-Hodgkin's lymphoma. There seems to be some predilection for the mucosa of the palate. The present report describes eight patients in whom a swelling of the palatal mucosa led to the diagnosis of non-Hodgkin's lymphoma. The emphasis is on the clinical and microscopic aspects. The present most accepted histologic classifications have been applied and are briefly discussed.


Neonatal herpes simplex infection possibly acquired via maternal breast milk. A newborn infant with disseminated herpes simplex virus type 1 (HSV-1) infection was determined serologically to have acquired the infection postnatally; his mother was found to have HSV-1 in her breast milk but had no history of genital lesions and negative viral cultures of cervix, vagina, and throat. We suggest that HSV-infected maternal breast milk may be a source of this infection for susceptible infants.


Growth increments with low dose intermittent growth hormone and fluoxymesterone in first year of therapy in hypopituitarism. The availability of a commercial preparation of human growth hormone (hGH) prompted a study in children with hypopituitarism to determine the efficacy of a lower dose of hGH. Thirteen children, ages 4 years 3 months to 13 years 7 months, were given hGH concomitant with fluoxymesterone in an intermittent regimen. The hGH was given intramuscularly, 1 IU daily for 12 to 36 days in each course. There were four courses per year. The fluoxymesterone was given orally, 1 to 2 mg. The total amount of hGH administered was between 48 and 112 IU per year, as compared with the regimen of 312 IU per year, 2 units three times a week. The growth velocity in all 13 children improved, and the mean growth velocity was 6.4 cm +/- 1.13 SD. The mean bone age increment was 0.57 years +/- 0.14 SEM in one chronological year of therapy. The low dose regimen permits a significant reduction in cost of hGH without causing undue advance in bone age.


[Ultrastructure of the cyst wall of Aploparakis polystictae and A. furcigera (Cestoda, Cyclophyllidaea) metacestodes]. The development of the additional membrane (exocyst) from the caudal appendage in diplocysts does not change essentially the structure of the cyst's wall in metacestodes of the genus Aploparaksis. In cytoplasmic connections between cytons and the surface syncytium there are two autonomous enough systems of transport: microtubes opening to the surface of tegument and matrix of bridges which proceed to the matrix of external syncytium. In addition to cytons, in the cyst's wall there are cells with an enlarged granulated endoplasmic network, which are miofibroblasts, secretory cells performing an unclear function, protonephridia and cells limiting the cavity of the cyst of the layer. Differences in the larval morphology of both species are quite negligible and can be due to their age peculiarities.


Ketotic hypoglycemia and hypopituitarism. A 5-year-old girl had hypoglycemia and was of short stature. Studies of pituitary function demonstrated combined growth hormone and adrenocorticotropic hormone (ACTH) deficiency. She was shown to have ketotic hypoglycemia. In contrast to patients previously reported with hypopituitarism and ketotic hypoglycemia, she had no deficiency of gluconeogenic substrate. Serum levels of alanine and other gluconeogenic amino acids were normal during fasting and hypoglycemia. These studies suggest that inadequate gluconeogenic precursors are not the cause of her ketotic hypoglycemia. Ketotic hypoglycemia in association with hypopituitarism may be secondary to multiple biochemical defects.


Learning capacities during sleep: a preliminary study in a group of schizophrenic inpatients. The relationship between sleep and learning processes is analysed in a sample of schizophrenic patients, starting from more recent hypotheses about the function of REM sleep in learning and memory processes. This is done by means of two experiments: in the first AA. evaluate the possibility to elicit a simple motor conditional reflex acquired during daytime in different sleep stages. With the second experiment daytime learning performances are evaluated with and without a reinforcement administered during REM sleep. Results for the first experiment underline a qualitative difference between REM and nREM sleep in a reflexological perspective. In nREM sleep the conditional response is better maintained than in REM sleep. The second experiment confirms the possibility to improve daytime learning performances after an additional presentation of learning material in REM. The joint study of sleep abnormalities and learning and cognitive impairment in schizophrenic patients is finally suggested.


Comparison of theoretical denaturation maps of phiX174 and SV40 with their gene maps. When the theoretical denaturation maps of phiX174 and SV40 are compared with their gene maps, it is observed that the beginning and the end of each gene in these two DNA's fall in a region of lower melting temperatures. Local (A+T)-contents evaluated from the known sequences at these regions support the above implication that the beginnings and the ends of nearly all the genes in phiX174 and SV40 are relatively rich in (A+T)-content.


Recovery of DNA synthesis after ultraviolet irradiation of xeroderma pigmentosum cells depends on excision repair and is blocked by caffeine. Normal human and xeroderma pigmentosum (XP, excision-defective group A) cells (both SV40-transformed) pulse-labeled with [(3)H]thymidine at various times after irradiation with ultraviolet light showed a decline and recovery of both the molecular weights of newly synthesized DNA and the rates of synthesis per cell. At the same ultraviolet dose, both molecular weights and rates of synthesis were inhibited more in XP than in normal cells. This indicates that excision repair plays a role in minimizing the inhibition of chain growth, possibly by excision of dimers ahead of the growing point. The ability to synthesize normal-sized DNA recovered more rapidly than rates of synthesis in normal cells, but both parameters recovered in phase in XP cells. During recovery in normal cells there are therefore fewer actively replicating clusters of replicons because the single-strand breaks involved in the excision of dimers inhibit replicon initiation. XP cells have few excision repair events and therefore fewer breaks to interfere with initiation, but chain growth is blocked by unexcised dimers. In both cell types recovery of the ability to synthesize normal-sized DNA was prevented by growing cells in caffeine after irradiation, possibly because of competition between the DNA binding properties of caffeine and replication proteins. Our observations imply that excision repair and semiconservative replication interact strongly in irradiated cells to produce a complex spectrum of changes in DNA replication which may be confused with parts of alternative systems such as post-replication repair.


The effect of the superhelicity on the double helix twist angle in DNA. An attempt to estimate the relative contributions of twisting and bending to the free energy of superhelix formation from the relaxed DNA is undertaken. The extent of teritiary ordering (number of DNA axis turns tau) and that of secondary ordering (duplex twist angle beta) have been taken as thermodynamical parameters, which characterize the state of the supercoild DNA at the fixed linking number (Lk) value. Such a thermodynamical approach implies the phenomenological parameters of rigidities of twisting and supercoiling (Gbeta, Gtau). Gtau/Gbeta ratio is estimated from the presented experimental data on the winding of the double helix upon increasing the ionic strength when twist alterations are followed by circular dichroism method. The adequacy of such interpretation of CD spectra changes are discussed. The values of Gtau and Gbeta are estimated to be of the same order of magnitude.


RSV-induced tumors in chickens: resistance to pulsed current in terminal and non-terminal types. Terminal Rous sarcoma virus-induced tumors in chickens had lower resistance to a pulsed current than non-terminal tumors or healthy tissues. This finding suggests the existence of some basic physiological difference between terminal and non-terminal tumors. The terminal tumors may have a higher concentration of mobile ions than either non-terminal types or healthy tissue.


