Ultrastructural studies of the dying-back process. IV. Differential vulnerability of PNS and CNS fibers in experimental central-peripheral distal axonopathies. A companion paper in this issue (46) described the evolution of peripheral nervous system dying-back disease of the giant axonal type in animals chronically intoxicated with the neurotoxic hexacarbons n-hexane (CH3CH2CH2CH2CH2CH3), methyl n-butyl ketone or MBK (CH3COCH2CH2CH2CH3), and 2,5-hexanedione (CH3COCH2CH2COCH3). The present study compares the distribution and pattern of peripheral (PNS) and central nervous system (CNS) dying-back disease produced by these three neurotoxic hexacarbons with that produced by acrylamide (CH2CHCONH2), and, in addition, employs these compounds to address unresolved issues in the dying-back process. In the PNS, large myelinated fibers in tibial nerve branches supplying calf muscles were especially sensitive in rats intoxicated with hexacarbons. These nerve branches and sensory plantar nerves in the hindfeet were equally vulnerable in acrylamide-treated rats. In both conditions, fibers located at these sites commenced degeneration before the distal regions of much longer and smaller diameter nerve fibers in nerve branches supplying the flexor digitorum brevis muscle and, in rats intoxicated with hexacarbons, before equivalent regions of plantar sensory branches to the digits. Pacinian corpuscles sited in the hindfeet of intoxicated cats were much less vulnerable to MBK than to acrylamide. Rats and cats intoxicated with hexacarbons displayed giant axonal swellings in vulnerable regions of the PNS degeneration in these animals was accompanied by pronounced endoneurial edema. In the CNS, rostral regions of long, ascending tracts (dorso-spino-cerebellar, gracile and, later, the cuneate) and the caudal end of long, descending tracts (lateral colums, ventrolateral and ventromedial tracts) of hexacarbon-treated animals were especially vulnerable. After prolonged intoxication of cats with MBK, giant axonal swelling was also found in preterminal and terminal axons in Rexed laminae V-VII at spinal levels C4 through S3-Neurofilament proliferation without giant axonal swelling was seen in CNS fibers of rats intoxicated with acrylamide. Taken in concert, the findings underline the importance of axon diameter and length in determining the hierarchy of fiber vulnerability and indicate the common sensitivity of selected regions of the PNS and CNS. The term central-peripheral distal axonopathy is introduced to emphasize the widespread, distal distribution of disease in these and in similar experimental conditions. It is suggested that certain human neuropathies (toxic, nutritional, uremic, diabetic and some hereditary polyneuropathies, and the neuropathy associated with multiple myeloma) are additional examples of central-peripheral distal axonopathies.


Superficial temporal-middle cerebral artery anastomosis associated with glioblastoma multiforme. The authors report a case in which glioblastoma multiforme was intimately associated with a surgical anastomosis of the superficial temporal artery to a branch of the middle cerebral artery.


Technetium-99m-pyrophosphate bone scans in hyperparathyroidism. Most patients with primary hyperparathyroidism have normal 5-hr bone-to-soft-tissue ratios for 99MTc-pyrophosphate. In contrast, all five patients with advanced secondary hyperparathyroidism in this study showed significant (p less than 0.001) increases of bone uptake. In the early period after parathyroidectomy, there was no quantitative or qualitative change in uptake. A limited decrease of bone uptake was observed only after prolonged periods of observation. In itself, parathyroid activity seems to have little direct influence on bone uptake of 99MTc-pyrophosphate.


An ultrastructural study of chronic sodium cyanate-indiuced neuropathy. Fifteen rats were given a sodium cyanate-rich diet for 18 months and at the end of that period, all of them had developed motor weakness and were perfused for ultrastructural study. A peripheral neuropathy involving mostly the roots and sciatic nerves was found and the main ultrastructural lesion was vacuolization of myelin. There was marked distinction of the myelin sheaths and phagocytosis of myelin. Axoplasmic changes were minimal and consisted of accumulation of glycogen within vacuoles. Invaginations of adaxonal Schwann cell membranes and axolemma forming loops and separate chambers were also present. There was active participation of macrophages in the splitting of myelin as well as in phagocytosis of myelin remnants. There was evidence of remyelination with the toxic damage. We concluded that cyanate induced neuropathy is due mostly to a myelinotoxic effect of the drug, although parallel but less intense axonal damage cannot be excluded.


Technetium-99m-Sn-pyrophosphate pharmaco-kinetics and bone image changes in parathyroid disease. Skeletal abnormalities in 12 patients with primary hyperparathyroidism, five patients with pseudohypoparathyroidism, and three patients with hypoparathyroidism were studied to compare the diagnostic sensitivity of bone radiologic examination to that of radionuclide studies using 99mTc-Sn-pyrophosphate (99mTc-PPi) a skeletal-seeking radiopharmaceutical. The results were compared with bone mineral content as measrued by the Norland--Cameron densitometer. Kinetic data of the blood disappearance and plasma clearance of 99mTc-PPi were obtained and compared with data of control subjects without evidence of parathyroid disease. Bone imaging with 99mTc-PPi may be more sensitive than routine skeletal radiographs and bone mineral analysis for the evaluation of skeletal abnormalities in patients with parathyroid disfunction. The enhanced plasma clearance of the tracer observed in patients with primary hyperparathyroidism may reflect the direct effect of excessive parathyroid hormone on the renal handling of 99mTc-Sn-pyrophosphate.


Rectal perchlorate for unconscious patients prior to brain scintigraphy with pertechnetate: concise communication. Patients undergoing brain scintigraphy with pertechnetate are frequently premedicated with oral perchlorate. However, the oral route is difficult to employ in unconscious or uncooperative patients or when oral intake is restricted. In such situations, rectal administration of sodium perchlorate dissolved in water is an effective alternative to oral administration.


Aortic aneurysm detected by 99mTc-pyrophosphate imaging: case report. An example of aneurysmal concentration of 99mTc-pyrophosphate (Tc-PPi) is described. An abdominal aortic aneurysm was suspected when a rectilinear bone scan showed an abnormal paraspinal area of activity. The aneurysm was confirmed by ultrasonic examination. Conventional radiographic examination failed to reveal calcification within the aneurysm. Aneurysmal concentration of Tc-PPi should be considered in patients showing abnormal radioactivity in the region of vascular structures on radionuclide bone images.


Studies of anabolic steroids. VI. Effect of prolonged administration of oxandrolone on growth in children and adolescents with gonadal dysgenesis. Twenty-five patients with Turner Syndrome were treated with oxandrolone for six or more months. Mean growth velocity for the first year of treatment was significantly greater than pretreatment control growth velocity. Overall, there was no excessive skeletal maturation. Mean "final" height in nine XO patients (146.4 cm) was significantly greater than mean adult height of an estrogen-treated control group (140.3 cm), while that for five mosaic patients (148.2 cm) was not significantly different from a mean untreated mosaic adult height (145.2 cm).


Lid lesions of childhood: a histopathologic survey at the Wilmer Institute (1923-1974). This study reports 398 excised eyelid lesions in 385 children from birth through age 15. This study analyzes and discusses the clinical and histological features of the 34 types of lesions which were encountered. This tabulation serves as a guide to the physician when confronted with lid lesions in children as to the types of lesions which may be found. More importantly, however, this study is the first comprehensive clinco-pathologic evaluation of eyelid lesions in children, a topic which had previously been written and discussed in a fragmentary manner. This study analyzes data from the Wilmer Institute during 1923-1974.


Unusual eyelid involvement in tuberous sclerosis. A two-week-old male infant had a nodular salmon-colored lesion on his right lower eyelid and hypopigmented mascular lesions on the abdomen and right thigh since birth. At five months of age he developed a generalized seizure disorder. Histologic examination of the eyelid lesion revealed an angiofibroma, which was an unusual initial site of involvement in tuberous sclerosis.


Potential long acting opiate antagonists: preparation, pharmacological activity, and opiate-receptor binding of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans. A homologous series of N-substituted 2'-hydroxy-5-methyl-9 alpha-propyl-6,7-benzomorphans (hydrogen to octyl inclusive, allyl, and cyclopropylmethyl) was prepared. In contradistinction to the normetazocine, normorphine, and (-)-3-hydroxymorphinan series, the N-pentyl and N-hexyl derivatives do not have the analgesic potency of the parent N-methyl compound; instead, they are narcotic antagonists with a long duration of action. All of the N-substituted 9 alpha-propylbenzomorphans, except for methyl, heptyl, and octyl, have antagonist activity. The receptor binding constants of the N-alkyl compounds are uniformly two- to threefold lower than those of the N-substituted normetazocines.


Effects of acute and chronic ethanol administration and withdrawal on adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate levels in the rat brain. The effect of ethanol on cyclic nucleotide levels was investigated in male Sprague-Dawley rats. The rats were sacrificed by microwave irradiation, the brains were divided into four areas, and cyclic nucleotides were measured by radioimmunoassays. Administration of a single dose of ethanol per os produced a dose-dependent decrease of adenosine 3':5'-monophosphate (cyclic AMP) in cerebral cortex, cerebellum, pons and medulla oblongata while guanosine 3':5'-monophosphate (cyclic GMP) was decreased in all brain areas. Dependence on ethanol was induced by three daily administrations of ethanol p.o. for 7 days. The last dose of ethanol did not produce any decrease of cyclic AMP levels while the decrease of cyclic GMP levels was still present. During ethanol withdrawal cyclic AMP levels increased in cerebral cortex, pons and medulla oblongata and did not change in cerebellum. Changes of cyclic AMP in subcortex were more complex. Cyclic GMP levels increased during ethanol withdrawal in cerebellum, pons and medulla oblongata and did not change in cerebral cortex and subcortex. These results indicate that changes of cyclic nucleotides might participate in the mechanism of ethanol dependence and withdrawal.


The presynaptic site of action of norepinephrine in the superior cervical ganglion of guinea pig. Supramaximal preganglionic volleys did not elicit detectable postsynaptic potential in the curare-treated superior cervical ganglion cell of the guinea pig whereas, a tetanic stimulation (10-30 Hz, 1-5 seconds) consistently evoked a monophasic depolarizing potential resembling the slow excitatory postsynaptic potential. The depolarizing potential was not preceded by a detectable hyperpolarization. In non-curare-treated preparations, norepinephrine in concentrations of 1 to 10 muM consistently and reversibly suppressed the fast excitatory postsynaptic potential elicited by submaximal preganglionic stimulation without appreciably affecting the resting membrane potential, the total membrane resistance or the cell membrane excitability. Pretreating the ganglion with phenoxybenzamine (10 muM) completely prevented, whereas propranolol (30 muM) failed to antagonize, the ganglionic depressant action of norepinephrine. The amplitude and time course of the iontophoretically induced acetylcholine potential were not significantly altered by norepinephrine in concentrations which markedly attenuated the response of the fast excitatory postsynaptic potential. The frequency but not the amplitude of the miniature excitatory postsynaptic potentials was significantly reduced by norepinephrine (1-10 muM). These results demonstrate that norepinephrine inhibits ganglionic transmission in the guinea pig principally by reducing the output of acetylcholine from the presynaptic nerve terminals. These data are discussed with respect to their relation to the presence in the guinea pig superior cervical ganglion of norepinephrine-containing small intensely fluorescent cells which are not connected synaptically with the postganglionic neurons.


