Mitochondrial abnormalities in some human muscular diseases and in experimental ischemic myopathy. Morphologic abnormalities have been observed in two cases of human polymyositis and in three cases of ocular myopathies. Similar findings can be observed in experimental ischemic myopathy. "Ragged red" fibres, with anomalous distribution of oxidative enzymes, mitochondrial alterations, with presence of intracristal paracrystalline inclusions and degenerative myofibrillar changes are the similar features. The similarity between some of these alterations, expecially mitochondrial changes, is remarkable, but it is difficult to correlate them to the primary etiology of described human myopathies.


Cleavage of damaged DNA by an enzymatic activity from human fibroblasts. An endonuclease activity isolated from normal, Xeroderma Pigmentosum and De Sanctis-Cacchione fibroblasts by DNA-cellulose chromatography has been evaluated by means of sedimentation analysis both in alkaline and neutral sucrose gradients. The partially purified enzyme is active at pH 7.5 in presence of Mg++ and cleaves UV-irradiated and alkylated DNA. Under identical experimental conditions, the enzyme is not active on untreated, depurinated and heat-denaturated DNA. The specificity on pyrimidine dimers has been further investigated to understand the mechanism of action of the enzyme.


Decreased amniotic fluid peroxidase in malignancy of the cervix. Studies of amniotic fluid obtained at various times throughout the last trimester of pregnancy from patients with carcinoma of the cervix indicate a complete deficiency of peroxidase activity. Dialysis partially restores the enzyme activity. Cervical epithelial tumor cells apparently release a dialyzable, low molecular weight inhibitory substance directed specifically toward peroxidase. If this proves to be true in future studies, the peroxidase assay could be a sensitive means of differentiating between carcinoma and dysplasia. A peroxidelike substance was also present in the amniotic fluids obtained from patients with carcinoma. Other investigators have demonstrated large amounts of peroxide in malignant tumors. These elevated peroxide levels might well be directly related to deficient peroxidase activity rather than being a result of other abnormal enzyme levels which have been regarded as being principally involved in the metabolism of this highly toxic molecule.


Cell proliferation in organs of rats bearing hepatoma 3924A: effects of X-rays of surgery. For inbred rats with Morris hepatoma 3924A, increases in tumor size were accompanied by increases in weight and DNA content of spleen, DNA content of tibial marrow, and peripheral white cell concentrations of blood. White blood cell concentrations of rats with tumors weighing more than 5 g were approximately two-fold greater than for rats without tumors. Neutrophils were primarily responsible for the increase in white cells. Local x-radiation of 3750R to the tumor when the tumor was small prevented tumor growth and the increases in spleen weight, incorporation of 3H-thymidine into spleen DNA, white blood cell count, and tibial marrow DNA content related to tumor growth. Surgical removal of large tumors resulted in a return of spleen weight and DNA content to near normal values within 1 week. Despite the evidence for increased cell proliferation in hematopoietic tissues of rats with hepatoma 3924A, no systematic relationship has been observed between tumor size and animal survival following treatment with the cell cycle specific agent 5-fluorouracil when tumors have varied in size from 0.5 g to 5 g at the time of drug treatment.


DNA polymerases during tumor growth.

DNA polymerases during tumor growth. DNA polymerase activity was studied as a function of stage of tumor growth and correlated with DNA synthesis measured by 3H-TdR uptake. Considerable variations in DNA synthesis activity occur at different growth stages and following host death. DNA alpha-polymerase activity did vary with growth stage in the ascites tumor. However, it did not have a clear correlation with DNA synthesis or with tumor growth. No striking fall in DNA polymerase enzyme levels occurred as the ascites tumor reached stationary phase in contrast to reports in some cell culture systems. A decrease occurred with advanced tumor stage and after host death. DNA beta-polymerase activity did not change with tumor growth stage.


The effect on macromolecular synthesis of amino acid deprivation of hamster kidney cells. Since asparagine has been found to inhibit growth of some tumors and to inhibit or delay mitotic activity in other cells, we have studied the effect of asparaginase and of deprivation of some essential amino acids (Arg, Asn, Leu, Ile, Trp) on nucleic acid and protein synthesis in an asparagine-requiring strain of BHK/21 cells. We find that: (1) there is no essential difference in the pattern of synthesis following deprivation of any of the amino acids we tested; (2) that the effect of asparaginase is similar to that of amino acid deprivation; (3) that RNA synthesis is inhibited more rapidly than DNA or protein synthesis; (4) that after 10 hr of amino acid starvation, DNA synthesis is almost totally (reversibly) inhibited while RAN synthesis continues at about 30-50% and protein at about 100% of the initial value.


The effectiveness of clinically useful antitumor agents as inhbitors of RNA polymerases. Many clinically useful antitumor agents effective inhibitors of both the exogenous Escherichia coli DNA-dependent RNA polymerases in vitro and the endogenous polymerase in mammalian cultured cells. The drug concentrations required for this inhibition are comparable to those achievable plasma levels in man for Actinomycin D, Adriamycin, 5-Fluorouracil, ICRF 159, Melphalan, Methotrexate and Vincristine. Therefore before the mechanisms of these drugs can be fully understood inhibition of RNA synthesis and its implications in the continued survival and replication of cells must be considered. Although chemotherapeutic agents have generally been considered to exert their cytotoxic affects by directly interfering with DNA metabolism or by inhibiting enzymatic pathways in purine and pyrimidine nucleotide metabolism, these data emphasize that this is an oversimplication. Most agents have multiple effective target sites within the cell and the primary cytotoxic events responsible for their clinical effectiveness remain to be elucidated.


The activity of the D-T diaphorase in experimental hepatomas. The study of some NAD(P)H dehydrogenating enzymes in one slow- and one fast-growing transplantable hepatoma has shown that the activity of the soluble enzyme D-T diaphorase is increased several-fold when compared with the activity of the control livers. The increase in enzyme activity is similar in both hepatomas, regardless of the rate of growth of the tumors. The activity of the glycerolphosphate, malic and lactic dehydrogenases are decreased in both tumors. The possible functional significance of these changes is discussed in the text.


In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas. Cannabinoids represent a novel class of drugs active in increasing the life span mice carrying Lewis lung tumors and decreasing primary tumor size. In the present studies, the effects of delta9-THC, delta8-THC, and cannabidiol on tumor macromolecular biosynthesis were studied. These drugs inhibit thymidine-3H incorporation into DNA acutely, but did not inhibit leucine uptake into tumor protein. At 24 h after treatment, cannabinoids did not inhibit thymidine-3H incorporation into DNA, leucine-3H uptake into protein or cytidine-3H into RNA.


Selective inhibition and kinetics of enzymatic reactions leading to irreversible binding of benzo[a]pyrene to microsomal macromolecules of mouse lung. Two enzymatic reactions, catalyzed by mouse lung microsomes and distinguishable by selective inhibition and kinetic studies, lead to irreversible binding of benzo[a]pyrene to macromolecules present in vitro reaction systems. One type (low Km) is inducible in the lungs of mice by treatment with benz[a]anthracene and is subject to inhibition by 7,8-benzoflavone. The other type (high Km) is predominant in lungs of untreated mice, but a small amount of low-Km activity is also present. The high-Km activity may be involved in carcinogenesis by benzo[a]pyrene, for it is inhibited by butylated hydroxytoluene, retinol or disulfiram, each of which is reported to have anticarcinogenic activity in intact animals.


In vivo metabolism of deutero-L-phenylalanine and deutero-L-tyrosine in normal and in various tumor-bearing rats. The hydroxylation rate and rate of tyrosine catabolism are measured by injection of ring-deuterated L-phenylalanine and ring-deuterated L-tyrosine and subsequent deuterium determination in the water fraction of the blood. The hydroxylation rate was confirmed as the rate-limiting step. Whereas tyrosine catabolism yields normal Michaelis-Menten kinetics, homotropic activation is demonstrated for the hydroxylation step. In all tumor rats under study, the rates of phenylalanine hydroxylation and tyrosine catabolism are decreased. The delta-values to control increase with tumor age. In tumor rats, the hydroxylation step remains the rate-limiting one. Kinetic data indicate that the decrease in hydroxylation is due to a decreased turnover rate of the enzyme, whereas the increase in tyrosine catabolism is caused by the branching off of tyrosine or an intermediate on the route to D2O formation. The results are discussed with respect to altered levels of tetrahydrobiopterin, phenylalanine and tyrosine found during parallel investigations.