Effect of dietary energy on hepatic glycogen metabolism in the turkey hen. An experiment was conducted with turkey hens to investigate the effect of substituting 30% of the carbohydrate calories with corn oil, 1,3-butanediol, or glycerol. Birds fed additional corn oil had the lowest liver glycogen concentration. Corn oil increased phosphorylase, a total phosphorylase, and glycogen synthetase I in comparison to the controls. Also, additional corn oil resulted in the highest specific activity of glucose-6-phosphatase. Dietary glycerol caused the highest concentration of liver glycogen. Glycerol increased glycogen synthetase I, but had little effect upon total activity in comparison to butanediol in the diet. Both butanediol and glycerol gave similar phosphorylase a activity, but butanediol increased total activity. The fat-fed and control-fed hens regulated hepatic glycogen concentration through phosphorylase, while glycerol and butanediol-fed hens regulated glycogen through glycogen synthetase. In vitro activation of glycogen synthetase I was deficient in hens fed additional corn oil, indicating a lack of glycogen synthetase phosphatase activity. The order of activation (glycerol greater than butanediol greater than control greater than corn oil) corresponds to the rank of glycogen concentrations


Characterization of an inhibitor of hepatic cholesterogenesis present in hepatic microsomes. An inhibitor of hepatic cholesterol synthesis present in hepatic microsomes can be solubilized either by an acetone or an ethanol powder preparation. Other methods such as methanol and chloroform:methanol powder preparations and treatment with EDTA do not solubilize the factor. The factor appears to be proteinaceous since its activity is lost after exposure to proteolytic enzymes and heat treatment. In addition, the inhibitor does not require a phospholipid for activity. 3this inhibitor is stable for long periods (60 hrs.) at room temperature and can be isolated in good yield from liver maintained at 4 degrees C for 8 hours postmortem.


Large scale, analytical method for isolating basal lateral plasma membranes from rat duodenum. A procedure is described for obtaining large amounts of basal lateral plasma membranes from the rat duodenal epithelium. The yield is approximately 50%, and the purification factor is 18; preparations from 25 rats routinely contain 100 mg of protein. The procedure depends on mild homogenization with a nitrogen cavitation bomb, followed by removal of brush borders by sedimentation in a weak centrifugal field. Basal lateral membranes in the resulting supernatant are partially purified by differential centrifugation in a medium which approximates their equilibrium density, and then further purified by equilibrium density gradient centrifugation in a high capacity zonal rotor. Brush border membranes may be isolated from the 450 x g pellet. Since both brush border and basal lateral membranes may be isolated from the same homogenate, this preparative procedure is suitable for such analytical purposes as determinations of distribution of enzyme activities between the two surfaces of the epithelium. The large scale of the isolation procedure makes it an appropriate starting point for purification of specific basal lateral membrane components.


Production of Ficoll, Percoll, and albumin gradients by the freeze-thaw method. Ficoll, sucrose, albumin, and Percoll, a modified colloidal silica centrifugation medium, all form density gradients upon freezing and thawing. The data suggest that any density gradient material will form gradients upon freezing and thawing, provided the material is stable to freezing.


Large-scale purification of Na,K-ATPase and its protein subunits from lamb kidney medulla. Procedures are described for the large-scale isolation of purified Na,K-ATPase (EC 3.6.1.3) from frozen lamb kidney outer medulla and for the separation of its two protein subunits by hydroxyapatite chromatography in sodium dodecyl sulfate (SDS). The methods described permit the routine isolation of up to 800 mg of purified Na,K-ATPase in one week, which can subsequently be separated into 500 mg of mr = 95,000 catalytic subunit and 200 mg of glycoprotein with four SDS-hydroxyapatite column runs.


Circular dichroic evidence for a conformational change in a cytochrome b--c1 complex by uncoupling agents. Circular dichroic spectra of the cytochrome b--c1 complex exhibit bilobe formation typical of exciton splitting in the presence of uncoupler. Bilobe formation occurs if both cytochrome c1 and cytochrome b are fully reduced. The fully oxidized and ascorbate-reduced complexes are not altered dichroically by uncouplers. The exciton splitting induced by uncoupler is consistent with heme--heme interaction: specifically, interaction between the two cytochromes b in the complex.


Coupling between oxidation state and hydrogen bond conformation in heme proteins. In all heme proteins for which crystal structures are available, the N(epsilon) of a histidyl residue is bonded to the heme iron and N(delta) is hydrogen bonded to a carbonyl oxygen of the peptide backbone. We investigate here the possibility that a change in oxidation state of the iron or a change in the geometry of this hydrogen bond might change the hydrogen bond strength in a functionally significant way. Dimerization energies obtained from ab initio molecular orbital calculations on the hydrogen-bonded dimer of imidazole and planar formamide are used to represent the strength of this hydrogen bond in heme proteins. The effect of a change in iron oxidation state is modeled by varying the positive charge on imidazole. The effect of a change in hydrogen bond geometry is studied by employing x-ray coordinates for reduced and oxidized cytochrome c, deoxy- and metmyoglobin, and deoxy- and methemoglobin. Our conclusions are that the strength of this hydrogen bond in heme proteins is sensitive to both the oxidation state of the iron atom and to geometry changes on the order of those obtained from the x-ray coordinates. We speculate that the changes in oxidation state may be functionally coupled with changes in hydrogen bond geometry and that this hydrogen bond represents a feasible pathway to link protein conformation with redox potential or reactivity of the iron atom.


Control of eIF-2 phosphatase activity in rabbit reticulocyte lysate. A sensitive assay requiring picomole amounts of [32P]eIF-2 to measure eIF-2 phosphatase activity has been developed. Dephosphorylation of [32P]eIF-2 alpha (38,000-dalton subunit) is extremely rapid (t 1/2 = 20 sec) and occurs at the same rate in both hemin-supplemented and hemin-depleted lysates. In contrast, [32P]eIF-2 beta phosphate is stable under all conditions studied. At concentrations required to produce a transient inhibition of protein synthesis, GDP prevents dephosphorylation of half of the phosphate introduced on eIF-2 alpha by the hemin-controlled repressor. Equimolar GTP is without effect. The concept that the energy charge of the guanylate pool may regulate accessibility of a phosphorylated site on eIF-2 alpha to its phosphatase and the implication of this to the mechanism of hemin-regulated translational control are discussed.