Cardiac histamine receptors: differences between left and right atria and right ventricle. Histamine can stiumulate the heart by directly interacting with cardiac histamine receptors. In the present study we have investigated the cardiac effects of histamine, 4-methylhistamine (a specific H2-receptor agonist) and 2-pyridylethylamine PEA, a specific H1-receptor agonist] on spontaneously beating right atria and electrically driven left atria and right ventricle strips of the guinea pig. Left atria were driven at 1 Hz and right ventricle strips at 2.5 Hz and at twice the threshold voltage. Histamine and PEA produced a dose-dependent positive inotropic effect on the left atria. The dose-response curves were shifted to the right in a parallel fashion by promethazine (3 x 10(-6)M)+... Burimamide did not affect either dose-response curve. Histamine and 4-methylhistamine had a positive chromnotropic effect on right atria and a positive inotropic effect on right ventricle strips.


The distribution of GABA sensitivity on crayfish muscle receptor organs. 1. The effectiveness of inhibition of gamma-aminobutyric acid (GABA) at various points on crayfish abdominal muscle receptor organs (MROs) was investigated by iontophoretic methods that have a spatial resolution of 8 mum. 2. The MROs in the rostral abdominal segments, which receive inhibitory innervation, were always strongly inhibited by focal iontophoretic application of GABA; MROs in the 6th abdominal segment, which do not receive inhibitory innervation, were usually not strongly inhibited. 3. In the rostral MROs, the magnitude of GABA current necessary to abolish stretch induced impulses was least for dendritic points; it increased as a function of distance from the dendrites, over an area extending from the receptor muscle to a point on the axon 200 mum from the cell body. 4. Outward currrents from NaCl-filled micropipettes had no effect on impulse production when applied to the dendritic region of rostral MROs, but could produce transient inhibition of impulses when applied to the axon. 5. It is suggested that a high degree of GABA sensitivity is localized to the rostral MRO dendrites, where inhibitory synapses are most numerous.


Cyclic adenosine 3', 5'-monophosphate in cerebrospinal fluid during thermoregulation and fever. 1. Samples of cerebrospinal fluid (c.s.f.) have been taken from the cisterna magna of unanaesthetized cats, whilst rectal temperature was recorded, during exposure of the animals to various ambient temperatures and during fever induced by pyrogen. The concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in samples of c.s.f. has been assayed. 2. Cats exposed to low ambient temperatures (-2 to +2 degrees C) for 3 h maintained body temperature by both behavioural and autonomic heat gain activity. Exposure of cats to high ambient temperatures (44 - 45 degrees C) for 3.5 h caused a rise in body temperatures of about 2.5 degrees C, despite behavioural and autonomic heat loss activity. Neither cold nor heat stress had a significant effect on c.s.f. cyclic AMP. 3. Fever induced by intravenous Shigella dysenteriae (2 and 20 mug/kg) was associated with a dose-related increase in the concentration of cyclic AMP in c.s.f. Paracetamol (75 mg/kg) injected I.P. before the onset of fever, suppressed the increase in both temperature and c.s.f. cyclic AMP in response to pyrogen. Paracetamol (50 and 100 mg/kg), injected after the onset of fever, caused a fall in temperature, which was not associated with a decrease in the concentration of cyclic AMP in c.s.f. 4. Fever induced in cats by intravenous Shigella dysenteriae (20 mug/kg) was associated with an increase in the concentration of cyclic AMP in plasma as well as in c.s.f. 5. The sodium salt of cyclic AMP (0.1-10 mg/kg) injected I.V. into unanaesthetized cats caused a dose-related hypothermia, which was associated with autonomic heat loss activity and a dose-related increase in the concentration of cyclic AMP in cisternal c.s.f., which was not mimicked by adenosine. 6. It is concluded that the raised concentrations of cyclic AMP in c.s.f., in response to pyrogen I.V., do not mediate fever in the cat and that the concentration of cyclic AMP in cisternal c.s.f. may be affected by changes in the plasma concentration of the nucleotide.


A quantitative analysis of local anaesthetic alteration of miniature end-plate currents and end-plate current fluctuations. 1. The effect of the local anaesthetic QX222 on the kinetics of miniature end-plate currents (m.e.p.c.s) and acetylcholine (ACh) induced end-plate current (e.p.c) fluctuations was studied in voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. In Ringer solution the m.e.p.c.s decayed with a single exponential time course and the e.p.c. fluctuation spectra were characterized by single Lorentzian functions, with the spectral cut-off frequency well predicted by the m.e.p.c. decay rate. 3. In the presence of 0-1-0-5 mm QX222 at-50 to -100 mV holding potential both the e.p.c. fluctuation spectrum and the m.e.p.c. decay consisted of a fast and a slow component, with the cut-off frequency of each spectral component predicted by the decay rate of the corresponding constituent of the m.e.p.c. 4. Hyperpolarization increased the decay rate and relative amplitude of the fast component of the m.e.p.c. and decreased the decay rate of the slow m.e.p.c. component. 5. With 0-05 mm QX222 and -70 mV holding potential the m.e.p.c.s. and e.p.c. fluctuation spectra consisted of three components. The third component of the m.e.p.c. and e.p.c. spectra had nearly the same decay rate and cut-off frequency as was found at the same end-plate under equivalent conditions before drug exposure. 6. The kinetic predictions of four different schemes for local anaesthetic action were compared with observed m.e.p.c.s. and e.p.c. fluctuations. 7. Schemes in which the local anaesthetic acted by creating two kinetically distinct populations of acetylcholine receptors or by interacting with ACh receptor to produce a biphasic exponential decay of the end-plate channel conductance did not accurately predict the e.p.c. fluctuation spectrum. 8. The variance of the e.p.c. fluctuations vanished at the reversal potential indicating that local anaesthetic action was not due to the presence of different ion selective end-plate channels. 9. QX222 action could be explained by alteration of the ACh receptors such that they sequentially c-hanged from one conductance state to another. A specific case in which QX222 binds to the ACh receptors in its open state creating a partially blocked state, was found to be the most parisimonious. 10. The conductance, gamma, of a single end-plate channel was estimated from e.p.c. fluctuations. In Ringer's solution gama = 24-4 +/- 1-2 (s.d.) pmho. In the presence of 0-1 mm to 0-5 mm QX222 the effective single channel conductance, gamma, varied from 14-2 to 1-39 pmho. 11. gamma decreased with increased local anesthetic concentration, hyperpolarization, or decreased temperature. The variation in gamma is thought to reflect the dependence on the experimental conditions of the relative probability that the ACh receptors is in an open vs a partially blocked state.


Dual effects of hemicholinium-3 at central cholinergic synapses. 1. Hemicholinium-3 (HC-3) has at least two presynaptic effects at cholinergic synapses between motor acon collaterals and spinal Renshaw cells, neither of which influenced non-cholinergic excitatory synapses on dorsal horn interneurones. 2. One, which occurred independently of repetitive activity of the synapses and which resulted in increased latency of synaptic excitation, presumably involved changes in the properties of presynaptic fibres and terminals which influenced transmitter release. 3. The other, which depended on continuous repetitive synaptic activity, was consistent with depletion by HC-3 of presynaptic stores of acetylcholine (ACh).


Assay of pertussis vaccine toxicity by a rat-paw-oedema method. A method is described of using the production of oedema in the foot pad of rats as an index of the ability of pertussis vaccines to cause local reactions. At a suitable time after the subcutaneous injection of the vaccine into hind paw of the rat, the foot is excised and weighed. The technique is reproducible and most useful for the detection of oedema produced by pertussis-vaccine components sensitive to heating at 80 degrees C for 30 min. Substances in pertussis vaccine that produce rat-paw oedema gave maximal reactions at 4 and 12 h. but were best differentiated 9 h after injection.


Experimental infection of monkeys with Herpesvirus suis (Aujeszky's-disease virus). Monkeys were infected intranasally with Herpesvirus suis. After an incubation period of 7 to 13 days the animals became acutely ill and rapidly died. Clinical signs included salivation, incoordination, ataxia and epileptiform convulsions, but not pruritus. Histopathological changes were confined to the central nervous system, and consisted of destruction of neurones with the formation of intranuclear inclusion bodies, gliosis and perivascular cuffing. Virus was isolated from the brain and spinal cord in the later stages of the illness but neutralising antibodies were not detected in serum. The distribution of lesions indicated direct spread of virus from the inoculation site along cranial nerves to the brain.


Small virus particles in faeces of patients with infectious hepatitis (hepatitis A). Forty-one faecal samples from infectious-hepatitis patients and their contacts were investigated for the presence of hepatitis-A-associated viral particles. Of these, 16 gave a positive result by immune electronmicroscopy or caesium-chloride density-gradient centrifugation. The latter method proved invaluable in detecting small numbers of virus particles. The particles found had buoyant density of 1-34-1-35 and a size range of 21-28 nm. Epidemiological evidence suggested that they might be the causative agent of hepatitis A.


Agonist induced release of intracellular Ca2+ in the rabbit aorta. The effects of hormonal agonists (norepinephrine, angiotensin, and histamine) on 45Ca efflux from the rabbit aorta were studied using a Ca-EGTA buffered efflux medium. Each caused a transient stimulation of efflux rate which probably reflected the release of an intracellular 45Ca store. The size of the stimulation of efflux correlated with the size of the initial rapid phase of contraction. The norepinephrine-sensitive intracellular Ca fraction was estimated to be greater than 21 mumoles/Kg wet tissue weight. This fraction is separate from intracellular Ca which is accumulated during relaxation. Evidence is presented for the lack of cyclic nucleotide involvement in the release of Ca2+, and possible alternative modes of coupling are discussed.