On the levels of phenylalanine, tyrosine and tetrahydrobiopterin in the blood of tumor-bearing organisms. The levels of free phenylalanine and free tyrosine (and m-tyrosine) as well as of protein-bound tyrosine were determined by means of automated aminoacid analysis and by reaction with 1-nitrosonaphthol(2). Their absolute values as well as their percentages relative to total aminoacids of the blood were markedly increased in all tumor patients tested, as well as in experimental tumor rats. Although tetrahydrobiopterin could scarcely be detected by fluorometric methods in the blood of control persons, it is accumulated blood of all tumor patients tested. The major part was found in the erythrocyte fraction. The results are discussed with respect to decreased phenylalanine hydroxylation rate and to depressed tyrosine catabolism recently found by means of in vivo experiments in tumor-bearing rats.


[Chronic granulomatosis in childhood].

[Chronic granulomatosis in childhood]. In a boy aged 8 years suffering from chronic granulomatosis of childhood necrotizing pneumonie and small pulmonary tuberculoid granulomas containing filaments of moulds were found at autopsy. Necrotizing leucocytic granulomas were present in the liver, spleen and the lymph nodes. All the organs showed aggregates of histiocytes containing yellowish cytoplasmic deposits of lipogment surrounded by a high acid phosphatase activity. The NBT-reduction leucocytic tests was repeatedly negative in vivo. The activities of NADH- and NADPH-tetrazolium reductase and succinate dehydrogenase in the tissues were histochemically normal.


[Ultrastructure of the red pulp of the spleen in various anemias]. Eighteen tissue samples of human spleens obtained from patients suffering from hereditary sphaerocytosis, acquired haemolytic anaemia, hypersplenism, Banti's syndrome and extralienal neoplastic disease were subjected to electron microscopical examinations. Lesioned erythrocytes were removed with the aid of the macrophages of the red pulp and in cases of a high number of injured erythrocytes the cells lining the sinuses were also involved. The proliferation of collagen connective tissue was possibly also involved in injuring the blood cells. The spleens obtained from patients with neoplastic disease not affecting the spleen could not be regarded as normal.


[Ultrastructural findings in the so-called minimal glomerular changes]. Fifty-eight needle biopsies of the kidneys with the light microscopical diagnosis of so-called minimal glomerular lesions were subjected to ultrastructural evaluation. The series contained children and adults under 25 years of age with the mean age of 16.9 years. The most frequent findings were those of the glomerular epithelia: vacuolation and swelling of their cytoplasm in 72.8%, microvilloustransformation in 13.6%. Endothelial lesions were less frequent: swelling and vacuolation of their cytoplasm occurred in 46.6%. The most important ultrastructural lesions appeared to be the mesangial ones. Focal increase in the mesangial matrix was seen in 44.8% and small intralobular scars in 13.6%. True focal increase in mesangial cells was rare (6.9%). The formation of duplicatures of the basement membranes in the glomeruli was exceptional (3.6%). Another important ultrastructural finding was a focal thickening of the basement membrane in a larger number of cases (32.3%). Deposits were found rarely (7 cases, 12.1%) most of them occurring in the mesangium. The cellularity of the glomeruli did not exceed the normal range.


[Simultaneous occurrence of structurally variegated cutaneous nevi in the dog]. In a boxer dog aged 12 years who had deceased from circulatory insufficiency due to purulent endomyocarditis, there occurred a Leydig cell adenoma of the testis and multiple cutaneous naevi (haemangioma, pigmented naevus and various cutanous organ naevi). The findings have been discussed with reference to the race disposal to neoplastic growth.


[The ciliated epithelium in the efferent ducts of the submandibular gland]. The examination of 442 bioptic and necroptic submandibular salivary glands revealed that in cases of chronic inflamation of the gland (125 cases) the epithelial lining of its ducts contained ciliated colummar epithelium in 57% of cases. The finding of ciliated epithelium was associated with lithiasis of the gland in nearly 79% of cases. Normal submandibular glands or glands affected with pathological conditions other than chronic inflammation did not contain ciliated epithelium. The present paper is the first one in the literature purposedly dealing with the presence of ciliated epithelium within the ducts of the submandibular gland.


[Morphology of ferritin-induced shock in sensitized guinea pigs]. With the aid of morphological methoda, differences have been described between the active ferritin shock and the ferritin-antiferritin shock in guinea-pigs, which clinically appear as identical. The two processes can be differentiated from each other on the light microscopical level, but with particular clarity on the electron microscopical level. In contrast to the active ferritin shock, the guinea pigs in whom the ferritin-antiferritin shock had been produced showed agglomerates of platelets and ferritin-antiferritin complexes either present free in the dirculation or ingested in macrophages or granulocytes.


[The syndrome of multicystic dysplasia of the kidney, spleen and liver with multiple malformations]. A genealogic analysis carried out in a neonate suffering from multicystic dysplasia of kidneys, pancreas and liver indivated an autosomal recessive type of heredity. Associated malformations of extremities with heterotaxis were present in hitherto undescribed combinations.


[Recurrent polychondritis].

[Recurrent polychondritis]. Clinical and histological findings are presented as occurring in a male aged 24 years suffering from relapsing polychondritis (r. p.) of 7 years duration. The presenting symptoms were fever, ataxia, vertigo and vomiting. During the later relapses there also occurred episcleritis, paresis of the glottic muscle and hypertrophic bronchitis. At the age of 22 the patient had had a tracheostomy because of acute respiratory insufficiency. The patient has a typical saddle nose and drooping auricles. Tissues obtained from the auricles showed destructive alterations of the cartilage with fragmentation and homobenization of the elestic fibres. The perichondrium showed fibrosis and a massive round-celled inflammatory infiltration.


[Generalized varicella and herpes].

[Generalized varicella and herpes]. Generalized varicella was recognized as the cause of death in three children previously treated with corticoids, whereas generalized herpes simplex was the cause of death in one immature neonate. In all the cases the findings in internal organs were similar. They included disseminated necroses and mucous ulcers with a leucohistiocytic inflammatory reaction, karyorrhectic disintegration of nuclei and the presence of intranuclear inclusions of the Cowdry A type.


[Hepatic cholestasis].

[Hepatic cholestasis]. In a series of 212 liver biopsies which had been subjected to ultrastructural examination, the picture of cholestasis was encountered in 60 cases. In 32 cases it was associated with subhepatal obtruction. The reminder included hepatitis, hepatic fibrosis and cirrhosis and other diseases. Experiments in rats showed that the main findings following the ligature of choledochus included oedema and disintegration of mucosal microvilli in the bile ducts. Such changes preceded those of the hepatocytes. Simple overload by parenteral bilirubin did not evoke comparable changes. Therefore the mechanical disturbance of the epithelial wall of the bile ducts has been regarded as the basic changes subjected to later secondary modifications.


[IgA nephropathy].

[IgA nephropathy]. A series of 150 samples of renal tissue obtained by needle biopsy from patients with haematuria were examined immunohistologically. In 15 cases mesangial deposits of IgA were demonstrated. In most cases they were young patients in whom no hypertension, oedema or laboratory findings indicating renal damage could be detected one year later during a follow-up examination. Electron microscopical examination was carried out in the renal tissue of 7 such cases, and showed dense mesangial deposits and a marked subendothelial rarefaction within the basement membrane. The light microscopical findings were variable. Three cases showed minimal lesions, 5 mesangial proliferative glomerulonephritis and 7  mesangial proliferative glomerulonephritis with focal segmental sclerotic alterations within the glomeruli.


[Aneurysms of the fossae ovalis].

[Aneurysms of the fossae ovalis]. A series of 8 patients serve to demonstrate an ill-recognized entity, viz. the aneurysm of the oval fossa. The factors primarily responsible for the development of the aneurysm include a connective-tissue disturbance in the interatrial septum and an alteration of the pressure ratio between the atria. The possible clinical significance has been stressed.


[Periductal pigmentophages in the mammary gland]. The periductal spaces of mammary glands and, less frequently, the perivascular spaces and the interstitial and intralobular tissue contain cells with lipopigment granules in their cytoplasm, resembling ceroid or lipofuscin. In a series of 100 surgical biopsies of mammary glands obtained from females aged 19 to 80 years the concentration of such cells, their histochemistry and frequency as related to mammary dysplasias and mammary neoplasm were evaluated. The results were compared with those of Davies.