Adenylate cyclase and acetylcholine release regulated by separate serotonin receptors of somatic cell hybrids. Serotonin activates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of NCB-20 neuroblastoma--brain hybrid cells with an activation constant of 530 nM, but has little or no effect on cellular cyclic AMP or cyclic GMP content of NIE-115 neuroblastoma or NG108-15 hybrid cells. In homogenates of NCB-20 hybrid cells, lysergic acid diethylamide stimulates adenylate cyclase activity (Kact = 12 nM) and partially inhibits (Ki = 10 nM) the stimulation of adenylate cyclase activity by serotonin. No desensitization was detected of serotonin receptors coupled to adenylate cyclase. Serotonin also depolarizes NCB-20, NG108-15, and NIE-115 cells and increases acetylcholine release. Serotonin receptors mediating depolarizing responses desensitize rapidly and reversibly, and the depolarizing effects of serotonin are neither mimicked nor inhibited by lysergic acid diethylamide. These results indicate that (i) NCB-20 cells possess at least two species of serotonin receptors, which independently regulate cellular functions, (ii) activation of adenylate cyclase does not directly affect membrane potential or acetylcholine release, and (iii) serotonin-dependent cell depolarization does not affect cyclic AMP or cyclic GMP synthesis in the cell lines tested.


Transfer of glucagon receptor from liver membranes to a foreign adenylate cyclase by a membrane fusion procedure. Previous work had demonstrated the coupling of a beta-adrenergic receptor on an erythrocyte with the adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] of a tissue culture cell when the two cells were fused by Sendai virus. The validity of this finding for animal tissues in general, for membrane preparations, and for peptide hormone receptors could hitherto not be assessed. Available fusion procedures worked efficiently only with certain intact cells from tissue culture and with erythrocytes. In the present work a membrane fusion method was developed that causes the transfer of the glucagon receptor from purified rat liver membranes to Friend erythroleukemia cells; even direct transfer to a membrane fraction prepared from Friend cells became feasible. It can therefore be concluded that a peptide hormone receptor in a normal tissue membrane has properties similar to those demonstrated for a beta-adrenergic receptor in an erythrocyte: it exists in the membrane as a dissociable independent unit that can readily couple with the adenylate cyclase of a foreign cell. The efficiency of the membrane fusion procedure is due to the combined action of polyethylene glycol, phospholipids, stearylamine, and ATP in a salt medium. The method promises to be applicable to membranes of various cells and tissues, and it can probably be used to analyze hormone receptors and adenylate cyclase systems in states of malfunction by transfer to their respective counterpart in a normal cell membrane. Studies in biochemical hybridization of membrane components need not be limited to hormone activation of adenylate cyclase. With the aid of the membrane fusion method, this approach could be applied to any dissociable multicomponent system in biological membranes.


BK virus DNA sequence: extent of homology with simian virus 40 DNA. The primary nucleotide sequence of three regions of BK virus (BKV) variant (MM) DNA has been determined. The region between map positions 0.715 and 0.900 includes the initiation points and partial coding sequences of the putative VP2 and VP3 proteins of BKV(MM), the amino acid sequences of which show over 80% homology with those of VP2 and VP3 of simian virus 40. The sequence of a potential leader protein X, 66 amino acids long for BKV(MM) and 62 long for simian virus 40, is also deduced. The regions between 0.595 and 0.398 and 0.310 and 0.175 include the coding sequence for the entire small t antigen and most of the large T antigen of BKV(MM). The DNA sequence within these regions comprises over 50% of the complete BKV(MM) genome and shows a 70% sequence homology with the corresponding regions of simian virus 40 DNA. This high degree of homology is at variance with the reported homology values of 11--20% estimated by hybridization measurements of heteroduplex analyses. Possible explanations for the discrepancy are discussed.


Preparation of a disulfide-linked dimer of human placental lactogen fragment 1--134 with immunologic and biologic activity. In order to determine the chemical features of human placental lactogen (hPL) necessary for its biologic activity we prepared the following fragments from the plasmin-cleaved hormone: reduced and alkylated 1--134, reduced and alkylated 141--191, and a 1--134 dimer joined through the single cysteinyl residue at position 53. In a radioimmunoassay using antibodies against native hPL, the two reduced and alkylated fragments produced nonparallel displacement and had less than 1% of the activity of hPL. The ability of reduced and alkylated 1--134 to bind to mammary gland receptors was less than 5% of that of hPL; reduced and alkylated 141--191 showed no detectable activity in the same assay. The 1--134 dimer, in contrast, had 20% of the immunologic activity and 30% of the ability to bind to lactogenic receptors relative to the native hormone. In an in vitro bioassay the lactogenic activity of the 1--134 dimer was equivalent to that of the native hormone. The circular dichroic spectra of hPL, reduced and alkylated 1--134, and 1--134 dimer indicated that the dimer had regained much of the helical content of the native hormone. Antibodies produced to reduced and alkylated 1--134 did not significantly crossreact with either native hPL or 1--134 dimer. From these data we conclude that the information for the lactogenic activity of hPL is contained in the first 134 amino acid residues and that the proper conformation is necessary for its biologic expression.


Lateral translational diffusion of cytochrome c oxidase in the mitochondrial energy-transducing membrane. The degree of freedom for lateral translational diffusion by cytochrome c oxidase and other integral proteins in the energy-transducing membrane of the mitochondrion was determined by combining the use of an immunoglobulin probe monospecific for the oxidase with thermotropic lipid phase transitions. Lateral mobility of the oxidase was monitored by observing the distribution of the immunoglobulin probe on the membrane surface by deep-etch electron microscopy and by observing the distribution of intramembrane particles (integral proteins) in the hydrophobic interior of the membrane by freeze-fracture electron microscopy. Incubation of the membrane with the immunoglobulin resulted in a time-dependent clustering of predominantly large intramembrane particles. Low temperature-induced lipid phase transitions resulted in the close packing of all intramembrane particles and cytochrome c oxidase by lateral exclusion from domains of gel-state bilayer lipid and was completely reversible. However, when cytochrome c oxidase was crosslinked through an immunoglobulin lattice prior to returning the membrane to above the lipid phase transition temperature, small intramembrane particles rerandomized while the large oxidase-related particles remained clustered. These observations reveal that cytochrome c oxidase can diffuse laterally in the energy-transducing membrane, either independently of all other integral proteins or in physical union with one or more other integral proteins. In addition, many other as yet unidentified smaller integral proteins can diffuse independently of the oxidase.


Reversion to methionine independence in simian virus 40-transformed human and malignant rat fibroblasts is associated with altered ploidy and altered properties of transformation. Many transformed and malignant cells, unlike normal cells, do not grow when methionine in the growth medium is replaced by its immediate precursor homocysteine [Chello, P. & Bertino, J. (1973) Cancer Res. 33, 1898-1904 and Hoffman, R. & Erbe, R. (1976) Proc. Natl. Acad. Sci. USA 73, 1523-1527]. Rare cells from those populations revert to methionine independence [Hoffman, R., Jacobsen, S. & Erbe, R. (1978) Biochem. Biophys. Res. Commun. 82, 228-234]. We report here that methionine-independent revertants of both human fibroblasts transformed by simian virus 40 and malignant rat fibroblasts concomitantly revert for some of the properties associated with the transformed state. Of the 13 methionine-independent revertants described here, 5 showed increased anchorage dependence as reflected by reduced cloning efficiences in methylcellulose; 8 showed an increased serum requirement for optimal growth; 8 showed decreased cell density in medium containing high serum; and 3 altered their cell morphology significantly. Eight of the 13 have increased chromosome numbers. All lines tested contained immunologically identifiable tumor antigen of simian virus 40. Thus by selecting for methionine independence it is possible to select for heterogeneous transformation revertants, indicating further a relationship between altered methionine metabolism and oncogenic transformation. Therefore a positive metabolic method to select for transformation revertants has been developed, and its use has resulted in selection of human transformation revertants.