Spin-label studies on rat liver and heart plasma membranes: do probe-probe interactions interfere with the measurement of membrane properties? The structures of purified rat liver and heart plasma membranes were studied with the 5-nitroxide stearic acid spin probe, I(12,3). ESR spectra were recorded with a 50 gauss field sweep, and also with a new technique which "expands" the spectrum by (1) recording pairs of adjoining peaks with a smaller field sweep and (2) superposing the common peaks. The hyperfine splittings measured from the "expanded" spectra were significantly more precise than those obtained from the "unexpanded" spectra. Both procedures were used to study the effects of various I(12,3) probe concentrations on the spectra of liver and heart membranes, as well as the effects of temperature and CaCl2 additions on the spectra of liver membranes, and revealed the following: The polarity-corrected order parameters of liver (31 degrees) and heart (22 degrees) membranes were found to be independent of the probe concentration, if experimentally-determined low I(12,3)/lipid ratios were employed. The absence of obvious radical-interaction broadening in the unexpanded spectra indicated that "intrinsic" membrane properties may be measured at these low probe/lipid ratios. Here, "intrinsic" properties are defined as those which are measured when probe-probe interactions are negligible, and do not refer to membrane behavior in the absence of a perturbing spin label. At higher I(12,3)/lipid ratios, the order parameters of liver and heart membranes were found to substantially decrease with increasing probe concentration. The increase in the "apparent" fluidity of both membrane systems is attributed to enhanced radical interactions; however, an examination of these spectra (without reference to "low" probe concentration spectra) might incorrectly suggest that radical interactions were absent. For the membrane concentrations employed in these studies, the presence of "liquid-lines" (or "fluid components") in the unexpanded ESR spectra was a convenient marker of high probe concentrations. A thermotropic phase separation was observed in liver membranes between 19 degrees and 28 degrees. Addition of CaCl2 to liver plasma membrane [labelled with "low" I(12,3) concentrations] increased the rigidity of the membrane at 31 degrees and 37 degrees, without inducing a segregation of the probe in the bilayer. Previously reported data are discussed in relation to these results, and suggested minimal criteria for performing membrane spin label studies are included.


Isolation and characterization of a hormone-producing cell line from human small cell anaplastic carcinoma of the lung. A continuous cell culture line was established from a bone marrow metastasis of small cell anaplastic carcinoma of the lung. The cultures were characterized by light and electron microscopy, and an unusual concentric arrangement of cells was observed, both in sectioned material from the patient's tumor and from the cell cultures. The cells had two types of specialized cell junctions and contained secretory-like granules of the type described in neuroendocrine cells. Lactic dehydrogenase isozyme patterns were the same as those observed in normal human serum, and the karyotype revealed the presence of several marker chromosomes. Vasopressin was present in the cells and secreted into the culture medium in the absence of neurophysin, as shown by the immunoperoxidase technique and radioimmunoassay. Oxytocin was also absent from cells.


Inhibition of glycolysis and interference with protein synthesis in hepatoma cells. Ascites hepatoma cells grown in Wistar rats were incubated anaerobically in the absence of glucose or in the presence of both glucose and D(+)glucosamine, or monoiodoacetate, or NADH, which interfered with glycolysis at different steps and with different mechanisms: Under all these conditions the incorporation of amino acids into the proteins of hepatoma cells was severely reduced without any clear relationship to the degree of inhibition of glycolysis. The postmitochondrial supernatants showed defective incorporation only when obtained from cells incubated in the absence of glucose or in the presence of monolodoacetate; inhibition of glycolysis by glucosamine and NADH did not seem to affect the subcellular basis for protein synthesis. When present, the defect of the cell sap (monoiodoacetate and absence of glucose) and to disaggregation and reduced functional capacity of the polysomes (absence of glucose). The results suggested that the effects of the inhibition of glycolysis on protein synthesis and on the integrity of the protein-synthesizing machinery--which were primarily due to the depletion of the energy stores--might have been modified by the particular mechanism of action of the inhibitor and by the way low levels of ATP were reached in the cell.


Immunosuppression in mice after inoculation with 334C, a murine lymphatic leukemia-inducing virus. 334C murine leukemia virus, which induces a high incidence of lymphatic leukemias (80-90%) in susceptible mice following a long latency period, was found to cause a severe in vivo suppression of direct plaque-forming cells from the spleen, following antigenic stimulation with sheep red blood cells. Neonatally infected inbred BALB/c and outbred Ha/ICR Swiss mice, which develop a sustained viremia, were highly susceptible to the immunosuppressive effect of this virus as early as 1 week after virus infection, long before any detectable histologic evidence of leukemia development. Ha/ICR Swiss mice, which are highly resistant to the leukemogenic potential of this virus following infection in adult life, were highly resistant to its immunosuppressive action; only a moderate and transient suppression, without viremia, occurred 2 weeks after virus infection. In marked contrast, BALB/c mice were highly susceptible to the immunosuppressive action of 334C murine leukemia virus following infection in adult life; a severe and sustained suppression was observed as early as 1 week after virus infection and was followed by a sustained viremia, beginning at 2 weeks, with a 55-60% incidence of leukemia observed over a period of 1 year. Infectious virus was essential to produce theimmunosuppressive effect; heat-inactivated (56 degrees C/30 min) and attenuated (4 degrees C/4 1/2 mo) virus preparations were ineffective. The plaque-forming response of spleen cells from lethally irradiated syngeneic adult BALB/c mice was markedly suppressed following reconstitution with thymus-dependent (T) or thymus-independent (B) cells from the thymus and bone marrow, respectively, of virus-infected mice, in combination with each other, or with the appropriate cell populations from normal mice.


Reduced incidence of Marek's disease gross lymphomas in T-cell-depleted chickens. Chickens of line 7, highly susceptible to Marek's disease (MD), were depleted of T-cells by neonatal thymectomy, total-body gamma-irradiation, and multiple injections with antithymocyte serum. In two replicate experiments, significantly fewer gross lymphomas were present in T-cell-depleted chickens than in intact or in T-cell-depleted, reconstituted hatchmates; these findings provided evidence that T-cells may be the principal target for MD virus (MDV) transformation, T-cell depletion was not complete, and the presence of microscopic lesions in T-cell-depleted chickens was attributed to residual T-cells. Ten lymphomas from intact chickens and 2 lymphomas from a T-cell-depleted chicken were examined for cellular composition. All lymphomas consisted predominantly of T-cells. The results of this and other published studies indicated that T-cells may have a dual role in MD; They may serve as a target for lymphoma formation by MDV and also may participate in immune surveillance against the disease in resistant chickens.


Temperature-sensitive variants for saturation density and anchorage dependencey of a simian virus 40-transformed human X mouse hybrid cell line. Several variant clones temperature sensitive for some parameters of transformation from a hybrid cell line containing a stable diploid mouse genome and two human chromosomes 7 carrying an integrated defective simian virus 40 have been isolated. Like the wild-type (wt) cells, at the permissive temperature the temperature-sensitive (ts) clones grew to high saturation densities and readily formed colonies in methyl cellulose. In contrast to the wt cells, at the nonpermissive temperature they had variable but always lower saturation densities and were unable to form colonies in methyl cellulose. The fraction of cells that synthesized DNA decreased at both temperatures when the cells reached saturation density, but it represented always at least 20% of the total population. All of the ts clones so far tested had a near triploid chromosome number, contained from one to three human chromosomes 7, and were T-antigen-positive both at the permissive and nonpermissive temperatures. The ts clones maintained low saturation density at the nonpermissive temperature because of a decrease in the number of cells that were actively proliferating and because of the shedding of cells into the medium. Temperature downshifts and refeeding allowed for expression of the permissive phenotype. In most of the isolated clones anchorage independency was not correlated with unrestricted cell proliferation. These variant clones may provide useful systems for a better understanding of the number of interdependent pathways involved in the expression of the phenotype of a transformed cell and elucidate the molecular mechanism required for the maintenance of a normal state in a cell population.


Isolation of polyoma virus-induced surface antigens in hamster cells: potassium chloride solubilization and differential precipitation. Surface antigens were extracted in soluble and active form with 3 M KCL from polyoma virus-transformed and embryonic hamster cells. These were tumor-specific transplantation antigens (TSTA), shown by tumor rejection, and a surface (S) antigen, demonstrated by the inhibition of surface fluorescence on living polyoma virus-transformed cells. The extracts were fractionated by salting out with ammonium sulfate. In tumor cell extracts, all TSTA activity and a part of S antigen activity were found in the fraction precipitated with 60% saturation in (NH/)2SO4. Another part of S antigen activity was found in the fraction precipitating at 80% saturation in tumor cell extracts. The precipitate at 60% saturation of embryonic cell extracts also had a part of S antigen activity. Receptor site activity for concanavalin A was also retained after solubilization and was confined to the 40% saturation (NH4)2SO4 precipitate in the case of tumor and embryonic cell extracts.


Inhibition of mammary tumors by incomplete T-cell depletion. The effects of neonatal and perinatal thymectomy on mammary tumorigenesis in (C57BL X I)F1fC3H hybrid female mice were determined. When hybrid females were neonatally thymectomized by controlled suction, a procedure that removes thymic lobes completely, a large proportion of animals developed stigmas of a fulminant wasting disease and died before tumors developed. However, when hybrid females were subjected to neonatal thymectomy by continuous suction, a procedure that resulted in retention of thymic remnants, they survived and manifested a significant prolongation of latent period before tumorigenesis. When complete removal of the thymus was carried out in the perinatal period, the effect on mammary tumorigenesis was critically dependent on the age at surgery. The procedure was without effect when performed at 1, 3, and 8 weeks of age. However, when it was performed at 9-12 days of age, there was a delay or a decrease in the appearance of mammary tumors. The extent of T-cell depletion and/or its timing in relationship to the introduction of murine mammary tumor virus appeared to play a critical role in determining the effect on eventual tumor development.


Antibodies to the R component of Epstein-Barr virus-induced early antigens in Burkitt's lymphoma exceeding in titer antibodies to Epstein-Barr capsid antigen. African patients with Burkitt's lymphoma (BL) may show antibodies to the R (restricted) component of the Epstein-Barr (EB) virus-induced early antigens that appear to match in titer the antibodies to EB viral capsid antigen (VCA) as determined with the aid of acetone-fixed smears of EB3 cells. Virus-producing EB3 cells, however, contain the R component as well as VCA so that the correct anti-VCA titers in such cases remain in doubt. Since the R component, but not VCA, was found to be denatured by methanol fixation, the parallel use of acetone- and methanol-fixed EB3 cell smears permitted the determination of the correct anti-VCA titer. Our results showed that the anti-R titers of BL patients can in fact be up to eightfold higher than the anti-VCA titers. Anti-R titers equaling or exceeding anti-VCA titers have been encountered thus far only in BL.