[Subendocardial cyst of the myocardium]. A small cyst lined with columnar ciliated epithelium was found under the endocarcium of the posterior wall of the left heart ventricle in a male aged 65 years. According to literary data, such cysts most probably originate from aberrant cell material descending from the primitive gut.


[Weight parameters of various internal organs]. The weight of some organs [brain, heart, lungs, kidneys, liver] was ascertained in a group of 1,598 persons who died a violent death, and a comparison was made with values obtained in a group of persons who died of cardiac insufficiency. The figures found were correlated according to sex with age, obesity, lipomatosis, physical size, the presence and stage of atherosclerosis. --Within the violent death group, a correlation was also made between a subgroup with minimal or no presence of atherosclerosis and one with ascertained atherosclerosis. The average weight of the brain was found to be 1419.6 g in men, 1266 g in women; the heart--394.7 or 343 g; kidney--149.0 g or 124.1 g; lungs 1280.0 or 973.4 g; liver--1770.9 g or 1522.0 g.


The relation between sodium transport and oxygen consumption in isolated perfused rat kidney. A non-filtering isolated perfused rat kidney model was developed to determine renal oxygen consumption in the absence of tubular reabsorption. The oxygen consumption in the absence of filtration was 3.1 +/- 0.8 micron of O2/min/g. This "basal" value was substantially higher than that of 2.0 micron of O2/min/g calculated by extrapolation of a plot of sodium reabsorption vs. oxygen consumption in filtering kidneys. It was also found that ouabain 10(-4) M decreased oxygen consumption in non-filtering kidneys and acetazolamide increased it in a dose dependent fashion. Furosemide did not change "basal" oxygen consumption. In filtering kidneys, the ratio of sodium reabsorbed to oxygen consumed averaged 36.8 muEq of Na/mumole of O2. It is concluded that basal oxygen consumption is not a fixed quantity and can be changed by experimental manipulations thereby changing the relation between transport activity and oxygen consumption.


Na+-electrochemical potential-mediated transport of D-glucose in renal brush border membrane vesicles. The uphill transport of D-glucose in renal brush border membrane vesicles was correlated with the Na+ electrochemical gradient. Each component of the electrochemical potential, the membrane potential or the Na+ chemical gradient, when assayed independently supported the concentrative uptake of the sugar. When the two components were combined the rates of D-glucose uptake were additive. Accumulation of D-glucose as a function of various Na+ gradients, in the absence of a membrane potential, suggests a 1:1 stoichiometry between sugar and Na+ uptake. These findings are consistent with the role of ionic gradients in energizing uphill solute transport and, thus, provide experimental evidence that extends the chemiosmotic theory to the Na+ electrochemical potential-mediated transport of D-glucose in mammalian tissues.


The role of oxidation in the renal metabolism of glutamine by rat kidney tubules in vitro. The metabolism of cold and 14C-[U]-glutamine in isolated kidney tubules of normal rats was studied in vitro to establish the relative importance of glucose synthesis and complete oxidation to CO2 for the metabolism of this amino acid in vitro. These metabolic fates were estimated by drawing a complete balance of the nitrogens and of the carbon chains of the extracted glutamine and studying the formation of 14CO2 from 14C-glutamine. It was found that glucose production constitutes the major fate for glutamine metabolism with 1 mM glutamine and that glutamine oxidation constitutes less than 20% of the metabolic fate of the carbon skeleton of this amino acid. With 5 or 10 mM glutamine however, the maximal oxidation to CO2 becomes more important (25%).


A comparative study of the renal glutaminase response to acidosis. The rates of ammonia excretion and the activities of renal glutaminase were measured in the rat, dog, guinea pig and chicken. The rate of ammonia excretion and the activity of renal glutaminase were less in guinea pig than in the other species. Renal glutaminase from all four species was activated by phosphate, but the degree of activation varied between species. Many organic acids activated renal glutaminase in the rat, dog and chicken, but these compounds were without affect or decreased glutaminase activity in the guinea pig. The optimal pH for renal glutaminase was 7.4, 8.0 and 8.8 for the guinea pig, rat and dog respectively, while in the chicken a plateau was reached between pH 7.5 and 9.5. The activation of renal glutaminase by phosphate in the chicken was greater at sub-optimal pH values than in the plateau region. In the absence of an activator acidosis did not affect glutaminase activity in any species. When phosphate was present in the incubation medium acidosis increased glutaminase activity in the rat and chicken, but did not alter enzyme activity in the guinea pig or dog. Acidosis did not affect the optimal pH or the shape of the activity versus pH curve in any of the species.


Regulation of phosphoenolpyruvate carboxykinase (GTP) synthesis in the kidney. Phosphoenolpyruvate carboxykinase activity increases in the kidney after glucocorticoid administration and in acidosis. In both cases, a selective stimulation of the synthesis of phosphoenolpyurvate carboxykinase can account for the augmentation of the enzyme level. Using an assay based on the translation of phosphoenolpyruvate carboxykinase mRNA in a heterologous cell-free protein synthesizing system, we show that the glucocorticoids and acidosis, acting by independent mechanisms, cause an increase in the level of functional mRNA coding for the enzyme of sufficient magnitude to explain the increase in the rate of enzyme synthesis.


Mechanism of carrier-mediated glutamine transport across the inner mitochondrial membrane. Mersalyl completely inhibits glutamine influx into kidney and liver mitochondria indicating clearly that this process requires the presence of functional thiol groups and probably a specific glutamine carrier. There is a close correlation between the transport of glutamine and the transport of inorganic phosphate. Glutamine crosses mitochondrial membrane as an electroneutral species driven by the concentration gradient. Proton gradient and membrane potential generated by the energization of kidney mitochondria stimulate the influx of glutamine. Glutaminase and glutamine carrier are probably distinct proteins.


Gluconeogenesis in kidney cortex slices of the guinea pig. Its relation to acidosis and to calcium. In contrast to rat kidney cortex the glucogenic capacity of kidney cortex slices from normally treated guinea pigs was very low. Reduction of the pH of the incubation medium by either lowering the HCO3-concentration or by increasing the pCO2 resulted only in varying stimulatory effects on glucose production from endogeneous or exogeneous sources. Considerable rates of net synthesis of glucose from lactate, pyruvate, malate, 2-oxoglutarate, glutamate, and glycerol--but not from glutamine--were only observed in kidneys from animals with prolonged metabolic acidosis. Neither in experiments with normally treated animals nor in those with acidotic guinea pigs the glucose production decreased, when calcium was omitted from the incubation medium. Though glutamine was not converted into glucose, it served as a substrate for ammoniagenesis. On the basis of the presented results it is concluded that species differences exist in the regulation of renal gluconeogenesis.


Quantitative studies of protein uptake in microperfused renal proximal tubules. Proximal convoluted tubules were microperfused with an iodine 125 egg-white-lysozyme containing perfusion solution. The intraluminal lysozyme concentration decreased about 10% per mm tubular length over a wide range of intraluminal lysozyme concentrations tested indicating a constant fractional reabsorption over a wide concentration range. Lysozyme reabsorption at a high intraluminal lysozyme concentration of 10 mg/ml indicated that the tubular protein uptake by endocytosis is a saturable process. High intraluminal concentrations of basic amino acids inhibited the cellular uptake of lysozyme, while neutral amino acids had no effect.


Effect of different preservation solutions and substrates on metabolic viability of kidney tubules. Glucose production, pyruvate uptake and lactate production were taken as metabolic viability tests for isolated rat kidney tubules preserved in hypothermia. The results depend on the type of preservation solution used. Species specific serum is the only solution sustaining cellular metabolism at a normal level. Using Collins solution all viability parameters showed the lowest results. Addition of certain substrates to the Krebs-Henseledt solution improves metabolic viability.


Renal cell metabolism in phosphate depletion: adenine nucleotide metabolism and gluconeogenesis. Effects of phosphate depletion (PD) in young rats on inorganic phosphate (Pi) and adenine nucleotide metabolism in kidney were examined to evaluate the role of altered adenine nucleotide metabolism in the pathogenesis of renal dysfunctions in PD. Despite a rapid fall in plasma pi, renal Pi and ATP levels did not fall until 2nd and 4th week, respectively. Concomitant with a fall in ATP, the equilibrium constant (Keq) of adenylate kinase decreased, suggesting an altered intracellular Mg ion concentration. The oral Mg supplement prevented a fall in plasma Mg occurring in PD as well as a fall in Keq of adenylate kinase without any effect on a decrease in tissue Pi and ATP. These data indicate that tissue levels of Pi and ATP did not fall until severe PF develops, and a concomitant Mg deficiency may play some role in the pathogenesis of some of the cellular dysfunctions seen in PD. Renal gluconeogenesis was inhibited in renal cortical tubules as early as on the 3rd day of PD. Although the mechanisms for such inhibition of gluconeogenesis are not known, this abnormal cell metabolism may underlie some of the tubular dysfunctions in PD.