Inducers of mammalian cell differentiation stimulate dome formation in a differentiated kidney epithelial cell line (MDCK). Cell cultures of a differentiated kidney epithelial cell line, MDCK, spontaneously form fluid-filled domes or hemicysts composed of numbers of cells as a manifestation of specialized epithelial transport phenomena. Addition to MDCK cells of a broad spectrum of compounds that are known as potent inducers of mammalian cell differentiation in cell culture caused a striking increase in the frequency of dome formation. Polar compounds such as N,N-dimethylformamide, dimethyl sulfoxide, or hexamethylene bisacetamide stimulated increased dome formation 15--30 hr after addition. Induction of domes by these compounds was prevented either by inhibitors of protein synthesis or by ouabain, cytochalasin B, or vinblastine. Inhibition of DNA synthesis did not block chemical induction of domes. Other inducers were compounds of physiological occurrence such as n-butyrate or adenosine. Furthermore, a variety of conditions expected to elevate intracellular levels of cyclic AMP also stimulated dome formation. These findings suggest the hypothesis that domes are formed in cell culture by a form of cell differentiation that is under positive control by cyclic AMP.


Molecular reorganization of lipid bilayers by complement: a possible mechanism for membranolysis. The interaction between the membrane attack complex (MAC) of complement and flat lipid bilayers was investigated. Using spin-labeled derivatives of phospholipids and cholesterol and electron paramagnetic resonance spectroscopy, we measured the penetration of the MAC into bilayers and its influence on the order of bilayers. The MAC precursor components C5b--6, C7, C8, and C9 did not exert any measurable influence on lipid membranes. Functional C5b--7 was shown to interact strongly with the bilayer surface without deep penetration into the bilayer. Formation of C5b--8 and especially C5b--9 caused a marked change in the anisotropy of spectra from probes located within the hydrocarbon phase. The spectral changes are not caused by changes in probe rotation and, in the case of the cholesterol probes, are not due to direct probe--protein interactions. For these reasons we interpret the spectral changes to be the result of reorientation of ordered bilayer lipids effected by strong binding of phospholipids to MAC proteins.


Biosynthesis in vitro of immunoreactive 31,000-dalton corticotropin/beta-endorphin-like material by bovine hypothalamus. Enzymatically dispersed bovine hypothalamic or cortical tissue was maintained in culture in the presence of (3)H-labeled amino acids. After such incubation, extracts of cells and of media contained (3)H-labeled products that were specifically bound by immobilized affinity-purified antisera to corticotropin (ACTH) and beta-endorphin. The majority of these products eluted in the void volume (V(0)) upon Sephadex G-50 gel filtration; minor (3)H-labeled products eluted in the regions of the ovine beta-lipotropin marker and in fractions having apparent molecular weights of approximately 12,000 and 3800. Sequential use of these immobilized antisera revealed that most of the V(0) material contained both ACTH and beta-endorphin antigenic determinants within the same molecule(s), whereas retarded material contained only one of the determinants. When this V(0) material was rerun on a Sephadex G-75 column, it coeluted with the 31-kilodalton precursor of both ACTH and beta-endorphin obtained from a bovine anterior pituitary extract. Thus, the high molecular weight immunoreactive ACTH/beta-endorphin-like (3)H-labeled product(s) derived from the hypothalamic culture is similar to the pituitary-derived precursor in containing the dual antigenic determinants and in its gel filtration characteristics. In contrast, the cortex-derived cell preparation was devoid of (3)H-labeled products specifically reactive with the antisera employed.


Depressed cyclic AMP levels in airways smooth muscle from asthmatic dogs. We tested mongrel dogs by intradermal injection and tracheobronchial aerosol challenge with Ascaris suum antigen extract. All dogs were skin-test positive but could be segregated, on the basis of airways resistance measurements, into "asthmatic" (bronchoreactive) and "nonasthmatic" (nonbronchoreactive) groups. By using tracheal rings from these dogs, we measured the abilities of the beta-adrenergic agonist, isoproterenol, to relax tracheal smooth muscle contracted by methacholine and to cause cyclic AMP (cAMP) accumulation in the presence and absence of methacholine. The magnitude of relaxation induced by any concentration of isoproterenol was always less in the smooth muscle from "asthmatic" dogs. In the same tissues the concentrations of cAMP after in vitro equilibration, but prior to isoproterenol addition, were significantly less in the "asthmatic" than "nonasthmatic" samples. The accumulation of cAMP due to isoproterenol was similar in both groups for every dose of isoproterenol so that the initial difference between groups in cAMP concentration was maintained in an additive fashion over the entire dose-response curve. Total protein content of trachealis muscles from both groups of dogs was the same. We conclude that beta-adrenergically sensitive adenylate cyclase is not impaired in tracheal smooth muscle from "asthmatic" dogs; rather, the basal concentration of cAMP is depressed in "asthmatic" airway smooth muscle, and this difference is maintained throughout the isoproterenol dose-response curve. The depressed intracellular cAMP concentrations may be related to the decreased relaxation induced by isoproterenol in the "asthmatic" tracheal smooth muscle.


Immunocytochemical localization of cyclic GMP: light and electron microscope evidence for involvement of neuroglia. Guanosine 3',5'-cyclic monophosphate (cGMP) immunoreactivity in the rat's cerebellum was studied with light and electron microscopy by the indirect fluorescence method and the peroxidase-antiperoxidase method. Labeled cells included neuroglial cells in the cerebellar cortex, white matter, and deep nuclei; some stellate and basket cells in the cortex; and some large neurons in the deep nuclei. No evidence was found for sagittal microzonation in the cGMP distribution. In the labeled cells, cGMP immunoreactive sites were localized to surface membranes, organelles, and the cytoplasmic matrix. Specificity was indicated by the same pattern of labeling after treatment with cGMP immunoglobulin that had been adsorbed with adenosine 3',5'-cyclic monophosphate (cAMP) and by the failure to label after treatment with normal rabbit sera or with cGMP immunoglobulin that had been adsorbed with 1 mM cGMP. Cerebella treated with cAMP antisera, however, showed immunoreactivity in Purkinje cells, granule cells, and Golgi cells in addition to neuroglia in cortex and deep nuclei. Sequential norepinephrine and glutamate superfusions generally intensified cGMP immunoreactivity, not only in neuroglial cells but also in the background. Under these conditions some Purkinje cells and some granule cells were also labeled. Increased cGMP immunoreactivity was also obtained by treatment with harmaline, gamma-aminobutyric acid and aminooxyacetic acid, muscimol, gamma-aminobutyric acid, or apomorphine in order of decreasing effectiveness. Serotonin and colchicine produced no detectable increase of cGMP immunoreactivity above normal, and diazepam and sodium pentobarbital decreased it. In these experiments, diethyl ether was preferable to sodium pentobarbital for anesthesia on account of the depressive action of the latter on cGMP immunoreactivity. Thus, drugs that increase cerebellar activity enhance cGMP levels, whereas those that decrease cerebellar activity decrease cGMP levels. However, it is not clear whether these fluctuations in cGMP levels are a direct consequence of neurotransmitter function or are sequelae to other related events. The present study suggests that some neurons and many neuroglial cells are the major sites of cGMP in the cerebellum.


ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats. These experiments examined the effects of an ACTH4-9 analog (ORG 2766) on an inhibitory avoidance response in rats. Graded doses of ORG 2766 were administered either 1 hr prior to training, immediately after training, or 1 hr prior to the retention test. The animals were tested 24 hr after training. A 5.0 mg/kg dose was administered prior to training significantly facilitated acquisition of the response. ORG 2766 did not significantly affect retention when administered after training or prior to the retention test. Since ORG 2766 only affected acquisition of the response, it is suggested that the drug acts by influencing sensory, motivationl or attentional variables rather than directly affecting memory consolidation or retrieval processes.


Possible participation of glucocorticoid in elevation of 3',5'-cyclic AMP levels through inhibition of cyclic AMP phosphodiesterase. Administration of prednisolone and cholate to rats elevated levels of cAMP (adenosine 3',5'-cyclic monophosphate) by 1.5- to 2.0-fold. Compounds such as prednisolone, hydrocortisone, cholate, and deoxycholate were found to be potent inhibitors of partially purified cAMP phosphodiesterase prepared from rat liver. Kinetic analysis showed that the prednisolone inhibition was noncompetitive with a Ki of 8.9 x 10(-4) M. These results suggest that in addition to increasing DNA-dependent RNA polymerase activity in vivo, a large application of glucocorticoid may incur elevation of intracellular cAMP levels.


Neural control of heartbeat in the leech and in some other invertebrates. The heartbeat of the leech Hirudo consists of the contractile rhythm of the circular muscles in the wall of a bilateral pair of celomic sinuses, the heart tubes, that run the length of the leech body. The constriction cycles of the segmental heart-tube sections are coordinated so that on one body side they constrict in a rear-to-front progression (peristalsis), while on the other side they constrict nearly in concert (nonperistalsis). Spontaneous right-left reciprocal transitions between peristaltic and nonperistaltic coordination modes occur every few dozen heartbeat cycles. The constriction of each segmental heart-tube section is controlled via excitatory synapses by a rhythmically active heart motor neuron, or HE cell, of which 17 bilateral pairs are iterated in segmental ganglia of the ventral nerve cord. The activity rhythm of the HE cell ensemble is in turn controlled via inhibitory synapses by a rhythmically active heart interneuron, the HN cell, of which seven bilateral pairs are iterated in the rostral segmental ganglia. The HN heart interneuron owes its activity rhythm to an endogenous polarization cycle, and the cycles of all members of the HN cell ensemble are locked into an appropriate phase relation thanks to their mutual interconnection via excitatory and inhibitory synaptic connections. The observed activity pattern and identified synaptic connections of HE cells and HN cells can account not only for the generation of the two bilaterally asymmetric heartbeat coordination modes but also for the right-left coordination mode transitions. In contrast to the heartbeat of Hirudo, the beat of the single-chambered heart of the lobsters Panulirus and Homarus is controlled by a set of nine rhythmically active neurons that make up the cardiac ganglion. Of these, five larger cells are heart motor neurons that innervate the heart muscle fibers via excitatory synapses. The remaining four smaller neurons of the cardiac ganglion are interneurons that provide excitatory input to each other and to the heart motor neurons. Although all the neurons of the cardiac ganglion appear capable of producing their own endogenous polarization rhythm, it is currently believed that one of the interneurons acts as a pacemaker for the whole ensemble of interneurons and motor neurons. The beat of the two-chambered heart of the marine snail Aplysia is generated by yet an entirely different mechanism. Here, the basic contractile rhythm of the heart is due to an endogenous polarization cycle of the heart muscle fibers. That myogenic rhythm is controlled and modulated by a set of cardiovascular motor neurons located in the abdominal ganglion, some of which make excitatory and others of which make inhibitory connections with the heart muscle fibers. The activity of these cardiovascular motor neurons is controlled by three types of heart interneurons via both inhibitory and excitatory connections. The interneurons are in turn interconnected in a manner that prevents the simultaneous activation of antagonistic cardiac motor acts...


Functional adaptation to reduction in renal mass. As the population of nephrons diminishes, while the dietary intake and/or endogenous production of water and solutes is unchanged, there is a proportional increase in the excretion of water and solute by individual residual nephrons. This adaptive change, which preserves zero net balance in the early phase of renal insufficiency, involves a reduction in the fractional reabsorption of substances derived from the initial glomerular ultrafiltrate and an increase in the rate of secretion of solutes that are extracted by tubular epithelial cells from peritubular blood. These compensatory changes are adequate to maintain electrolyte and water homeostasis until severe renal failure ensures (GFR less than 20% of normal). After a moderate reduction in nephron population there is no evidence that the factors that modulate ion transport are qualitatively different from those that regulate renal function in the intact subject, when the excretory load of solute is varied by changes in intake or endogenous production. In severe renal insufficiency, however, it seems likely that several factors, not present in the subject with intact renal function, also play an important role in modifying the excretion of water and electrolytes. For example, an osmotic diuresis in severe renal failure apparently decreases the tubular reabsorption of sodium and divalent cations and that of water. Moreover, elaboration of a partially identified "natriuretic" substance may participate in the regulation of electrolyte excretion in severe renal insufficiency. The appearance of these factors in severe renal insufficiency probably complements mechanisms that normally regulate the transfer of water and ions across tubular epithelium, since even after a marked reduction in GFR the urinary excretion of solutes and water changes proportionally with intake, although within narrower limits than exist in normal subjects. Studies in experimental animals and in man with acquired renal disease demonstrate the important role of other factors in compensatory adaptation, in addition to changes in tubular transport. The marked increases in glomerular filtration rate and nephron blood flow, which occur at least in some conditions, increase the absolute amount of water and solute delivered to the various nephron segments in ultrafiltrate and peritubular blood. Moreover, the expansion of extracellular fluid in severe renal failure inhibits tubular reabsorption of filtered water and solute in the same qualitative way that has been demonstrated in subjects with intact renal function. Quantitatively the response to acute volume expansion is exaggerated compared with control. Concomitant changes in renal hypertrophy and hyperplasia probably play an important role in functional adaptation. The apparent marked capacity for compensatory growth in all nephron segments and even in portions of tubular segments in parenchymal renal disease increases the area for transport by tubular epithelia in residual nephrons, as the overall number of nephrons diminishes...