Preparation of cell-free feline oncornavirus-associated cell membrane antigen. Cell-free feline oncornavirus-associated cell membrane antigen (FOCMA) was prepared from a feline lymphoblastoid cell line of tumor origin (FL-74). Membrane fractions, separated on sucrose density gradients, and papain-solubilized products were found to contain FOCMA as determined by their capacity to inhibit reference cytotoxic cat antisera.


Intracytoplasmic type A particles in viper spleen cells. Structures resembling typical type A particles were observed in paranuclear inclusions in cultured C-type particle-producing viper cells (VSW cell line). The incidence of type A particle inclusions was low (approximately 0.5% of cell profiles examined) in untreated cells, but both the incidence and size of the inclusions were slightly increased in cells treated with ethidium bromide. This is apparently the first observation of type A particles in cells of a poikilothermic vertebrate.


Enhancement of R3230AC rat mammary tumor growth and cellular differentiation by dibutyryl cyclic adenosine monophosphate. Daily sc injections of 8 mg N6, O2'-dibutyryl 3',5'-cyclic AMP (DBcAMP) beginning 1 day after tumor implantation significantly increased the growth rate of R32230AC rat mammary adenocarcinomas, which nearly doubled in in situ volume by day 40 compared to similarly implanted tumors in saline-injected controls. Weights of excised tumors, intact, drained, and dried all increased approximately 80%, which suggested that the increase in tumor size was not due to accumulation of secreted fluid or tissue water. Injections of 17beta-estradiol valerate (0.1 mg/wk) from day 1 or of DBcAMP from day 22 resulted in insignificant changes in growth--28% and 35% increases in tumor volume and a 5% decrease and an 18% increase, respectively, in drained wet weight. Electron microscopic examination revealed that estrogen and DBcAMP caused differentiation of the tumor cells into two different states: Estrogen-treated tumors resembled lactating mammary glands; they contained large lipid droplets, organized rough endoplasmic reticulum, and vesicles containing electron dense granules resembling protein. DBcAMP-treated tumor cells were marked by a proliferation of the Golgi complex and numerous vesicles containing fine granular material.


Culicoides, the vector of epizootic hemorrhagic disease in white-tailed deer in Kentucky in 1971. The biting gnat, Culicoides variipennis (Coquillett), was shown to be a vector of epizootic hemorrhagic disease (EHD) in white-tailed deer, Odocoileus virginianus, in Kentucky because of virus isolations from parous females. Epidemiological evidence showed a close relationship of this vector to the animal host during an outbreak of EHD in penned deer. Larval breeding sites of C. variipennis were found and C. variipennis was the most abundant biting fly present during the outbreak. Females of C. variipennis were commonly observed biting deer, swine, cattle and, occasionally, man.


Viruses isolated from captive and free-ranging wild ruminants in Alberta. Nasal secretions, leukocytes and preputial or vaginal swabs from a group of 15 captive wild ruminants, comprising six pronghorn antelope (Antilocapra americana), seven fallow deer (Dama dama) and two mule deer (Odocoileus hemionus), and from 50 free-ranging pronghorns in southern Alberta, were examined for viral agents. Captive animals were given injections of dexamethasone daily for 6 days in attempts to reactivate latent infections. Specimens were collected at 2-3 day intervals from days 0 to 18. Free-ranging pronghorns were sampled only once, at the time of capture. Fifteen viral isolates were obtained from the animals: six isolates of parainfluenza 3 (PI3) from nasal swabs from one fallow deer and one mule deer; five isolates of herpesvirus from leukocytes, vaginal, preputial and nasal swabs from three fallow deer; and four isolates of PI3 from nasal secretions of the 50 free-ranging pronghorns.


Herpesvirus sylvilagus in cottontail rabbits: evidence of shedding but not transplacental transmission. Herpesvirus sylvilagus was inoculated into five cottontail rabbits (Sylvilagus floridanus) at various stages of pregnancy; they subsequently had litters in the laboratory. Three other cottontails chronically infected with the virus were bred and bore young in large outdoor pens. Thirty-four living neonates and dead fetuses were weighed, measured and aseptically necropsied. A total of 31 liver, spleen and kidney samples, 16 lymph node, 28 heart and 10 brain samples were collected and processed for inoculation into rabbit kidney cell cultures to attempt virus isolation. Virus was not detected in the 147 tissue samples tested. Pre-conception viremias ranged from 10-21 plaque-forming units per 0.5 ml. Virus isolation was attempted from 26 oral and lacrymal, 23 genital, nine urine and fecal, and four milk and male ejaculate samples from eight infected rabbits. Virus was recovered from two salivary samples from the same rabbit. Triamcinolone acetonide administered daily for four days to five rabbits did not stimulate excretion of virus.


Transmission of two strains of epizootic hemorrhagic disease virus in deer by Culicoides variipennis. Two strains of epizootic hemorrhagic disease virus (EHDV), New Jersey (NJ) and Kentucky (KY), of deer were biologically transmitted between white-tailed deer, Odocoileus virginianus, by Culicoides variipennis. The KY strain, isolated from C. variipennis collected during an epizootic in deer, was identified as EHDV by serological tests. Deer exposed to the KY or the NJ strains of EHDV developed an acute hemorrhagic disease; most deer died 6 to 13 days after infection. Sheep inoculated with EHDV developed no clinical signs of disease.


Herpesvirus sylvilagus in cottontail rabbits: attempted laboratory transmission by two insect species. The vector potential of the rabbit flea (Cediopsylla simplex) and a mosquito (Aedes triseriatus) was investigated for Herpesvirus sylvilagus transmission among cottontail rabbits (Sylvilagus floridanus). Twelve groups of 12-50 fleas were fed on three viremic cottontails for 2-21 days before transfer to 12 susceptible rabbits. Standard interrupted feeding trials employed five groups of 6-12 mosquitoes, two viremic donor cottontails anf five healthy recipients. No evidence of virus was detected from recipients' blood nor did they develop specific antibody. Virus acquisition and persistence in the insects was evaluated by attempting to recover the virus from 19 pools of mosquitoes engorged on viremic blood and 36 pools of engorged fleas or those living on viremic hosts for 1-21 days. Results were negative.


Dietary treatment of type IV hyperlipoproteinemia. This communication describes an investigation of the effectiveness of dietary counseling in the treatment of patients classified phenotypically as having type IV hyperlipoproteinemia or endogenous hypertriglyceridemia. Over a period of two years, 103 patients who received instructions for a therapeutic diet and regular dietary counseling by a physician and dietitian had a large decline in the concentration of serum triglycerides, as compared to 175 patients with the same diagnosis who received similar diets but little dietary counseling. Over the period of the study, the median plasma triglyceride concentration decreased from 302 to 210 mg/100 ml, the mean triglyceride value from 381 to 263 mg/100 ml, and the mean weight from 84 to 80 kg in the group receiving dietary counseling.


Combination chemotherapy and radiation therapy for small cell carcinoma. A three-drug combination of the chemotherapeutic agents cyclophosphamide, vincristine sulfate, and doxorubicin hydrochloride was given to 45 patients with small cell bronchogenic carcinoma. In addition, patients with limited disease received radiation therapy to the primary tumor. The complete response rate was 44%, with a median survival of 50 weeks. The partial response rate was 29%, with a median survival of 35 weeks. Patients who did not respond to therapy showed a median survival of only 12 weeks. Twenty percent of the patients had their first recurrence in the brain, and the median survival from the time of disease recurrence was ten weeks. Bone marrow metastasis was encountered in 24% of the patient population, but this did not adversely affect survival.


Serological relationships among some Pichia species. Antigenic analyses of five species of the genus Pichia were carried out for taxonomic study by the slide agglutination method using monospecific and absorbed antisera and the agglutinin absorption technique. Comparative studies were also performed with a few strains of each of the same species and their classifications are discussed with respect to the antigenic structures and the patterns of proton magnetic resonance (PMR) spectra of their cell wall polysaccharides. ichia delftensis and Pichia zaruensis possessed thermostable antigens 1,2,5 and 11, and the former had also thermoabile antigen m. Both species were closely related to Candida krusei. Pichia toletana possessed thermostable antigens 1,2,5,11,17 and 49. Pichia bovis contained thermostable antigens 1,2,14,15,16,20 and 21, and it was related to most species of the genus Hansenula, although assimilation of potassium nitrate was negative. Finally, Pichia etchellsii possessed thermostable antigens 1,2,3,4,9 and 14, and was closely related to Pichia vini. Patterns of PMR spectra of mannans of these species also supported their serological relationships. Therfore, P. delftensis, P. zaruensis and P. etchellsii are considered to be the synonyms of Pichia fluxuum, Pichia dispora and P. vini respectively, although P. toletanan and P. bovis are independent species.


Modulation of mouse anti-trinitrophenyl plaque-forming cell affinity by adjuvants or lectins. The efffects of several kinds of adjuvants or lectins, such as Corynebacterium parvum, dextran, poly AU, poly IC, dibutyryl cAMP, concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM) on anti-trinitrophenyl (TNP) direct plaque-forming cells (PFC) in the spleen of mice and the affinity of antibodies produced by these PFC were examined. The numbers of anti-TNP PFC in the spleens of mice which had been injected with C. parvum 7 days in advance were greater than those in controls after immunization with TNP-coupled heterologous erythrocytes, while the affinity of antibodies released by these PFC. Copolymers of nucleotides, poly AU and poly IC, were capable of enhancing splenic anti-TNP PFC responses, but showed almost no altering of PFC affinity. Dibutyryl cAMP did not have any effect on this system. Con A had potencies to both augment the number of anti-TNP PFC and heighten the PFC affinity, while PHA seemed to lack these potencies. Injection of PWM in the presence of antigen increased the number of anti-TNP PFC and heightened slightly the PFC affinity. These results indicate that the heightening of the affinity at the cellular level is regulated in ways different from the augmenting effects on the number of anti-TNP PFC by adjuvants or lectins. These results are discussed in the light of the mode of action of the substances used.


Effect of intestinal distention on levels of cyclic AMP and fluid secretion. The effect of distention on levels of intestinal cyclic AMP has been examined in rabbit jejunal loops under conditions of distention causing fluid secretion. Cyclic AMP levels were not significantly changed when compared with control loops. Histologic examination of the distended loops showed no significant changes from normal. The data indicate that the secretion in response to distention can occur in absence of morphological alteration and is not mediated by the cyclic AMP system.