Fatty acid transport and metabolism in the isolated perfused rat kidney. Transport and metabolism of endogenous fatty acids was studied using an isolated rat kidney preparation. Results tended to confirm the inhibitory effects of probenecid on fatty acid uptake by the kidney but, at the concentration used, probenecid was ineffective in changing the distribution of 14C palmitate within tissue lipids. Alpha-bromopalmitate (alphaBP) (0.4 mM), an inhibitor of fatty acid oxidation, caused an initial enhancement of 14C palmitate uptake, a decrease in esterification into tissue phospholipids and an increase in 14C recovered as free fatty acid in the tissue. This increase had no inhibitory effect on entry of fatty acids. alpha BP had no effect on 14C octanoate uptake and appeared not to affect general metabolism. The results are consistent with the possibility that alphaBP interacts with a renal fatty acid binding protein.


Relationship between the renal metabolism of glutamine, fatty acids and ketone bodies. Using renal cortical slices from acidotic and normal dogs we show that fatty acids such as crotonate, octanoate, palmitate and oleate as well as ketone bodies (beta-hydroxybutyrate and acetoacetate) in concentrations ranging from 0.5 to 5.0 mM induce a 30 to 50% decrease in glutamine uptake and ammonia production when glutamine (1 mM) is used as the basic substrate. Glucose production also decreases by 20 to 30%. Glutamate release in the incubation medium is significantly augmented by fatty acids or ketones. When glutamate 5 mM is used as substrate instead of glutamine, glutamate uptake, ammoniagenesis and glucose production are significantly depressed by fatty acids and ketones. Increased glutamate release from glutamine, decreased glutamate uptake and decreased gluconeogenesis from glutamine or glutamate provide evidence that ketone bodies and fatty acids depress the net flux through the glutamate dehydrogenase reaction invovled in glutamine metabolism. This is further supported by the fact that addition of ketones to alpha-ketoglutarate and ammonia stimulates net glutamate synthesis by kidney tubules.


On the renal balances for different lipid fractions in dog. (1) Six dogs were kept fasting for 12 h and the uptake or release of various lipid fractions by the kidney was determined. (2) Free and esterified fatty acids were generally taken up during the fasting state. More fatty acids were taken up than could be oxidized with respect to the normal oxygen consumption of the kidney. (3) When glucose was infused a release of fatty acids was observed in general. (4) The critical role of endogenous fatty acids for the energy metabolism of the kidney is pointed out.


Comparison of the oxidation rates of glucose and lactate in relation to support of Na+ reabsorption. The renal oxidation rates of glucose and lactate in the dog in vivo, in the dog cortical slice and in the isolated perfused rat kidney were compared. Lactate decarboxylation rate, on a carbon-atom basis, was from 2 to 10 fold greater than that of glucose. In the substrate-limited perfused kidney, glucose replaced only 30-40% of the substrates oxidized in vivo, while lactate replaced up to 80% of the substrates oxidized in vivo. Insulin lack does not account for these differences in the rates of lactate and glucose oxidation. Glucose and lactate support GFR and Na+ reabsorption to approximately the same extent in spite of their different rates of oxidation. Thus Na+ reabsorptive rate: CO2 production rate is not a constant and depends on the substrate being oxidized. The virtual absence of glucose oxidation by the dog cortical slice suggests either that: 1) glucose oxidation supports primarily medullary Na+ reabsorption while lactate oxidation supports cortical Na+ reabsorption as well of 2) glucose oxidation is more selectively coupled to Na+ reabsorptive work than is lactate oxidation.


Ultrastructural characterization of the connecting tubule and the different segments of the collecting duct system in the rabbit kidney. In the rabbit kidney, the connecting tubule is a clearly delimited tubular portion interposed between the convoluted part of the distal tubule and the cortical collecting duct. Superficial nephrons have individual connecting tubules; the connecting tubules of deeper nephrons fuse together to form a so-called arcade. The collecting duct is subdivided, with respect to localization, into cortical, outer medullary and inner medullary collecting duct. Connecting tubule and collecting duct are lined by a total of three different cell types: the connecting tubule by the connecting tubule cell and the intercalated cell; the collecting duct by the principal cell and the intercalated cell present only in the cortical and outer medullary segment. The intercalated cell can have different manifestations ("gray", "black", and "light"). The principal cell undergoes gradual alterations from a very complicatedly organized prismatic cell (approximately 7.5 micron cellular height) in the cortical collecting duct to a very simply organized, high prismatic cell (approximately 75 micron cellular height) in the inner medullary collecting duct.


Cytotoxic effects of emetine hydrochloride in the kidney of Long-Evans rats. Emetine hydrochloride has been used to study its effects in the rat kidney, Sublethal doses of the drug at 10.0 mg/kg body weight of the animal were administered at 12 and 24 h intervals. Certain morphological changes occurred within the kidney. These changes involved the formation of vacuoles, swelling of mitochondria, disruption of basal membranes, deterioration of red blood cells, production of convoluted membranes and fibril-like structures. The earliest changes were observed 12 h after treatment with the drug.


Kidney microvillus peptidases--are they transmembrane proteins? The membrane of kidney microvilli is richly endowed with peptidases. Present information is that there are at least eight examples located in this membrane. Three of the group are known to be among the major proteins that can be identified by dodecyl sulphate electrophoresis of the purified microvillus fraction. These three peptidases, aminopeptidase M, serine peptidase (dipeptidyl peptidase IV) and neutral endopeptidase can be labelled by lactoperoxidase iodination from either the luminal or the inner surfaces of the membrane, a result consistent with the view that the polypeptide chains span the microvillus membrane. The serine peptidase has been purified by two methods, permitting a comparison of the detergent-released and proteinase-released forms. The two forms differ in the presence and absence of the hydrophobic anchor that secures the enzyme to the membrane. Preliminary studies support the view that this hydrophobic domain is relatively small and that it includes the N-terminal region of the polypeptide chain.


Chromatin ultrastructure changes during spermatogenesis in armadillos. The chromatin fibres of the male gamete nucleus of Dasypus novemcinctus contain fibrils. Measurements indicate that the chromatin fibre diameter and the number of fibrils within the fibre increase, whereas the diameter of the fibrils decreases during spermiogenesis. It is suggested that the fibrils represent a DNA-protein complex. It is further suggested that the increased fibre diameter, and the increased number of fibrils correlates with the formation of larger fibres during the condensation of the spermatid nucleus, whereas the decrease in fibril diameter is correlated with the replacement of histones with new low molecular weight acid-soluble proteins.


Restoration of the phosphaturic effect of parathyroid hormone in lithium-treated rats. The purpose of this study was to clarify the means by which lithium induced a greatly diminished phosphaturic response to parathyroid hormone (PTH). Acutely thyroparathyroidectomized lithium-treated rats did not respond to PTH whereas similarly prepared animals in the presence of metabolic or respiratory acidosis exhibited a large phosphaturic response. Respiratory alkalosis significantly decreased fractional phosphate excretion and blocked the phosphaturic effect of PTH whereas PTH induced increases in cyclic AMP excretion in these animals. Lithium increased urinary excretion of oxoglutarate and citrate. In metabolic acidosis the restoration of PTH-dependent phosphaturia is accompanied by decreased organic acid excretion. No significant decrease of urinary citrate and oxoglutarate excretion occurred in respiratory acidosis in lithium-treated rats. It is suggested that PTH-dependent phosphate transport is mediated by intracellular pH but the increased excretion of citrate and oxoglutarate may reflect high intracellular levels of bicarbonate.