Specific 3H-PGE1 binding sites in rat ovary in estrous cycle and pregnancy. Stimulation of cAMP synthesis by prostaglandins E series in the rat ovary is consistent with the presence of a prostaglandin receptor in this tissue. Prostaglandin binding sites with specificity for PGE1 in vitro incubation systems have been demonstrated in rat ovary slices and corpora lutea. The binding of 3H-PGE1 was progressively inhibited with increasing amounts of unlabelled PGE1 and PGE2. PGF2alpha inhibitory effect was markedly smaller than that of PGE. 3H-PGE1 binding to the ovary was higher in 3-day-old rats than in 5-day-old and adult animals, when the highest binding was present in estrus. The specific binding of 3H-PGE1 to rat corpora lutea (CL) decreased on days 11 and 13 of pregnancy and then gradually returned to the level found on day 1 during the second half of gestation. This binding of labelled prostaglandin during pregnancy has been studied in relation to the PGE1 stimulation of cAMP synthesis in rat corpora lutea, but no consistent changes were observed in responsiveness.


The stress induced increase of liver phosphorylase A and cyclic AMP in adrenomedullectomized and adrenalectomized rats. In adult male rats injected with Pentobarbital, 50 mg.kg-1 i.p. and subjected immediately after administration of the anaesthetic to 400 revolutions (lasting of 6 min and 40 s) in rotating Noble-Collip drums the activity of the active form of hepatic phosphorylase was increased at time 0 after injury without respect to previous adrenomedullectomy or adrenalectomy (7 weeks or 10 days before, respectively). Completeness of surgery was checked by plasma catecholamines which were essentially near zero. The level of liver cAMP was increased in intact and adrenomedullectomized animals at time zero. 90 min after injury a recovery of enzyme activity towards basal levels was observed in contrast to cAMP which was increased in all the three groups. A net glycogenolytic response was found in the injured animals irrespective of previous surgery. It is concluded that for the stress induced activation of hepatic phosphorylase the presence of adrenal cortical and medullary tissue is not always indispensable.


A method of quantitating aggressive behaviour revealing possible dissociation of motor activity and aggression. A method is described for quantitating isolation-induced aggression in wild male mice by measuring coarse motor activity. It is based on the operational definition that aggression is the form of motor activity in which two (or more) animals are involved in behaviour patterns, such as physical attack and/or defence including pursuit and flight. Both coarse and fine motor activity were measured by means of an electromagnetic activity meter. Four hundred ninety-two fights occurring among mice treated with various hormones, neurotransmitter antagonists, hashish, and cyproterone acetate were recorded; a positive significant correlation (P less than 0.001) between indices of fighting behaviour as well as fighting time and coarse motor activity were found. The simultaneous measurement of motor activity and aggression revealed dissociated effects of some drugs on non-aggressive fine motor activity and aggression.


Long-term effect of ovariectomy on dopamine-stimulated adenylate cyclase in rat striatum and nucleus accumbens. The long-term effects on dopamine-sensitive adenylate cyclase of deprivation of gonadal steroids resulting from ovariectomy were studied in extrahypothalamic areas of the brain, i.e. corpus striatum and nucleus accumbens. The results obtained show that in both central nervous system areas dopamine- and apomorphine-stimulated adenylate cyclase were significantly reduced, suggesting that the function of dopamine receptors in these areas was depressed.


Tardive dyskinesia: a clinical test of the supersensitivity hypothesis. Patients with tardive dyskinesia showed no significant difference in CSF HVA when compared with groups of schizophrenic or depressives. CSF cAMP in the tardive dyskinesia group was significantly lower when compared to schizophrenics but not depressives. These results do not support a dopamine-receptor supersensitivity hypothesis in permanent tardive dyskinesia.


The effect of the combination of lithium and haloperidol on brain intermediary metabolism in vivo. The effect of the chronic administration of the combination of lithium and haloperidol has been studied in rat brain in vivo. Lithium was administered in food in amounts sufficient to maintain serum lithium levels of 1.0 +/- 0.1 mEq/l; haloperidol (1.5 mg/kg) was given i.p. once daily. Control animals pair-fed with the lithium/haloperidol alone, or neither drug. Fifteen days after the beginning of the experiments the brains were instantaneously frozen with a rapid brain-freezing device and multiple metabolites were measured in the perchloric acid extract of the tissue. Intermediates examined included selected metabolites of the glycolytic pathway and the tricarboxylic acid cycle, N-acetylaspartate and cofactors such as ATP, CoA, and acetyl-CoA. Estimates of the effects of the treatments on cytoplasmic and mitochondrial redox states were also made. The results showed only minor effects of any of the treatments on any of the parameters studied and little or nothing to distinguish the combination of lithium and haloperidol from either treatment alone.


ACTH 4-10 in the amelioration of neuropsychological symptomatology associated with senile organic brain syndrome. Eighteen male and female volunteers over the age of sixty who exhibited mild senile organic brain syndrome were administered ACTH 4-10 (Org OI 63) (30 mg, s.c.) or saline in a 2 X 2 Latin square design. Subjects experienced a reduction in depression and confusion and an increase in vigor. This evidence of an increase in vigor was supported behaviorally by a delay in the onset of increased latency in reaction time. Data also indicated that retrieval from memory may be enhanced by this compound. The electroencephalogram evinced a shift to lower frequencies under ACTH 4-10, but this effect was primarily noted in the females who received drug followed by placebo. These effects of ACTH 4-10 are intriguing and suggest that further work in this area should be encouraged.


Cerebrospinal fluid cyclic AMP and acid monoamine metabolites following probenecid: studies in psychiatric patients. At probenecid levels greater than 10 microgram/ml, CSF cAMP was independent of CSF probenecid concentration. At these levels of probenecid, cAMP transport out of CSF is probably maximally blocked and cAMP levels reflect cAMP release into CSF. CSF cAMP was significantly higher in RDC-diagnosed schizophrenics than in other psychotics or depressives. A significant decrease in CSF cAMP was found in psychotic patients treated with chlorpromazine, No changes in CSF cAMP were observed in patients treated with tricyclic antidepressants or lithium.


Enhancement of central norepinephrine and 5-hydroxytryptamine transmission by tricyclic antidepressants. A comparison. The relative abilities of 1--3 mg/kg of desipramine (DES), imipramine (IMIP), amitriptyline (AMI), and chlorimipramine (CI-IMIP) to enhance synaptic transmission mediated by either NE or 5-HT were determined by testing their effects directly on NE or 5-HT transmission to sympathetic preganglionic neurons in unanesthetized, spinal cats. Effects on NE transmission were assessed on intraspinal excitatory pathways which utilize NE as a transmitter. Effects on 5-HT transmission were assessed on 5-HT-mediated depression of spinal sympathetic reflexes produced by 30 mg/kg of 5-HTP. Both DES and IMIP markedly enhanced transmission through the intraspinal excitatory NE pathways whereas AMI and CI-IMIP depressed transmission. However, both AMI and CI-IMIP modestly enhanced transmission in cats depleted of central 5-HT by pretreatment with parachlorophenylalanine. The relative potencies of the four drugs on excitatory NE transmission were DES greater than IMIP greater than AMI greater than CI-IMIP. Each of the four drugs also enhanced the 5-HTP-induced depression of spinal sympathetic reflexes, but their relative potencies on 5-HT transmission were just the opposite to those found on NE transmission. Therefore, all four drugs enhanced transmission by both NE and 5-HT, but their relative selectivities for the two transmitters differed markedly and were complementary. In general, the results support those of previous studies based on less direct methods for assessing inhibition of amine reuptake by tricyclic antidepressants.