Reduction of plasma triglycerides by diet in subjects with chronic renal failure. The response of plasma triglyceride levels to changes in the composition of meal formula diets was studied in 12 subjects who had moderate to severe chronic renal failure. Fasting hypertriglyceridemia (greater than 150 mg/100 ml) was present in seven of 12 subjects. Fasting plasma triglyceride levels decreased in all subjects in response to a reduction in the proportion of carbohydrate (from 50 to 35% of total daily calories) and an increase in the poly-unsaturated to saturated fat ratio (from 0.2 to 2.0) in an isocaloric diet. Fasting plasma cholesterol and postprandial triglyceride levels were unchanged. Both the triglyceride production rate and the insulin response were significantly lower on a diet in carbohydrate and higher in polyunsaturated fat. These data indicate that hypertriglyceridemia occurs in subjects with moderate to severe chronic renal failure, and that dietary modification promptly reduces triglycerides levels over an 11 day period. A long term study on a dietary program incorporating these changes is indicated to determine whether this effect is sustained.


[Metaherpetic keratitis clinical and virological findings (author's transl)]. 2,277 specimens from 901 eyes were cultured for herpes simplex virus (HSV). 161 of 391 herpes-diseased eyes yielded HSV. The clinico-virological correlation led to a simple diagnostic and therapeutic scheme which is applicable by the ophthalmologist in his office without virological confirmation: 1. Superficial viral herpes (dendritic keratitis and allied disorders), HSV-isolating rate 96%. 2. Stromal herpes (disciform edema, different types of interstitial herpetic keratitis), only sporadical findings of HSV in the lacrimal fluid. The rate of virus-recovery increases, however, when an interstitial herpetic keratitis ulcerates. 3. Metaherpetic corneal disease = chronic or chronic recurrent superficial postherpetic disease without any detectable HSV-activity (main types: metaherpetic erosion, metaherpetic ulcer, metaherpetic bullous keratopathy). One of four superficial herpetic corneal diseases proved to be nonviral, i.e. metaherpetic in our series. Metaherpetic diseases may be widely considered as a therapeutic entity. The differential diagnosis with the slitlamp only and the proposed therapy (highly hydrophilic soft lenses plus adequate additional eye drops) are discussed in detail. Being aware of the diagnostic criteria and taking advantage of a combined soft lens therapy the treatment of metaherpetic corneal disease is easier and more successful than commonly accepted.


[Diurnal patterns of plasma lipids and lipoproteins in primary endogenous hypertriglyceridemia (type IV-hyperlipoproteinemia) (author's transl)]. Acute and chronic effects of three isocaloric diets on plasma lipids and plasma lipoproteins were studied in 10 patients with primary endogenous hypertriglyceridemia (type IV-hyperlipoproteinemia). The diets used contained 20% protein, 50, 37 and 1% fat and 30, 43 and 79% carbohydrates respectively. Cholesterol levels were similar with all diets. Fasting values of plasma triglycerides were lower with the fat-containing diets compared to the high-carbohydrate diet. Diurnal patterns, however, were significantly higher with the former diets in 8 of the 10 patients.  Postprandial lipoprotein patterns on fat-containing diets are characterized by chylomicronemia and marked changes of concentration and composition of other lipoprotein classes. If, analogous to diabetic therapy, control of hypertriglyceridemia is meant to imply low all-day levels rather than low fasting levels, a rather low-fat, high-carbohydrate diet seems to be superior in most patients with endogenous hypertriglyceridemia to diets containing more than 35 calorie per cent of fat.


The use of a simple barrier system to exclude murine pathogens. A simple barrier system was used successfully to exclude Mycoplasma pulmonis and Sendai virus from a conventional mouse room. 49 weeks after introduction of the barrier system of management Pasteurella pneumotropica was first isolated from animals in the room.


Sertoli-Leydig cell tumor in a chimpanzee. Microscopic analysis of a 38-year-old chimpanzee (Pan troglodytes) revealed a well differentiated Sertoli-Leydig cell tumor (arrhenoblastoma), 4 mm in diameter. Extensive follicular atresia and thecal hypertrophy were noted. The endometrium showed extensive adenomatous hyperplasia, an indication of hyperestrinism. It was suggested that the apparent excessive estrogenic secretion might have originated in the hypertrophic thecal tissue rather than in the tumor.


Microbial agents of the owl monkey (Aotus trivirgatus). A survey of the microbial flora in the owl monkey (Aotus trivirgatus) has led to the isolation of numerous bacterial, fungal, and viral agents. Some of the bacterial and fungal agents, particularly Dermatophilus, Pasteurella, Salmonella, Shigella, Yersinia, Streptococcus, Staphylococcus, and Candida are known pathogens. Viruses belonging to the herpesvirus, adenovirus, paramyxovirus, and papovavirus groups have been isolated from the owl monkey. Most of these viruses were recovered as latent agents from kidney cell cultures. Thus far, they have not been associated with clinical illness or specific lesions in the owl monkey and their infectivity for other animal hosts and for man is unknown.


Glomerulonephritis in the owl monkey (Aotus trivirgatus): ultrastructural observations. The kidneys of 11 clinically healthy owl monkeys (Aotus trivirgatus) acquired from four different sources were examined by light and electron microscopy. Eight of the 11 animals had morphologic evidence of glomerulonephritis. The lesions were characterized by one or more of the following changes: focal or segmental thickening of the glomerular basement membrane; proliferation of mesangial cells with increased production of mesangial matrix; and fibrosis and hyalinization of glomeruli with and without inflammatory cellular infiltration. Five of the eight animals with one or more of the above described changes had electron-dense deposits compatible with immune complex deposits in the intra-membranous and subepithelial regions of the basement membrane. The nature and source of the antigen or antigens responsible for the lesions are unknown.


The owl monkey (Aotus trivirgatus) as an animal model for viral diseases and oncologic studies. The owl monkey (Aotus trivirgatus) has been shown to be an excellent model for studies of oncogenic and non-oncogenic viruses. Studies at this institution have been primarily concerned with Herpesvirus saimiri, the Epstein-Barr virus, H tamarinus, and H simplex. These studies have shown that H saimiri is oncogenic when inoculated into primates, that the malignancy induced by H saimiri can be naturally transmitted from the squirrel monkey to the owl monkey, that in vitro pathogenicity of H saimiri can be modified by passing the virus in a nonpermissive cellular host, that the owl monkey is a useful model for studying the oncogenicity of the Epstein-Barr virus, and the fatal disease induced in owl monkeys by H tamarinus and H simplex can be prevented by vaccination with nonpathogenic variants of these viruses.


Studies of cultured lymphocytes of the owl monkey (Aotus trivirgatus) infected with Herpesvirus saimiri. The lymphocytes of five owl monkeys (Aotus trivirgatus) infected with Herpesvirus saimiri and three control monkeys were studied. Lymphocytes were separated on Ficoll-Hypaque gradients, incubated in suspension cultures, and prepared for electron microscopic and immunofluorescent study at 24, 48, and 72 hours after the beginning of culture. Buffy coats of whole blood obtained immediately after bleeding were also prepared for study. At the time of the study, four of the five infected monkeys had died with malignant lymphoma and lymphocytic leukemia. Herpesvirus saimiri virions were demonstrated by electron microscopy and H saimiri antigens by immunofluorescence in 1-20% of the lymphocytes from infected monkey in two of five cultures at 24 hours after culture, four of five at 48 hours after culture, and all of five at 72 hours after culture. There was good agreement between the electron microscopic and the immunofluorescent data. None of the control monkey cultures and none of the buffy coat preparations contained H saimiri virions or antigens. By electron microscopy, the great majority of the virus particles were nucleocapsids within the nuclei of lymphocytes. Enveloped virions were seldom observed. There was some evidence to suggest that the higher the percentage of lymphocyte containing H saimiri, the poorer the prognosis for the monkey. Herpesvirus saimiri was isolated from all five infected monkeys by co-cultivation of lymphocytes with Vero cells. Control lymphocyte co-cultivations were negative.


EB virus in the owl monkey (Aotus trivirgatus). Owl monkeys (Aotus trivirgatus) were inoculated with EB (Epstein-Barr) virus-containing material or virion-free control material. One out of three animals given the virus died after 14 weeks with a reticuloproliferative disease compatible with malignant lymphoma. A cell line was established from an abnormal lymph node of the diseased monkey and was found by electronmicroscopy to carry a herpesvirus identified as EB virus by two types of immunofluorescence test, by its biological behavior and by nucleic acid hybridization studies. None of the inoculated animals developed heterophile antibodies, and only the diseased animal had an antibody response to EB virus. The findings were discussed in relation to a possible oncogenic capacity of EB virus in vivo.


The transplacental toxicity of methyl mercury to fetal rat liver mitochondria. Morphometric and biochemical studies. Ultrastructural morphometric and biochemical changes in liver mitochondria of fetal rats whose mothers were exposed to methyl mercury hydroxide in their drinking water at concentrations of 0, 3, 5, or 10 p.p.m. for 4 weeks prior to mating and through day 19 of pregnancy are described. A dose-related decrease in the volume density of mitochondria was observed in fetal hepatocytes of dams given the 5- and 10-p.p.m. dose levels. This finding was associated with decreased mitochondrial protein synthesis, which appeared to result primarily from decreased synthesis of mitochondrial structural proteins. Loss of respiratory control was observed in mitochondria from animals in the 3-p.p.m. dose group whereas state 3 respiration was abolished in animals exposed to the 5- and 10-p.p.m. dose levels. The specific activities of monoamine oxidase and cytochrome oxidase, outer and inner mitochondrial membrane marker enzymes respectively, showed dose-related decreases of up to 62 and 78 per cent of control, respectively. delta-Aminolevulinic acid synthetase, which is loosely bound to the inner mitochondrial membrane, also showed dose-related decreases of up to 68 per cent of control. Malate dehydrogenase, a mitochondrial matrix marker enzyme, showed no change in activity at any dose level tested. These observations were correlated with dose-related tissue concentrations of methyl and inormpaired mitochondrial biogenesis and functional development is one basis for explaining the sensitivity of fetal animals to methyl mercury toxicity.


The peroxisomes of human hepatocytes.