Glucagon induced functional changes of isolated perfused rat kidney. The influence of glucagon on renal function and hemodynamics was studied on isolated perfused rat kidneys. During perfusion with solutions containing no vasoactive substances glucagon increased total renal perfusion flow, while the GFR remained unchanged. The autoregulation of blood flow under these conditions was completely abolished. Na-excretion was slightly reduced under the action of glucagon, due to an increased fractional Na-reabsorption. However, increased fractional Na-reabsorption was not due to a direct influence of glucagon on tubular transport mechanism as comparison of TNa at identical Na-loads demonstrated. In presence of angiotensin II renal perfusion flow was markedly reduced and doubled almost after starting glucagon infusion. GFR under these conditions rose by about 100%. It is concluded from the results that changes of kidney function following glucagon infusion are mainly due to a reduced vascular resistance.


Chromatin fibre differences between condensed and dispersed chromatin: a comparative ultrastructure study. Cells of different types from different species were investigated to determine if there are significant variations between chromatin fibre measurements in electron micrographs of thin sections. A larger chromatin fibre of 20 plus nm is seen in both condensed chromatin and dispersed chromatin and contains an irregularly folded or coiled fibril of 2.1 to 3.7 nm. In all cell types the larger fibre of dispersed chromatin was significantly thicker than the larger fibre of condensed chromatin. Numerous significant differences were also found between chromatin measurements of the different species. The ultrastructural differences may help explain the functional differences already known to exist between dispersed and condensed chromatin.


Kidney as a site of uptake and metabolism of gamma-glutamyl compounds. gamma-Glutamyl derivatives of amino acids are extensively metabolized and accumulated in the kidney. The kideny also has a high capacity to synthesize ophthalmic acid, an analog of glutathione. These processes can be attributed to the high activity in the kidney of enzymes that both degrade and synthesize glutathione. Th possibility of using the gamma-glutamyl group as a carrier for the introduction of compounds containing an amino function into kidney metabolism was explored. Administration of L-gamma-glutamyl-L-3,4-di-hydroxyphenylalanine (gamma-glutamyl-DOPA) to rats led to the accumulation of gamma-glutamyl-DOPA in the kidney, release of DOPA and its conversion to dopamine by the action of aromatic amino acid decarboxylase. Dopamine actively generated in the kidney increased renal plasma flow and sodium excretion. No systemic effects or untoward reactions attributable to this amine were observed. It is suggested that gamma-glutamyl derivatives of certain drugs may be useful as kidney specific prodrugs.


The degradation of glutathione derivatives in the rat kidney. Single proximal rat kidney tubules and Henle loops were microperfused with labelled S-substituted glutathione derivatives which are physiological mercapturic acid precursors. S-methyl-glutathione as well as the non-permeating bromo-sulfaleinglutathione adduct were degraded in the proximal convolution with a half-life of about 3.5 sec. The findings demonstrate that the brush-border membrane-bound renal gamma-glutamyl transpeptidase acts on luminal substrates and is involved in mercapturic acid synthesis and splitting of extracellular glutathione.


Different hormonal target sites along the mouse and rabbit nephrons. Adenylate-cyclase (AC) activity measurements were performed in the different segments of the mouse nephron. It was found that: --the medullary portion of the thick ascending limb is sensitive to AVP alone. --Three hormones, parathyroid hormone, calcitonin and isoproterenol, stimulate the enzyme activity located in the "bright" and "granular" portions of the distal convoluted tubule. The "granular" portion is, in addition, sensitive to AVP. --a single type of collecting tubules is present and every distal convoluted tubule is connected to it. In the cortex, this collecting segment is sensitive to AVP, calcitonin and isoproterenol. In the medulla, it is sensitive to AVP alone. The enzyme sensitivity to hormones was found in the mouse to be different from that previously described in the rabbit; this is particularly true for the distal segments of the nephron. Thus, hormonal segmentation and more over, regulation of physiological function may be different from one species to another.


Combination chemotherapy for solid tumors using 5-fluorouracil, chromomycin-A, and prednisolone. Clinical effect of 5-fluorouracil or chromomycin-A3 alone, 5-fluorouracil + chromomycin-A3, and of the first two plus prednisolone on gastrointestinal and other solid tumors was evaluated. Out of 133 cases acceptable for evaluation, the number of responders was as follows: 3 (18.8%) of 6 cases treated with 5-fluorouracil alone, 1 (9.1%) of 11 cases treated with chromomycin-A3 or chromomycin-A3 hemisuccinate, 13 (21.7%) of 60 cases on the two-drug regimen, and 21 (45.7%) of 46 cases on the three-drug regimen. In cases of stomach carcinoma, response rate to the three-drug regimen was 54.2% (13/24), significantly higher than that of other regimens. At least 25% regression in the size of primary tumor was observed in 2 (7.1%) of 28 cases on the two-drug regimen and in 6 (33.3%) of 18 cases on the three-drug regimen. Of 51 cases on the three-drug regimen, steroid diabetes developed in 5 cases, moon face in 4 cases, and gastric ulcer in 1 case. However, toxic effect of these regimens (especially appearance of leucopenia) was less than those of previously tried combined regimens. The duration of response, on an average, was 10.8 weeks in 13 cases on the two-drug regimen and 11.7 weeks in 21 cases on the three-drug regimen. It was concluded from these results that a better response is obtained by the three-drug regimen than other regimens, and that prednisolone in combination, in addition to its favorable effect in improving the general condition of the patients, might enhance the anticancer effect of the drugs used in combination.


Antitumor activity of macrophages induced by Corynebacterium liquefaciens. Corynebacterium liquefaciens can induce a marked resistance to tumor cell (AH-7974) challenge in Donryu rats. This effect was also induced in T-cell-deficient athymic nude mice. The macrophages harvested from the peritoneal cavity of a rat injected with C. liquefaciens showed a marked inhibition of tumor growth in vitro. Therefore, the effector cells were assumed to be peritoneal macrophages. The time needed for activation of macrophages in vivo was within 3 to 5 days after injection of C. liquefaciens. Before or after this period, the peritoneal macrophages did not inhibit tumor cell proliferation. Furthermore, normal peritoneal macrophages were activated in vitro by C. liquefaciens and displayed remarkable antitumor activity. These results suggest that C. liquefaciens rendered the macrophages inhibitory to tumor cells even under T-cell depleted condition. On the other hand, in vitro antitumor activity of the activated macrophages disappeared completely after in vivo treatment of the peritoneal cavity of a rat with Trypan Blue, a lysosomal enzyme blocker. Resistance of the rat induced by C. liquefaciens to tumor cells was also abrogated by Trypan Blue treatment just 1 day before tumor cell inoculation. Trypan Blue blocked the acid-phosphatase (a marker enzyme of lysosomes) activity of the activated macrophages but it seemed not to affect other macrophage activities, at least in the following two points; normal macrophages treated with Trypan Blue had almost normal phogocytic function of India ink particles and, moreover, they could be rendered tumoricidal, same as normal macrophages, in vitro by C. liquefaciens.


Interaction of antitumor agents including doxorubicin or daunorubicin in sarcoma-180 system. Combination effect of antitumor agents, including doxorubicin and daunorubicin, was evaluated on the concept of pharmacological synergism in ascites sarcoma-180 system. In alternate adminsitration, combinations of doxorubicin plus cyclophosphamide, thio-TEPA, carboquone, actinomycin-D, vinblastine, vincristine, methotrexate, cytarabine, 6-mercaptopurine, or L-asparaginase showed synergism, but in simultaneous one, only three agents, cyclophosphamide, carboquone, and cytarabine, were synergistic. On the other hand, combination of daunorubicin plus one of 8 agents (thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, vinblastine, ancytabine, 6-mercaptopurine, and L-asparaginase) and 6 agents (cyclophosphamide, thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, and vinblastine) provided synergism in alternate and simultaneous administration. Combination effect of agents was affected by the schedule of drug administration for doxorubicin, but weak for daunorubicin. Toxicity of doxorubicin or daunorubicin in combination with other drugs was also affected by the schedule of administration. Combination of a larger number of agents in simultaneous administration provided antagonism compared with an alternate administration.


Carcinogenicity of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2) fed to female Sprague-Dawley rats. The carcinogenicity of 2-(2-furyl)-3-(5-nitro-5-furyl)acrylamide (AF-2) was investigated by administering it orally to Sprague-Dawley female weanling rats in a grain diet at a dose of 0.2% for 46 weeks, followed by 20 weeks of unmedicated control diet. The total mean cumulative dose of AF-2 was 10.1 g (41.6 mmol) per rat during the 46 weeks of the experiment. Weight gains of rats fed AF-2 was comparable to that of unmedicated control rats. Survival of rats fed AF-2 was 52 +/- 12 (SD) weeds compared to 65 +/- 5 weeks for the unmedicated controls (P less than 0.001). Twenty-four of 29 rats fed AF-2 developed multiple breast tumors, 15 of which were adenocarcinomas. Two of 29 unmedicated control rats had single fibroadenomas of the breast.