Studies of hypoparathyroidism and pseudohypoparathyroidism. Twenty eight hypocalcaemic patients were studied, 14 with primary hypoparathyroidism, nine with pseudohypoparathyroidism and two with hypo-hyperparathyroidism, to characterized the essential features of these disorders. Like tetany, which was present in 12 of the patients, epilepsy was a common symptom, occurring in 13, seven of whom had received anticonvulsants for two to eight years before hypocalcaemia was detected. Differentiation between primary and pseudohypoparathyroidism could not be made with certainty on clinical grounds but confident distinction could be made by measurement of endogenous parathyroid hormone concentrations and by testing for renal resistance to exogenous parathyroid hormone. This was achieved by measurement of the plasma and, in some patients, the urinary cyclic AMP response to an intravenous injection of highly purified bovine parathyroid hormone. These investigations were also valuable in the assessment of the other three hypocalcaemic patients in whom a diagnosis of parathyroid dysfunction would otherwise have been made. In 10 of the patients synthetic 1 alpha-hydroxylated forms of vitamin D were used to establish and maintain normocalcaemia, though their use required careful monitoring.


[Alpha-lipoproteins and viral hepatitis (author's transl)]. The plasma levels of alpha-lipoproteins, triglycerides, cholesterol, bilirubin, ALT and AST were followed serially in a group of 10 patients with acute viral hepatitis. Hypertrygliceridaemia, low level of cholesterol and very low level of alpha band of the lipoproteins were found at the onset of the disease. Alpha-lipoprotein reappeared gradually during the course of the disease and was sensitive indices of improvement of liver function. A negative linear correlation was found between alpha-lipoprotein and total bilirubin and between alpha-lipoprotein and ALT.


Evaluation of angiography in Zollinger-Ellison syndrome. Of 20 patients with the Zollinger-Ellison syndrome who underwent visceral angiography, only 3 had unequivocally positive studies for primary pancreatic tumors; another 5 patients had equivocal diagnoses based on adequate studies. Eight patients had no abnormalities of any kind detected by angiography (except for an obstructed splenic vein in one patient). Five patients were shown to have hypervascular liver metastases. These results contrast with most reports of findings in islet cell tumors in general and specifically with the findings in several small series of the Zollinger-Ellison syndrome.


Ultrasound manifestations of hepatocellular carcinoma. The ultrasound patterns of primary hepatocellular carcinoma are described. Three types were found: a densely echogenic mass, diffuse disease, and a mixture of the two. These three patterns correspond to the previously reported angiographic and pathological manifestations of disease. The differential diagnosis is discussed.


Renal hyperconcentration of 99mTc-HEDP in experimental acute tubular necrosis. The effect of transient renal ischemia on renal concentration and distribution of 99mTc-HEDP, 99mTc-DMSA, and 99mTc-DTPA was compared in rabbits with acute tubular necrosis. Scintigrams were obtained after injection in normal rabbits or ones with unilateral or bilateral ischemia. 99mTc-HEDP concentration in ischemic tissue was 8 to 18 times normal 1--4 hours after injection, and the resulting images delineated the morphological changes in the ischemic kidneys more accurately than those obtained with DMSA or DTPA. Calcium concentration in the ischemic kidneys increased sixfold. 99mTc-HEDP may be useful in evaluation of renal failure secondary to tubular injury.


A comparison of the effects of PGI2, PGE2 and PGH2 on the cyclic nucleotide levels in rat anterior pituitary gland in vitro. Rat anterior pituitary explants were incubated with PGI2, PGH2 and PGE2 in the presence of theophylline (1mM) and the production of cyclic AMP was measured. PGE2 was found to be about 20 times more potent than PGI2 while PGH2 was slightly more effective than PGI2. The results suggest that PGI2 does not play a AMP was measured. PGE was found to be about 20 times more potent than physiological role in cyclic AMP mediated events in the rat anterior pituitary.


Prostacyclin (PGI2) in pregnant human uterus. Prostacyclin lowers the tonus and reduces the spontaneous motility of isolated pregnant human myometrium. This effect seems to be related to coclic-AMP accumulation, since PGI2 increases the formation of this cyclic nucleotide in incubated minces of pregnant and non-pregnant uterus. The ability of this tissue to generate a labile substance which inhibits platelets aggregation, has been demonstrated and discussed.


Pre-ovulatory changes in cyclic AMP and prostaglandin concentrations in follicular fluid of gilts. The concentrations of cyclic adenosine 3', 5'-monophosphate (cyclic AMP) and prostaglandins E and F (PGE and PGF) were determined in follicular fluid collected from follicles of prepubertal gilts at various times after treatment with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) to induced ovulation. The concentrations of cyclic AMP, PGE and PGF in the follicular fluid after PMSG treatment but prior to hCG injection were about 1 pmol/ml, 1 ng/ml and 0.2 ng/ml, respectively. After hCG administration, the follicular fluid levels of cyclic AMP increased markedly, reaching a peak (400-fold increase) about 4 h after injection and then declined gradually to pre-hCG levels. A second rise (2.5- to 5-fold increase) occurred about 30 h after hCG with the levels being sustained up to the expected time of ovulation. In contrast, the levels of PGE and PGF remained relatively constant until 28-30 h after hCG treatment. Thereafter, the concentrations of both prostaglandins began to rise with the increases becoming more pronounced and reaching maximal values as the expected time of ovulation approached. These data provide further evidence for a physiological role of follicular prostaglandins in the process of ovulation but do not support an obligatory role for prostaglandins in the acute gonadotropin stimulation of cyclic AMP formation.


Use of mini-columns packed with acid-washed Florisil for the rapid separation of A, E and F series prostaglandins. A new procedure was developed for the rapid isolation of the A, E and F series prostaglandins from plasma extracts. This new procedure involves the use of mini-columns packed with acid-washed Florisil to rapidly separate the A, E and F series prostaglandins. These new mini-columns give flow rates of around 1 ml/min. and they generate a well-resolved chromatographic pattern while at the same time producing good recoveries for [3H]-labeled prostaglandins of the A, E and F series. Using these new mini-columns, large numbers of plasma extracts can be processed in a short period of time.