The peroxisomes of human hepatocytes. In an ultrastructural study of human liver biopsy specimens we found that peroxisomes are regularly present in normal human hepatocytes. Their relationships with the endoplasmic reticulum observed in other species and in other organs were also demonstrable in this material. Some normal peroxisomes were found to display marginal plates or peripheral crystalline inclusions which were present in pathologic specimens as well. In certain inherited metabolic disorders (Menkes' steely hair disease, analbuminemia) the volume of the individual peroxisomes appeared to be considerably reduced. But most pathologic processes affecting hepatocytes seem to produce any or several of the following: increased volume or numbers per cell, changes of shapes, alterations of the consistency of the matrix, appearance of dense numbers per cell, changes of shapes, alterations of the consistency of the matrix, appearance of dense inclusions, or clustering of peroxisomes in some portions of the cytoplasm. Some of these abnormalities are reversible based on observations in three patients with Wilson's disease treated with D-penicillamine. The mean +/- standard deviation of diameters of peroxisomes in four normal subjects was 0.618 +/- 0.143 mum. Significant reductions or increases in mean diameters of peroxisomes were noted in all but two of the 16 pathologic specimens. There were other morphologic abnormalities present in the remaining two specimens. We conclude that various pathologic processes involving the hepatocytic cytoplasm exert different effects on peroxisomes. Although no specific pattern of morphologic alteration emerged from this exploratory study, a possible involvement of peroxisomes ought to be considered whenever metabolic or pathologic processes affect the liver.


Symptoms and signs of cancer in the school-age child. The American Cancer Society's seven warning signs of cancer are: 1. Unusual bleeding or discharge. 2. A lump or thickening in the breast or elsewhere. 3. A sore that does not heal. 4. Change in bowel or bladder habits. 5. Hoarseness or cough. 6. Indigestion or difficulty in swallowing. 7. Change in size or color of a wart or mole. These signs apply to children as well as to adults. Cancer in children, however, is often more insidious than in adults and may well mimic many other diseases, developmental processess, or childhood psychologic problems. The knowledge that cancer kills more children than any other disease and the awareness of the presenting symptoms and signs may well save a child's life. Early detection with prompt, aggressive therapy is of paramount importance in achieving cures in childhood cancer.


Obesity obscuring breast cancer: a case report. There is normally a layer of fat in the breast between the parenchyma of the breast and the skin. This is frequently thin and does not preclude the palpation of a tumor mass which involves the breast parenchyma. In patients suffering from obesity this fat pad becomes much thicker and obscures any underlying masses arising from the breast parenchyma. A case is reported in which a woman who was markedly obese lost a significant amount of weight and presented a bulge which was found to be carcinoma. This situation, in which fat obscures underlying breast lesion, has been observed in a number of patients. Attention is called to the limited value of physical examination of the breast in markedly obese patients. If any suspicion exists or if the patient is a candidate for cancer from a familial standpoint, mammograms are indicated.


Cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) in lymphocytes from patients with stage III and IV squamous cell carcinoma of the head and neck. In vivo skin tests using multiple recall and primary antigens such as dinitrochlorobenzine (DNCB) have established that there is decreased cellular-mediated immune response in patients with squamous cell carcinomas of the head and neck. In vitro testing of lymphocytes using blastogenic mitogens as a measure of lymphocyte function has not always shown a statistical difference between patients and controls.cAMP-PDE was assayed in lymphocytes from normal controls-patients with benign conditions in various age groups. No significant difference was found in the specific activity (Vmax) or affinity (Km) in these groups. The mean average was used as a normal control value. In lymphocytes from untreated patients with Stage III and IV squamous cell carcinomas of the head and neck, the Vmax and Km of cAMP-PDE were higher than the controls. This difference was statistically significant. Postoperative values were also determined byt were not statistically different. There were no differences found in blastogenesis in these two groups.


Paget's disease of the breast.

Paget's disease of the breast. Twenty-nine histologically verified cases of Paget's disease of the breast treated at the Hadassah University Hospital in the years 1949-1972 were followed up and analyzed. Dividing this material into two groups according to the presence or absence of a palpable breast tumor revealed significant difference in behavior and survival. Patients with a breast mass (34%) had a 50% axillary lymph node involvement and behaved as with any other ordinary breast cancer, with a 5-year survival rate of 40% and a 10-year survival rate of 33%. Patients with no palpable breast mass (66%) had only a 10.5% lymph node involvement, the 5-year survival rate being 94% and the 10-year survival rate being 91%. Delay in diagnosis seems to play no significant factor in survival rates and outcome. We believe radical mastectomy to be the treatment of choice in all cases of Paget's disease of the breast.


[Mixed plantar tumor clinically simulating eccrine poroma]. The case of a 39 years old female patient suffering from a painful, ulcerated nodule on the sole of her left foot for the last 15 months is presented. Clinically, for its localization and resemblance to a pyogenic granuloma, the lesion was considered to be an eccrine poroma. However its depth and tense, cystic feeling on palpation, were considered somewhat unusual. Microscopically the lesion was a "mixed tumour" of the salivary type with ductal differentiation and no cartilage formation. Seven other cases of plantar "mixed tumours" were gathered from the literature but neither ulceration nor poroma looking features were mentioned in any of them.


[Krukenberg's tumor of the ovary and uterine myoma]. A case of Krukenberg's tumour of the ovary in a 41-year-old patient is described. A year before admission she had mild gastric trouble, repeated short-lasting amenorrhea followed by prolonged bleeding. The menstruations preceding hospitalization were normal and painless. More serious trouble developed suddenly, four days before admission, in the form of intense pain in the lower abdomen and moderate bleeding. The woman had delivered twice and had 6 abortions. Her mother died of intestinal cancer. On examination, the patient was found to have two tumours: one on the right side, the size of a newborn's head, and one on the left side, the size of a female fist, both kidney-shaped and mobile. Also numerous small knots on the small intestine, peritoneum, and omentum, as well as a considerable amount of ascites were observed. An uterine myoma was found as well. Histerectomy and ablation of both adnexa were performed. The therapy was continued by radiation but the patient died 5 months following the operation.


Surgical management of nasopharyngeal angiofibroma with intracranial extension. Intracranial extension of nasopharyngeal angiofibroma is a condition difficult to diagnose and even more difficult to treat. Often the diagnosis is not suspected until autopsy. The management of intracranial extension has included incomplete removal via the extracranial approach, radiation therapy, hormonal therapy and cryosurgery. The results of these therapeutic efforts have been characterized by persistent tumor, severe hemorrhage, intracranial complications and death. The combined intra-extracranial approach shows some promise of total tumor removal in the patient with intracranial extension with minimal morbidity. The general criteria of patient selection, risks, surgical technique and case histories of two patients are presented.


Transpalatal approach to deeper cranial structures. The approach to deep midline cranial structures is technically difficult. The transpalatal approach has a relatively wide exposure as compared to the transnasal, transantral and transethmoidal approches. The added advantage of a medial approach which follows medial landmarks and the flexibility of being able to extend exposure to the maxillary sinuses and pterygomaxillary space makes this an attractive approach for large lesions in the nasal passages, nasopharynx and sphenoid sinuses. Large mucoperiosteal flaps, care to avoid the palatine vessels, and application of palatal splint postoperatively, minimize complications and patient discomfort. The authors have used this approach to repair nasopharyngeal atresia, remove nasopharyngeal angiofibromas, approach the pituitary, craniopharyngioma and isolated sphenoid sinus opacification as well as sphenoid sinusitis with cavernous sinus thrombosis.


Unusual parotid tumors.

Unusual parotid tumors. The patient presenting with a mass lesion of the parotid gland is frequently found to have a mixed tumor of salivary tissue origin. However, less common lesions occur in the anatomical region of the parotid gland. These pathological entities deserve consideration in the differential diagnosis. This report presents nine patients with unusual lesions occurring in the parotid region. These regions include cervicofacial actinomycosis, branchial cleft cyst, parapharyngeal tumors, bony lesion of the mandible, non-parotid origin malignant tumor, and metastatic malignant tumors. Each class of lesions demonstrated is also discussed.


Cranial neuropathies in sinus disease.

Cranial neuropathies in sinus disease. To study the problem of cranial neuropathies in sinus disease the inpatient experience at the University of California, San Francisco, and San Francisco General Hospitals was reviewed. The incidence of cranial nerve involvement in acute and chronic sinus inflammations was low (8 percent and 4 percent respectively). The incidence in neoplastic disease of the sinuses was considerably higher (32 percent). Cranial neuropathies occurred in inflammatory disease more frequently when associated with mucopyocele, mucormycosis, and orbital cellulitis. In both inflammatory and neoplastic disease, when cranial nerve deficits occurred, there was a high predelication for sphenoid sinus involvement. Several instructive case histories are included. The important anatomy of the cavernous sinus region and of the orbital apex as it pertains to this problem is discussed.


Evidence for an etiologic relation of the Epstein-Barr virus to human malignancies. Studies on virus-induced animal tumors have provided indirect approaches to a search for viruses causing human malignancies. Epstein-Barr virus (EBV), the cause of infectious mononucleosis, served to illustrate the usefulness of these approaches in linking EBV with Burkitt's lymphoma and nasopharyngeal carcinoma. Despite its demonstrated intimate association with these tumors the role of EBV in their causation remains uncertain. While a passenger role seems excluded, it cannot be decided whether EBV is the primary or a secondary agent in the etiology of the tumors. If the primary cause, immunologic, genetic, virologic or other environmental factors are undoubtedly needed for EBV to express its obvious oncogenic potential. The data illustrate the difficulties encountered in proving a viral etiology of human malignancies.


[TDI determination in polyurethane paints and in work environment (author's transl)]. A simple gas chromatographic method is described for the analytical determination of free monomeric TDL in polyurethane paints. Analyses of commercial products used in furniture plants showed a high percentage of free monomer with repercussion on the air and work environment.


[The relation of infection with the hepatitis B-agent to primary hepatic carcinoma (author's transl)]. In Asia, Africa and other tropical areas primary hepatic carcinoma (PHC) is associated with liver cirrhosis of the post-necrotic (macronodular) type. Chronic viral hepatitis is likely to be the cause of this cirrhosis in many patients from regions where chronic infection with the hepatitis B virus (HBV) is common. More than 95% of patients with hepatoma (in Mali and Senegal) have evidence of infection with HBV, a much higher frequency than in controls. Thirty-nine of 62 PHC patients had hepatitis B surface antigen (HBSAg) (controls: 8 of 98) and 56 of 63 (controls: 26 of 100) had antibody against hepatitis B core antigen (anti-HBC). In earlier studies we demonstrated a maternal effect of HBSAg. If the mother has the antigen and the father does not, the children are much more likely to also have HBSAg than if the father has the antigen and the mother does not (93/161 = 57.8% when mother is positive vs. 28/135 = 20.7% when father is positive; p = 0.6 X 10(-10)). Studies in Greece and in the Solomon Islands show that presence of HBSAg in parents affects the sex ratio of the offspring of the mating. This implies that the presence of the agent in a parent can affect the fetus early in life. Parental studies in the African hepatoma patients showed that there is a very high frequency of HBSAg in mothers (71.6%) while the frequency in fathers (18.5%) is significantly less. This suggests that the development of hepatoma in offspring is related to infection in parents. We described a vaccine several years ago which may be useful in preventing infection with hepatitis B. Strategies are discussed which might be effective in preventing the development of carriers with, it is hoped, a consequent decrease in the frequency of HBV carriers, chronic hepatitis and primary hepatic carcinoma. The strategy would employ methods for decreasing the frequency of the agent in the environment by the application of public health methods including the vaccination of appropriate newborns and other members of the population.