Rebound phenomenon of phytohemagglutinin skin reactivity in leukemia and malignant lymphoma after chemotherapy. Serial evaluation of host immunocompetence was made by the phytohemagglutinin (PHA) skin test in 13 patients with leukemia and malignant lymphoma, receiving antineoplastic chemotherapy to induce remission. A rebound phenomenon of skin reactivity to PHA was observed after each period of chemotherapeutic treatment in patients with a good response to therapy, but not in patients with a poor prognosis. It is concluded that sequential evaluation of skin reactivity to PHA, as well as in vitro lymphocyte stimulation, is valuable clinically in assessing the progress of malignancies and the response of patients to therapy.


Induction of tumors of peripheral nervous system in female Donryu rats by continuous oral administration of 1-methyl-1-nitrosourea. Groups 1, 2, and 3 of female Donryu rats were given continuously 400, 200, or 100 ppm solution of 1-methyl-1-nitrosourea (MNU) as their drinking water. The incidence of neurogenic tumors was 12/27 (44%), 39/33 (91%), and 33/36 (92%) in Groups 1, 2, and 3, respectively. Among the neurogenic tumors, neurinomas developing from the spinal nerve roots were the most frequent. In addition, tumors of the digestive tract were found in 12, 1, and 2 rats in Groups 1, 2, and 3, respectively, and tumors in hematopoietic tissues developed in 6 rats. Tumors in other organs were infrequent.


Effect of drying with hot forced draft and of mincing bracken fern on its carcinogenic activity. The carcinogenic activity of young bracken dried at a high temperature or minced by a mechanical chopper was compared with that of unprocessed bracken dried at room temperature. Inbred strain ACI rats of both sexes were divided into 4 groups; Group 1 received a diet containing the unprocessed bracken dried at a room temperature of below 30 degrees, Group 2 received a diet containing bracken dried at 70 approximately 90 degrees with a hot, forced draft, and Group 3 received the diet containing processed bracken that had been minced to a paste-like consistency using a mechanical chopper. The control group was fed a normal diet. Rats fed a bracken-containing diet developed tumors most frequently in the ileum. Comparison of Group 1 with Groups 2 and 3 showed no significant difference in the latent period, incidence, histologic types, or multiplicity of the intestinal tumors found in each animal.


Experimental autologous transplantation of the knee joint: contributions of microvascular surgery (a preliminary report). Free autologous transplantations of joints can be successfully performed, if careful microsurgical techniques are used. We have carried out autologous exchange transplants of the knee in 28 cats, anastomosing the vessels supplying the knee on one side and leaving the other side with no anastomosis as a control. The operational procedures and the general anaesthesia require special precautions. The permeability of a vascular anastomosis can be judged with scintigraphic and arteriographic techniques. The vascularization and bone remodeling as measured scintigraphically are in direct relation to the blood supply of the operated knee joints. Histological examinations have confirmed the clinical and radiographic findings.


High tibial osteotomy in osteoarthrosis of the knee (a long term clinical study of 187 knees). This is a clinical research study of 415 cases of high tibial osteotomy in arthrosis of the knee, supported by radiographic and aetiopathogenetic data. It is the largest series with complete documentation so far reported in the literature. It is a critical study based on the clinical findings which marks the beginning of a work intended to evaluate the quality of the results during a period of 5-15 years following surgery (187 knees). The results so far confirm the value of the procedure and emphasize the importance of the fixed flexion factor in the probable pathogenesis of pain. It also shows that perfect axial reconstruction in the frontal plane is of lesser comparative importance.


Surgical treatment of congenital radial clubhand. In choosing the surgical method of correction of radial clubhand, one must take into consideration the age of the patient, the anatomical, radiographic and pathological alterations, and lastly the function of the homolateral elbow. Angiographic studies of the malformation have proved of value in revealing the possible coexistence of a normal vascular bed with hypogenesis of the radius. The esthetic and functional results obtained with two different surgical techniques, and followed up over the years, are reported in a fifteen year old boy and an eight year old girl.


Delayed closed endomedullary osteosynthesis in complicated fractures of the femur and tibia. The results obtained with delayed closed endomedullary osteosynthesis in 230 cases are considered. This method greatly extends the use of endomedullary nailing to open fractures and those in which controindications of a mechanical nature (multiple fractures, or at several levels) rule out the immediate use of implants. The techniques proposed (osteosynthesis with triflanged nail in fractures of the diaphysis and osteosynthesis with double Rush nails in metaphysio-diaphysis fractures) have two advantages. Due to the non opening of the fracture focus there is minimal risk of infection and early restoration of function.


Techniques of osteosynthesis of pathological fractures due to skeletal metastases. In using internal fixation in the treatment of fractures due to skeletal metastases the objective is to obtain rapid rehabilitation of the patient. The fixation must therefore be particularly stable and it is consequently often necessary to use acrylic cement. This treatment aims to alleviate pain, to shorten the time spent in hospital, and to restore the patient, as far as possible, to his social background, so alleviating the psychological suffering that complicates such disease states. The elective techniques for the various skeletal segments affected are reported, based on 64 cases of osteosynthesis and 26 prosthetic substitutions.


Surgery for the post-cricoid carcinoma. Report on 23 cases in which replacement by stomach was attempted. A report on 23 cases of post-cricoid carcinoma treated by pharyngolaryngectomy and pharyngogastric anastomosis. The results, complications, and causes of death are reported. The series showed that, when the tumor recurred it was in the regional lymph nodes and in only one case was the primary site involved. Metastasis occurred elsewhere only after regional node involvement.


Pseudohypertelorism and its implications in the treatment of facial fractures. The traumatic displacement of the medial canthal ligament results in telecanthus which produces the clinical appearance of pseudohypertelorism. Early recognition of this injury is imperative so that repair is carried out in the acute stage. Because of close anatomical relationships medial canthal injuries are associated with disruptions of the lacrimal system which must be recognized and repaired at the same time.


Rehabilitative treatment of hearing-impaired children. The prevalence of hearing impairment and the educational effects of untreated hearing problems are described and the conditions required for verbal learning among severely and profoundly hearing-impaired children are outlined. Results of a longitudinal study undertaken at McGill University are briefly presented and the spoken language skills acquired by profoundly hearing-impaired children enrolled in this study are discussed.


Ménière's disease associated with serous retinopathy. A case history is presented of a patient suffering from classical Ménière's disease who concurrently developed central serous retinopathy. On review, these conditions are found to have several features in common and on the basis of the changes seen by fluorescein angiography in the eye, an hypothesis is presented for the development of endolymphatic hydrops.


[Basilar migraine].

[Basilar migraine]. Basilar migraine has been studied by Bickerstaff who considers that there is a vasoconstriction in the basilar territory resulting in transient ischemia with the corresponding neurological symptoms including vertigo, and followed by the vasodilatation causing the headache. Three cases, treated in neurology, have had an audiovestibular investigation with an E.N.G. and an audiogram and are described herein. Nystagmus and hearing loss have been observed in one of these cases and it is suggested that the internal auditory artery participates in the basilar migrainous processes. The diagnosis of basilar migraine is impossible to prove and the investigation is very limited. Finally it is the evolution of the patient which helps in establishing the diagnosis of basilar migraine.


Corrosion casts of the temporal bone.

Corrosion casts of the temporal bone. This paper compares the size of the bony labyrinth in infants to that in adults. Fusible metal was injected in dried temporal bones and after the overlying bone was removed by dissolving in weak acid, the semicircular canals and cochlea were measured and compared. A summary of the method of preparation is also included.