Actions of prostacyclin (PGI2) on adrenergic neuroeffector transmission in the rabbit kidney. In the Tyrode's perfused rabbit kidney PGI2 (1.3 x 10(-8)-3.3 x 10(-7)M) dose-dependently inhibited vasoconstrictor responses to sympathetic nerve stimulation, as did PGE2. The dose-effect curve of the two compounds differed, making PGI2 the less potent in the low concentration and the more potent in the high. PGI2 also inhibited the vasoconstrictor response to exogenous noradrenaline, but it had no effect on transmitter release. The main metabolite of PGI2, 6-keto-PGF1 alpha, was ineffective both on noradrenaline release and on vascular responses to nerve stimulation or exogenous noradrenaline. It is suggested that PGI2, if a significant renal prostaglandin, may modulate renal neuroeffector transmission post-junctionally, thereby forming a complement to the prejunctional action of PGE2.


[Study of distribution of 203Hg-chlormerodrin, 203Hg-nitrate and 99mTc-DMSA in kidney by macroautoradiography (author's transl)]. Serial macroautoradiograms were obtained to determine the distribution of 203Hg-chlormerodrin, 203Hg-nigrate and 99mTc-DMSA in kidney. In the study, normal rats were used and these three radiopharmaceuticals were injected intravenously. Initial images of 203Hg-chlormerodrin showed the accumulation in the outer cortex, but no significant radioactivity in the medullary. On the other hand, delayed images revealed radioactivity shifting in concentration from the outer cortex to the inner cortex. Distribution pattern of 203Hg-nitrate was similar to that of 203Hg-chlormerodrin. In contrast to 203Hg-chlormerodrin and 203Hg-nitrate, 99mTc-DMSA was retained in the outer cortex without temporal changes in the distribution.


[Immediate effects of thermal shocks on the plasma level of various components in the Rainbow trout: compounds indicating stress and protein fraction]. Rainbow trout were subjected to thermal shocks (9 degrees water temperature increase, 1 hr stay at 21 degrees and return to initial temperature) at the rate of 2 shocks a day during 1 day or 3 successive days. The observed changes only show a moderate reaction. cAMP does not vary; lactate slightly increases at 17 hr after the end of the shocks. Glucose seems to be the most reliable stress indicator; it increases at 2 hr and remains again above control value at 17 hr after a 3 day shock time. Fibrinogen increases after a 3 day shock time. Lastly, a strong decrease in low density lipoprotein level is seen at 17 hr following both shock duration times and from 2 hr in case of a 3 day shock time.


[Effect of piribedil on nocturnal sleep (author's transl)]. Piribedil, a dopamine agonist, was administered to 5 normal male subjects for two weeks. During the first two nights there was a reduction of about 17 p. 100 in paradoxical sleep (PS) and an increase of about 13 p. 100 in slow sleep II. There was a 15 p. 100 increase in PS during the third night. This increase is maintained for 8 nights in 3 subjects and 13 nights in 2 subjects. Other sleep parameters were not altered. Piribedil appears to give the impression of satisfactory sleep by reducing the subjective period before falling asleep. Piribedil also diminishes the remembrance of dreams.


Dual tracer single breath studies of gas transport in the lung. We studied the ratio of the expired He and SF6 concentrations (He/SF6) after 1 litre inspirations of a gas mixture containing 5% of He and SF6. Five subjects aged 49 to 60 yrs. performed the maneuvers with both inspiration and expiration at 0.2--0.41/s or 1.5--2.01/s. In all subjects separation of the tracer gases was observed, the He/SF6 falling early to a minimum of 0.80 +/- 0.01 (mean +/- 1 SE), and increasing gradually during expiration to a maximum of 1.08 +/- 0.01. The slope of the SF6 alveolar plateau was 1.45 +/- 0.09 times that for He. Computer simulations of simultaneous convection and diffusion in an axisymmetrical series lung model predicted a pattern of He/SF6 early in expiration which corresponded qualitatively to that observed experimentally. However, the model did not predict a rising He/SF6 ratio late in expiration. This was simulated only by incorporation of parallel inhomogeneity with sequential emptying into the model analysis. Consideration of Taylor type dispersion and airway asymmetry did not influence the simulations significantly. The results suggest that differing slopes of the alveolar plateau of two tracer gases may be due to diffusion dependent concentration differences among lung units ventilated in parallel rather than due to stratification alone.


[Hypertrophic neuropathy with myotonia (author's transl)]. A case of distal amyotrophia is reported, in which there was associated isolated clinical and electrical myotonia. Nerve conduction rates were very reduced. The nerves showed rarefaction of nerve fibers with segmentary demyelinization and the formation of bulbar swellings. The signification of this observation is discussed, and it would not appear to be related to peripheral nerve lesions of the type sometimes seen in Steinert's disease or from an association of this affection with Charcot-Marie's disease. It would seem more reasonable to suggest the hypothesis of a particular type of association of a peroneal hypertrophic neuropathy and a myotonia similar to certain cases reported in the published literature.


Immunopathological mechanisms in rheumatoid arthritis at the dual interface of the synovial membrane: the joint cavity and the pannus. The significance of immune responses is examined in relation to clinicopathological changes in the rheumatoid joint and the concept of a dual site of action is developed. In the joint cavity interaction between immune complexes and complement is central to the phenomena observed, which depend on the generation of chemotactic factors and the ingress of polymorphs. Other chemical mediators--e.g. prostaglandins and lymphokines--are envisaged as playing a secondary or augmentory role. At the pannus-cartilage (and bone) junction the possibility is considered that changes are due to activation of a variety of cell types which results in enzymatic degradation of collagen in cartilage, osteolastic activity in bone and prostaglandin-induced depletion of bone. The production of migration inhibition factors by rheumatoid membranes is examined and some evidence in support of their lymphokine nature is found by gel filtration; their role as cell activators is considered.


A bile-acid-rich high-density lipoprotein (HDL) in acute hepatitis. Severe liver dysfunction is often associated with alterations of plasma lipids and lipoproteins. In this study the high-density lipoprotein (HDL) class has been further investigated. HDL from patients with acute, cholestatic hepatitis (n = 10) was isolated and compared with that of normals. Lipid and protein analyses were performed during the acute stage of the disease, with consequent follow-up studies. It was found that (1) only apo A-I was decreased by 50% in the isolated HDL fractions, whereas apo A-II remained unchanged; apo A-I in total plasma was normal; (2) immunoelectrophoresis of hepatitis HDL against monospecific anti-A-II revealed one precipitin line but two or more bands against anti-A-I; (3) concomitant with an increase of phospholipids and a decrease of triglycerides and the total cholesterol fraction, hepatitis HDL contained 10--12 times more bile acid than normal HDL. Chenodeoxycholic acid was the predominant bile acid. These alterations were fully reversible when patients recovered. These parameters seem to be sensitive markers for the degree of disturbance and restoration of liver function. The structural-functional implications of the observed compositional changes of HDL during cholestasis are discussed.


Metabolic and cardiovascular effects of salbutamol in atopic subjects with and without asthma. An intravenous injection of 100 microgram salbutamol sulphate was administered to a group of atopic asthmatics and a group of atopic control subjects without asthma. There was no difference in the metabolic and cardiovascular reponses of the two groups.