[Serum lactic dehydrogenase isoenzymes in metastatic and primary liver carcinoma (author's transl)]. Serum LDH isoenzymes were comparatively evaluated in experimental and human liver carcinoma. In our experimental studies, LDH4 increased in AH 66 F metastatic hepatic cancer, but DAB hepatic cancer showed a significant increase of LDH5. In clinical studies, LDH4 and LDH5 increased significantly in metastatic liver carcinoma, and 15 (79%) out of 19 cases showed higher values of LDH4. In primary liver carcinoma LDH5 increased significantly, and 12 (92%) out of 13 cases showed a higher LDH5. Therefore, analyses of serum LDH isoenzymes would aid in differential diagnosis of metastatic and primary liver carcinoma.


[Multiple nodular densities on chest X-ray in liver cirrhosis--a diagnostic problem? (author's transl)]. A case report is given of a 49 year old white male patient, who had suffered for several years from liver cirrhosis and who finally died from hepatoma. Although a hepatoma was suspected in this case it was not demonstrated intra vitam, though at autopsy it was found to have invaded the lower vena cava, continuing into the right atrium. Problems of early diagnosis of hepatoma are discussed in context with this case.


[Adrenergic receptors in the pathogenesis of congenital megacolon (author's transl)]. Contractions of fresh specimens of taenial musculature from human colon were investigated under the influence of depolarization (bathing in solutions high in potassium), of acetylcholine, and of adrenaline; definite changes of contractile tension could be induced by these agents. The investigations were carried out using normal musculature as well as specimens from patients with congenital megacolon taken from the narrow segment. Contractions after depolarization and after cholinergic stimulation were equal in all specimens investigated, pre-extension of these specimens not differing significantly. Relaxation of colon musculature mediated by adrenergic receptors was very pronounced in normal musculature, but was lacking in specimens taken from the narrow segments of congenital megacolon. Sympathetic stimulation of normal taenial musculature does abolish completely cholinergically induced contractions. On the other hand, a preparation relaxed by adrenaline contracts very little after additional application of acetylcholine. These findings do suggest a severe disturbance of adrenergic receptors in the colon, or of adrenergic neuromuscular transmission in congenital megacolon.


The association of oral androgenic-anabolic steroids and life-threatening disease. The use of androgenic anabolic steroids in the therapeutic dose range by strength athletes is well documented. The benign side effects of these drugs are well known but more disturbing are the increasingly frequent reports of potentially fatal diseases in association with the therapeutic use of these agents. A review is made of the clinical evidence indicating a direct association between androgenic steroids and peliosis hepatis, heptocellular carcinoma and acute myelogenous leukemia, all potentially fatal disorders.


Measurement of antibodies to Herpesvirus hominis by indirect immunofluorescent antibody method. Antibodies to Herpesvirus hominis (HVH) were evaluated by indirect immunofluorescent antibody (FA) method. Frozen sections of HVH infected mouse brain provided antigens for FA staining. Our data indicate that indirect FA staining is a rapid, sensitive, and reproducible method for measurement of antibodies to HVH. Indirect FA method can be applied as an additional tool for the measurement of antibodies to HVH and can be applied for epidemiological survey of HVH infections.


[The index of leukocyte alkaline phosphatase in patients with hemodialysis (author's transl)]. The index of the leukocyte alkaline phosphatase activity (LAP-I) was evaluated in 15 patients suffering from chronic uremia immediately before and after hemodialysis, as well as 16 or 18 and 40 or 42 hours thereafter. Immediately following hemodialysis the LAP-I was significantly reduced in comparison with to predialysis values. 16 and 18 hours after hemodialysis the LAP-I had again increased and at 40 and 42 hours exceeded the starting predialysis values. These results are discussed in relation to the dialysis-induced decrease of plasma cortisol and to the consequent ACTH and cortisol overproduction.


A gal region mutant that requires cAMP for growth on galactose in an adenyl cyclase negative (cya delta) background. Strains of Escherichia coli K12 that contain a deletion of the adenyl cyclase gen (cya delta), required for the synthesis of cyclic adenosine-3';5' monophosphate (cAMP), grow on galactose-containing minimal medium. A mutant was isolated that grows on this medium only if cAMP is added. The mutation (designated galP20) is linked to the gal operon region as determined by both generalized transduction with bacteriophage P1 and specialized transduction with bacteriophage lambda. Studies with galP20 cya delta strains as well as gal delta (deletions of the gal operon) cya delta strains indicate that synthesis of the physiologically important transport mechanism for galactose (galactose permease) requires either cAMP or a function mission from both the galdelta strains and the galP20 strain.


[Adrenocortical adenoma in a 2 1/2 year old girl causing virilization and accelerated growth. Clinical and morphological results (author's transl)]. A 2 1/2 year old girl with virilization and advanced bone age was found to have a leftsided adrenocortical adenoma. The secretion of mainly androgens besides estrogens was not suppressible with dexamethasone. Plasma cortisol levels were not elevated but did not show any circadian rhythm. The tumor was localized by retroperitoneal instillation of gas, intravenous urography and tomography. After complete removal of the tumor the originally strongly elevated excretion of 17-ketosteroids sank back to normal, the acceleration of skeletal development slowed down. The right adrenal cortex was not atrophic, 2 1/2 years after the operation the child is well and without evidence of recurrent disease. Differential diagnosis as well as ultrastructor and histology of the tumor are discussed with reference to the literature.


ESR spectra of quasirandomly oriented centers: application to radiation damage centers in bone. The angular dependence of the ESR line shape from polycrystalline samples due to incomplete randomness in the orientation of the crystallites is calculated for centers with axial symmetry. The effect of a preferential axis of orientation is considered and the results are applied to radiation produce centers in bone.


Pesticide induced DNA damage and its repair in cultured human cells. The effects of pesticides on the induction of unscheduled DNA synthesis in SV-40 transformed human cells (VA-4) in culture with and without metabolic activation by liver microsomes was studied. Results showed that ten of the thirteen compounds examined either directly or upon metabolic activation induced unscheduled DNA synthesis in the human cell system used. The DNA repair kinetics and size of the repaired regions resulting from treatment with four of the chemicals (Carbaryl, Chlordane, Dieldrin and 2.4-D Fluid) were studied by 313 nm photolysis of repaired regions containing bromodeoxyuridine (BUdR). The size of the repaired regions differed between compounds but could generally be classified as either of the X-ray (short) or UV-type (long).


Inhibition of initiation of HeLa cell replicons by methyl methanesulfonate. Methyl methanesulfonate (MMS) in the culture medium inhibits the rate of DNA synthesis in HeLa cells in a dose-dependent manner. By using short (5 min) incubations with [3H]thymidine and analyzing the newly made DNA by velocity sedimentation on alkaline sucrose gradients, we found that the first affect of MMS on DNA replication, at 0.5 h after treatment, was inhibition of initiation of replicons. Recovery from this effect seemed to have begun by 2 3/4 h after treatment. The second effect of MMS, which was evident at 2 h after treatment, was to slow or block chain elongation.


Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme. To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.


Structure of an antibody combining site by magnetic resonance. The structure of the combining site of the DNP binding IgA mouse myeloma protein MOPC 315 has been determined by a combination of high resolution nuclear magnetic resonance, electron spin resonance, model building and chemical modifications. This approach yields that general dimensions of the site, its polarity and asymmetry features, the assignment of the DNP-contact residues and their three-dimensional coordinates.


Embryonic development and mitochondrial function. 2. Thiamphenicol induced embryotoxicity. Inhibition of mitochondrial protein synthesis in rat embryos during late organogenesis leads to impaired embryonic development. 1. Thiamphenicol (TAP), similar to chloramphenicol, inhibits in vivo the synthesis of cytochrome oxidase (cytox), which is partially synthesized by the mitochondrion. Subsequently, DNA synthesis and embryonic growth are affected. 2. Embryos on day 10 and 11, in contrast to embryos on day 9 of gestation, show a high sensitivity of mitochondrial protein synthesis, measured as cytox activity. From day 10 onwards, such an inhibition leads to pronounced impairment of DNA synthesis. The rat hemochorial placenta starts functioning on day 12 of gestation. Larger doses of TAP are required to inhibit cytox and DNA synthesis for treatment after placentation rather than before placentation. 3. Dose-response relationships differ depending on the date and duration of treatment. Application of TAP for 1 day requires 10-30 mg/kg TAP to inhibit cytox synthesis and 60-100 mg/kg to impair embryonic growth. Prolongation of treatment to 4 days (day 10-13) lowers the dose required for inhibition of DNA synthesis to 10 mg TAP/kg/day. This is lower than the human therapeutic dose. Larger doses lead to embryolethality. 4. The extent of inhibition of DNA synthesis provoked by inhibition of mitochondrial protein synthesis depends on a number of factors which include: different growth rates during organogenesis, the number of mitochondria present prior to treatment, availability of extramitochondrial ATP sources and placental permeability barrier.


[Effect of ammonium acetate on depolarization processes in the central terminals of primary afferents]. Experiments on cats determined that ammonium acetate injected intravenously (2-4 mM/kg) supressed the processes of primary afferent depolarization (PAD) which are thought to be responsible for the presynaptic inhibition of spinal reflexes. The supression was transient and proceeded in paralle to depression of postsynaptic inhibition of monosynaptic reflexes. Ammonium acetate slightly decreased the amplitude of the negative postsynaptic potentials recorded form the dorsal surface of lumbar cord in response to stimulation of hind limb afferent nerves and increased polysynaptic reflex discharges in appropriate ventral roots. These findings make it unlikely that the ammonium depression of PAD is a result of impairment of interneuronal activity. A suggestion is made that ammonium depression of PAD results from diminition of the EMF for synaptic currents producing PAD.