Reconstitution of D-glucose transport in vesicles composed of lipids and intrinsic protein (zone 4.5) of the human erythrocyte membrane. Elucidation of the mechanism of facilitated D-glucose transport in human erythrocytes is dependent on the identification and isolation of the membrane protein(s) mediating this process. Based on the fact that stereospecific D-glucose transport is reconstituted in liposomes prepared by sonication of a lipid suspension with ghosts or fractions derived from ghosts, a quantitative assay for the stereospecific D-glucose transport activity of these fractions was developed (Zala CA, Kahlenberg A: Biochem Biophys Res Commun 72:866, 1976). This assay was used to monitor the purification of ghosts. The solubilized membrane protein fraction was chromatographed on a column of diethylaminoethyl cellulose which was eluted stepwise with NaCl-phosphate buffers of increasing ionic strength. A fraction, eluted at an ionic strength of 0.1, displayed a 13- and 27-fold increase in reconstituted transport activity relative to ghosts and to the unfractionated Triton X-100 extract, respectively. This fraction, when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, consisted predominantly of the ghost proteins with an apparent molecular weight of 55,000, commonly designated as zone 4.5; periodic acid-Schiff-sensitive membrane glycoproteins 1-4 were absent. Transport reconstituted by this preparation of zone 4.5 membrane proteins was almost completely abolished by 1-fluoro-2,4-dinitrobenzene, mercuric chloride, and p-chloromercuribenzene sulfonate, but was unaffected by sodium iodoacetate. Extra- and intraliposomal phloretin and cytochalasin B, respectively, exhibited partial inhibition. The stereospecificity and inhibition characteristics of the reconstituted transport imply that all the components of the erythrocyte D-glucose transport system are contained in the zone 4.5 membrane protein preparation.


Cell surface changes accompanying myoblast differentiation. Myoblasts are mononucleated cells and associated with differentiation undergo cell fusion and become multinucleated. The current studies have examined cell surface dynamic changes of Concanavalin A lectin receptor mobility and the role of hormones in modulating myoblast differentiation. A uniform distribution of Con-A receptors is observed in undifferentiated cells when reacted with Con-A at 37 degrees C. Cells from differentiating cultures or fully differentiated myotubes reacted similarly at 37 degrees C show a significant redistribution of Con-A into patches, "caps," and endocytic vesicles containing Con-A. If undifferentiated and differentiated cells are first prefixed with glutaraldehyde then reacted with Con-A continuous distribution of Con-A is seen across the cell surface. This suggests redistribution of Con-A and its receptors occurs in differentiated cells reacted with lectin at 37 degrees C. It is further shown that insulin (10 microgram/ml) significantly enhances myoblast differentiation but that this occurs after an apparent stimulation of proliferation. In contrast to insulin, dexamethasone (10 micron and 100 micron) profoundly inhibits myoblast differentiation while having different effects on proliferation; 10 micron dex stimulates cell growth while 100 micron dex suppresses cell proliferation. Lastly, an extracellular filamentous matrix which binds Con-A is observed at the ultrastructural level in high density cultures. No significant redistribution of Con-A is observed on this matrix in distinction to the redistribution observed on the cell membrane in differentiated cells.


Comparison of the carbohydrate of Sinbis virus glycoproteins with the carbohydrate of host glycoproteins. The carbohydrate portions of the Sindbis virus glycoproteins were compared with the carbohydrate portions of cell surface glycoproteins from uninfected host cells. Comparisons of the size of glycopeptides were made using gel filtrations. Comparisons of sugar linkages were made by methylation analysis. The conclusion was that the Sindbis carbohydrate is similar to a portion of the host carbohydrate. Thus, the Sindbis carbohydrate structures appear to be structures normally made in the uninfected host cell, but which are added to the Sindbis glycoproteins in virus-infected cells.


The biosynthesis of mannolipids and mannose-containing complex glycans by the retina. Large-scale incubations were carried out with homogenates of the retinas of the 15--16-day-old chick embryo in the presence of GDP[U-14C] mannose, from which there were isolated mannolipid (Lipid I), oligosaccharide-lipids (Lipid II), and glycoprotein (residue). These incubations were performed in the presence of endogenous acceptors as well as dolichyl phosphate. [14C] Mannolipid I was subjected to chromatography on DEAE cellulose and silicic acid. The response to these, as well as TLC, enzymatic, and chemical treatments, were consistent with the product being dolichyl phosphomannose. [14C] Lipid II was purified by DEAE cellulose chromatography and gel filtration on LH-20. Responses to these treatments, as well as TLC and paper chromatography, were consistent with this product being of the class of the oligosaccharide-pyrophosphate-lipids. The residue remaining after removal of the lipids was shown to contain glycoproteins by conversion of high-molecular-weight radioactive material to low-molecular-weight [14C] mannose-containing glycopeptides by the action of pronase. These reactions and their products are consistent with there being in the retina, the pathway for glycoprotein synthesis involving the participation of the lipid-activated carbohydrates. When the incubations were performed in the presence of ATP or ADP there was a decrease in the labeling of Lipid I, accompanied by an increase in the labeling of Lipid II and glycoprotein. When incubated in the presence of dolichyl phosphate and detergent, however, the stimulatory effect of ATP did not occur. The effect on these activities of a variety of other nucleotide phosphates was also examined.


Synthesis, secretion, and attachment of LETS glycoprotein in normal and transformed cells. LETS glycoprotein is a surface glycoprotein which is absent or greatly diminished on the surfaces of transformed cells. Normal cells secrete large amounts of this protein into the medium; transformed cell medium contains much less. The difference is not due to degradation of the soluble LETS protein. Biosynthesis of LETS protein can be studied by analysis of cell extracts by detergent extraction and immune precipitation and appears to proceed in transformed cells at a reduced rate compared with normal cells. Addition of inhibitors of protein synthesis to transformed cell cultures causes the small amount of LETS protein in the medium to attach to the cells. Addition of normal conditioned medium, which contains LETS protein, to transformed cells alters their morphology towards normal. Addition of purified LETS protein to transformed cells causes the cells to attach, spread, align with one another, and regain actin cables. The results indicate that LETS protein can exchange between cell surface and medium and that it affects cellular adhesion, morphology, and cytoskeleton.


The turnover of a tissue specific cell surface ligand which inhibits lectin induced capping. Ten-day-old embryonic chick neural retina release into the environment glycoprotein ligands which bind to homologous cells, inhibiting the lectin-induced redistribution of cell surface receptors. Material with identical activity is released from trypsin-dissociated neural retina cells that are allowed to repair in culture for 2 h and are then transferred to fresh medium. Release of ligand is inhibited by cytosine arabinoside, hydroxyurea, UDP, and EDTA, and is potentiated by MnCl2. These data suggest that a glycosyltransferase reaction plays a critical role in the turnover of the cell surface ligand. Reactivation of enzymatically deglycosylated ligand solutions by intact cells provides further support for this hypothesis. Release of ligand is also accompanied by a loss of the agglutinability of the cells by a tissue-specific component which accumulates in monolayer conditioned medium. Conditions which inhibit release maintain maximal agglutinability suggesting similar mechanisms mediate both processes.


An electron microscopic and enzymic study of rat liver peroxisomal nucleoid core and its association with urate oxidase. The appearance of the characteristic crystalloid core of rat liver peroxisomes is emulated by the electron microscopic (EM) appearance of highly purified urate oxidase prepared from the same tissue. The purity of the enzyme preparation was established by gel electrophoresis under various conditions and the specific enzyme activity was at least as high as any previously reported. The amino acid composition of urate oxidase was determined. As additional evidence for close association of the peroxisomal core with urate oxidase, it was demonstrated that the biphasic changes in rat liver urate oxidase activity in response to prolonged starvation were paralleled by changes in the EM appearance of peroxisomes. Under comparable conditions catalase, another peroxisomal enzyme, did not show the same changes in activity as did urate oxidase. Evidence for the possible identity of urate oxidase with the peroxisomal crystalloid of rat liver has been presented, all materials having been obtained from, and experiments performed with, the rat.


The structure of intrinsic membrane proteins. Intrinsic membrane proteins are embedded in the lipid bilayer so that the polypeptides come in contact with the non-polar region of the bilayer. There are two major types of intrinsic proteins: those with most of their mass outside the cytoplasm (Type I) and those with most of their mass inside the cytoplasm (Type II). In the latter group are the membrane transport systems. The anion exchange system of the human erythrocyte is a dimer of band 3 polypeptides. These polypeptides span the bilary, have most of their mass in the cytoplasm, and are glycosylated. About 20-25% of the polypeptide, however, is in the bilayer. Arguments are presented to support the view that the intramembrane segments of the protein are alpha-helical and that the major protein-protein interactions between the subunits are in the cytoplasmic portion of the protein.