Serum enzyme activity in bone tumors and osteomyelitis (LDH, GOT, GPT, CPK, CHE, ALP, AP, PP, ALD). Enzyme activity of lactate dehydrogenase, glutamate-oxalacetate and glutamate-pyruvate transaminase, creatine phosphokinase, cholinesterase, alkaline, acid and prostatic phosphatase and aldolase has been studied in a total of 213 subjects, of whom 97 were of good health, 63 had bone tumors and 53 suffered from osteomyelitis. The activities of the majority of the enzymes were found to become significantly changed in comparison with the norm. In both patient groups, the more striking differences being noted in that of osteomyelitis. However, enzymatic activity alone does not allow to differentiate the group of bone tumors from that of osteomyelitis, the differences between these two groups not being of significance in any one of the enzymes followed.


Body temperature and tumor virus infection. I. Tumorogenicity of Rous sarcoma virus for reptiles. Rous sarcoma virus (RSV) was oncogenic for the following nine species of reptiles representing 6 families from Chelonia and Squamata orders: family of Testudinidae: 1. Testudo horsfieldi, family Agamidae: 2. Agama sanguinolenta; 3. Agama erythrogastra, family Lacertidae: 4. Eremias persica; 5. Eremias velox; 6. Eremias grammica, family Scincidae: 7. Eumeces taeniolatus, family Boidea: 8. Erix tataricus, 9. Ancistrodom blomhoffi. RSV did not induce tumors in 13 studied species of reptiles. Histologically 26 reptile tumors studied were polymorphous sarcomas with spindle-shaped (fibroblast-like), round and polygonal macrophage-like cells and sometimes peculiar giant polynuclear cells. Chromosomal analysis showed that reptile tumors arose out of reptile cells. RSV was pathogenic for adult reptiles. Reptile tumors did not contain a mature infectious virus. The tumors of 2 snakes were virogenic. The effect of increased temperature at the body level on the transformation of a symptomless viral infection into a viral disease is discussed in the evolutionary aspect.


Effect of heterologous antimacrophage serum on growth of Rous virus-induced sarcoma in the allogeneic and syngeneic system. The effect of heterologous antimacrophage serum (AMS) and normal rabbit serum (NRS) on the immune reaction against Rous virus-induced sarcoma (RSL) was studied in rats. The growth of RSL sarcoma transplanted against the H-1 barrier in AMS-treated rats was more progressive than in the untreated or NRS-treated control group. On the other hand, the growth of RSL sarcoma was significantly suppressed in syngeneic AMS- or NRS-treated recipients compared to the untreated control rats.


Evidence of nycterohemeral periodicity in stress-induced pituitary-adrenal activation. Plasma ACTH and corticosterone were measured under basal conditions and after ether or tourniquet stress during the nadir (a.m.) and zenith (p.m.) of the nycterohemeral pituitary-adrenal cycle. Exogenous ACTH was also given at these 2 times to assess adrenal sensitivity to ACTH and the maximal adrenal capacity for corticosterone secretion. Ether stress caused a greater rise in plasma ACTH in the a.m. than in the p.m., even though basal plasma ACTH and corticosterone concentrations were lower in the a.m. than in the p.m. When given in the p.m., pentobarbital anesthesia depressed plasma corticosterone and ACTH to the a.m. level; under these conditions the rise in plasma ACTH produced by tourniquet stress was the same in the a.m. and p.m. Both tourniquet and ether stresses caused maximal activation of adrenal corticosterone secretion, but ether produced a much greater rise in plasma ACTH. It is concluded that: (1) the greater ether-induced rise in plasma ACTH in the a.m. than in the p.m. is probably due to the lower plasma (and probably tissue) corticosterone concentration at that time; (2) the plasma ACTH concentration for inducing maximal adrenal activation is relatively low; and (3) the higher basal levels of plasma corticosterone in the p.m. than in the a.m. are due to a slight increase in basal ACTH secretion in the p.m.


Correlation between hypothalamic catecholamine synthesis and ether stress-induced ACTH secretion. The rates of synthesis of norepinephrine (NE) and dopamine (DA) in several regions of the hypothalamus have been estimated after exposure of rats to stresses that increase ACTH secretion. The rate of 3H-NE and 3H-DA accumulation from 3H-tyrosine in vitro was used as an index of catecholamine synthesis rates. Exposure to ether vapor, 30 min of cold environment, or laparotomy increased ACTH secretion significantly, as indicated by plasma corticosterone levels. However, only the ether stress affected hypothalamic catecholamines; both NE and DA synthesis rates were increased in the arcuate nucleus are (ANA), but not in the median eminence (ME) or the residual hypothalamus (RH). Dexamethasone treatment blocked the stress-induced ACTH secretion, but had no affect on basal or stress-induced rates of amine synthesis. It is concluded that catecholamines in the ANA participate in mediating ether stress-induced ACTH secretion.


[Immune humoral response in epilepsy].

[Immune humoral response in epilepsy]. In 68 epileptics in serum immunoglobulin level, antibodies against Kunin CA antigen, S. typhi O and viruses parainfluenzae type I, II and III were determined. The serum IgA leeel (-/x = 106.27, SE = 8.14) was lower than in controls (-/x = = 155.55, SE = 8.12). In 25% of epileptics the IgA level had raised IgG and low IgM levels in the serum. In epileptics the level of antibodies to parainfluenza virus III (-/xg = 71.52) was lower than in the control group (-/xg = 92.29). The investigations gave results which could not answer the question whether disturbances of immune humoral response in epileptics are primary or are due to immunosuppressive action of anticonvulsants.


[Usefulness of a strain of mice with genetically determined audiogenic epilepsy as a model of experimental epilepsy]. Behavioural and bioelectric characteristics of epileptic seizures caused by acoustic stimulus in mice from the Swiss Albino Rb strain with genetically determined audiogenic epilepsy are presented. The value of this epilepsy model is emphasized stressing that the epileptogenic stimulus acts from a distance, causing no damage to the nervous system and no artifacts. Besides that, seizures can be provoked at a definite frequency and at arbitrarily chosen time. A disadvantage of the model is the necessity of provoking each seizure separately which causes that this model cannot meet one of the conditions of Jasper's definition concerning spontaneity of seizure development. With regard to the course of seizure it is emphasized that it is somewhat similar to human grand mal epilepsy representing the basic phases of seizure. Electrophysiological investigations carried out under conditions of long-term fully reproducible experiment demonstrated presence of very evident and rich electrocorticographic symptomatology of audiogenic epileptic seizure whose behavioural phases show a high correlation with phasic changes in bioelectric brain activity. The investigations carried out in sleep failed to demonstrate differences in the susceptibility to seizure development when the stimulus was applied in waking state or in any of both phases of sleep. This strain is useful to morphological ultrastructural, biochemical and possibly electrophysiological investigations.


[Glomus tumors in unusual sites].

[Glomus tumors in unusual sites]. Two cases of glomus tumour in unusual sites are described. Their indistinct symptomatology, site and histological polymorphism are made the basis of a general discussion of the histogenesis and possible ongoing pictures of glomus tumours, the classification of which is also felt to be unsatisfactory.


Molar pregnancy of hyperthyroidism.

Molar pregnancy of hyperthyroidism. A report on a patient with clinical hyperthyroidism associated with hydatidiform mole is presented. Some biochemical characteristics of the thyroid stimulator isolated from the tumour are discussed.


The effect of conjugated estrogens on coagulability in menopausal women. To investigate the effect of conjugated equine estrogens on the coagulability in menopausal women, blood samples were drawn from 69 menopausal females--35 receiving estrogens and 34 receiving no replacement therapy. Using tests for antithrombin and heparin-antithrombin activities, 14.7% of the control patients were found to be hypercoagulable. This is a 289% increase in the incidence of hypercoagulability in the group treated with estrogens. The particular relevance of this finding to menopausal women and the importance of the use of the coagulation profile in managing such patients is discussed.


The value of erythropoietin assay in the follow-up of Wilms' tumor patients. Ectopic tumor associated erythropoietin release was measured preoperatively and postoperatively in 36 Wilms' tumor patients followed for an average of three years. Erythropoietin assay results in plasma and urine were related independently to tumor stage as well as to the general clinical judgment following appropriate and exhaustive tests as to whether the disease was active or inactive at the time of the assay. Consistent erythropoietin plasma elevations were correlated with the presence of active disease in all stages of Wilms' tumor. Less consistent elevations were noted in urine specimens concomitantly obtained and assayed. This hormonal assay continues to be of consistent and long-term benefit in predicting or correlating disease recurrence or persistence in Wilms' tumor.


Male breast cancer: two cases with objective regressions from calusterone (7 alpha, 17 beta-dimethyltestosterone) after failure of orchiectomy. Calusterone (7 alpha, 17beta-dimethyltestosterone) is an orally effective weakly androgenic steroid. The antitumor efficacy of calusterone, 200 mg per day against objectively progressing advanced breast cancer in females has already been reported. In the present study calusterone was used in metastatic breast cancer in two male patients. Both had failed to continue respond to orchiectomy and had measurable lesions one in the lungs, the other in the bones. Both patients showed objective regression (blastic response of osteolytic lesions and disappearance of lung metastases) lasting five months in one patients and more than seven months in the other, who is still in regression. Further experience is necessary for statistically adequate results.


Intranuclear inclusion bodies in recurrent aphthous ulcers with a herpetiform pattern. Spherical granular and filamentous intranuclear bodies were found in the marginal epithelial cells of recurrent aphthous ulcers with a herpetiform pattern. They ranged from 0.8 to 1.2 mu in size with one to four bodies being present in any one nucleus. Because of their size and the demonstrated lack of DNA or RNA, it was thought that they were not viral in nature, as has been previously reported. It is hypothesized that intranuclear bodies of the type found in this study represent a common manifestation of altered cellular metabolsim produced by several etiologic factors.


Mucin-producing cholangiocarcinoma: an autopsy study in Hong Kong. Fifty autopsy cases (35 male and 15 female) of mucin-secreting cholangiocarcinoma in Chinese were reviewed. The peak incidence was in the 7th decade for males and in the 6th for females. Massive (37), multinodular (8), diffuse (1) and hilar (4) types were recognized grossly. The hilar tumours arose from the main intrahepatic ducts and the other types originated from smaller ducts. The overall association with stones was 20% and clonorchiasis 92%. Cirrhosis occurred in only 4% of cases. There was an association between the degree of mucin secretion and the presence and severity of clonorchiasis.


Primary Epstein-Barr virus infections in children. During a serioepidemiologic survey of a community, 13 (6.2%) of 209 children were found to be experiencing a current or recent primary Epstein-Barr virus (EBV) infection. The sera contained elevated antibody titers to viral capsid antigen of EBV, antibodies to early antigen (EA) of EBV, and specific IgM. The frequency of primary infections was highest in the first decade of life. The primary EBV infections were usually asymptomatic. The antibody to EA was directed predominantly to the R component. A heterophil antibody response was not detected.