Regulation of glucose carriers in chick fibroblasts. The derepression of glucose transport initiated by removing glucose from the incubation medium requires both protein and RNA synthesis. The synthesis and accumulation of putative mRNA for the carrier protein(s) can be demonstrated by inhibiting protein synthesis with cycloheximide (2 microgram/ml). Release from inhibition with simultaneous addition of actinomycin D (1-5 microgram/ml) results in a burst of carrier synthesis that achieves virtually maximal derepression in 4-6 h. An external energy source provided by a "nonrepressive" sugar (D-fructose, D-xylose) or by pyruvate is required to accomplish carrier synthesis. Previous failure to demonstrate mRNA accumulation was due to the depletion of energy in the starved cells. Glucose acts as a repressor at a posttranscriptional step, probably at the level of turnover of formed carrier. The protection of formed carrier in the absence of glucose and by inhibitors of protein synthesis even in the presence of glucose has encouraged conjecture that a protease is activated by a metabolic product of glucose that is analogous to a corepressor. The glucose metabolite either activates the protease by direct interaction with it or alters the conformation of the carrier to expose a critical region to protease attack. Indeed the regulation of carrier density in the membrane of chick fibroblasts may be achieved entirely by carrier inactivation, the rate of which is a function of glucose concentration in the culture medium.


The area-code hypothesis: the immune system provides clues to understanding the genetic and molecular basis of cell recognition during development. Numberous studies of embryogenesis have provided evidence for highly specific cell-surface recognition phenomena. These include both the interactions of neighboring cells and the specific cellular migrations which occur as the developmental program of the embryo progresses. The area-code hypothesis elaborate here is an attempt to provide a framework for understanding cell-recognition phenomena in development. This hypothesis is based on extensive genetic, molecular, and cellular studies of the immune system. These studies suggest that the following events occur during the differentiation of antibody-producing cells. 1) Somatic cell lines of antibody-producing cells undergo a modification of their DNA as they become committed to synthesize a particular type of antibody molecule. This chromosomal modification event is probably a DNA translocation which leads to a somatic rearrangement of certain antibody genes. 2) In each of the specific cell lineages the new arrangement of DNA is inherited by all subsequent generations of cells. 3) The developmental programs which control these genetic alterations may be employed in a programmed and reproducible fashion. This programming of antibody development is suggested because different embryos appear to become committed to the production of identical antibody molecules in the same developmental sequence. 4) Antibody molecules are initially displayed on the cell surface where they serve as highly specifici receptors to trigger the cell to proliferate and differentiate upon interacting with appropriate external molecular signals. 5) Antibody-producing cells display combinations of different molecules on their surfaces which cause each of a very large number of different cells to interact differently with their environment. 6) The genes which code for many of these cell-surface molecules are organized into multigene families. These observations as well as information from other developmental systems have led us to propose the area-code hypothesis. This hypothesis is concerned with the structure, function, and regulation of cell-surface molecules that mediate recognition phenomena during embryogenesis. Area-code molecules are cell-surface molecules which are involved in the specific recognition phenomena during growth and development. These molecules provide cells with distinct cell-surface addresses or phenotypes, and provide the basis for the specificity in cell-cell recognition during cell migrations and cell-cell interactions, as well as serving as receptors for diffusible differentiation signals. The area-code hypothesis has 3 main postulates. i) There is a progressive display of specific combinations of area-code molecules on the surfaces of cells during development. ii) The genetic programs which determine the specific expression of area-code molecules are in part controlled by DNA modifications. These chromosomal modifications are believed to channel cells into specific lineages uith progressively restricted developmental options...


Effects of addition of chloramphenicol on the growth and ultrastructure of Streptomyces venezuelae. The effects of adding chloramphenicol before inoculation and during exponential growth of Streptomyces venezuelae (3022a) in fermentors were studied. The responses of the organism during synthesis of chloramphenicol (in a glycerol-serine-lactate medium) were compared with those in media supporting less (glycerol-nutrient broth-yeast extract) or no synthesis (glucosemineral salts). In systems where little or no synthesis of the chloramphenicol occurred, addition of the antibiotic induced micromorphological and ultrastructural abnormalities similar to those reported for sensitive bacteria. There was also an increase in the frequency of mesosomes and electron-light areas. It was suggested that the former may be associated with activity of chloramphenicol hydrolase and the latter with storage and/or excretion of the breakdown product; N-acetyl p-nitro-phenylserinol. When chloramphenicol synthesis occurred, addition of the antibiotic had less effect on the micromorphology or ultrastructure of S. venezuelae as permeability barriers to external chloramphenicol had been established. Electron-light areas were frequent, possibly being associated with storage and excretion of precursors of chloramphenicol.


Spatial and visuomotor performance with agenesis of the corpus callosum. The extent to which the cerebral hemispheres and their ipsilateral projection systems compensate for congenital absence of the corpus callosum was studied in an intelligent young adult with radiologically verified total agenesis. She was found to have bilateral speech and the ability to readily integrate visual, tactile, and verbal information simultaneously presented to both hemispheres. However, spatial performance, as demonstrated in blind tactile form board learning, was subnormal compared to normal controls. The results further suggest this impairment, especially severe in the nondominant hand, reflects ipsilateral projection of kinesthetic input, thus maximizing hemispheric competition for motor control of the minor hand. In contrast, the agenic's performance on a simple visuomotor discrimination task (with reduced opportunity for hemispheric interaction) was almost normal. Moreover, she exhibited a doubling of attentional and processing capacity in comparison to the control group. Both hands simultaneously performed this task as rapidly and as accurately as either hand alone. The findings affirm the functionally important, yet limited compensatory role of a developmentally elaborated ipsilateral somatosensory projection system in agenesis of the corpus callosum.


Aphasia due to lesions of the kinesthetic speech areas. The study of two groups of right handed aphasics, group A and group B, is presented. Each group was formed by four subjects, both groups showed an aphasic syndrome craracterized by alteration in the efferent sphere of oral and written language, principally in the latter. There was almost no alteration in the sensory interchange sphere, except for a right hypoesthesia and astereognosis in two subjects of each group. The aspect in which both groups differed profoundly was the efferent sphere of written language. Group B patients could not write with the dominant hand because of a right hemiplegia. Nevertheless, they could do it with the left, nondominant hand. Group A patients were unable to write with either hand in spite of the absence of motor deficit or incoordination which could explain this inability. The different possible topographical localizations responsible for the deficit are analyzed. It is concluded that there are three main possibilities that could explain the writing difficulty found in group B patients: a) a lesion located in the white frontal matter of the left hemisphere just underneath the kinesthetic area; b) a lesion in the kinesthetic dominant area itself; c) a lesion in the dominant cerebral hemisphere white matter underlying the primary receptor somesthetic and the primary effector areas, but without directly involving them, and extending also in depth toward the anterior third of the corpus callosum. Any one of these lesions could impair the transmission of information from the dominant kinesthetic hand area to the primary effector motor area of both cerebral hemispheres.


[Epidemiology of cysticercosis in Peru]. To determine the frequency and distribution of cysticercosis in Peru, we have reviewed the post mortem examinations of 12 years in the morgue in Lima (necropsies of persons apparently healthy, who died suddenly for different reasons) and in 11 hospitals: 6 in Lima (5 from adults and 1 from children) and from 5 hospitals from other cities located north and south of the capital. The material includes 50 000 necropsies and in those the frequency of cysticercosis was determined; its geographical distribution by states and regions and the frequency by age and sex. Comparison with other similar studies done in Latin America is made and prevalence determined. Frequency of porcine cysticercosis was determined in 82 452 animals killed in Lima in a 3 years period. frequency of cysticercosis in Peru's hospitals is 1.15%, while in the morgue, which represents approximately what happens in general population in 0.15%. Prevalence is 450 for 100 000 inhabitants.


Epidemiology of spinal cord injury.

Epidemiology of spinal cord injury. Accidents are the cause of some 50 deaths per 100 000 population each year in the US; some 3% of these are from traumatic spinal cord injury alone. Traumatic spinal cord injury in socioeconomically advanced countries, has a probably annual incidence rate of 3 per 100 000 population. Males are affected five times as often as females, and in the US, Negroes have twice the rates of whites. Half the cases are due to motor vehicle accidents, 1/4 to falls, and 1/10 to sports injuries. Maximal ages at risk are 15 to 34; only for cord damage due to falls do this risk differ, and here elderly are the more prone. Associated injuries are common in traumatic cord injury, and head injury and pulmonary dysfunction are frequent causes of the acute deaths in traumatic SCI which is why complete quadriplegia has a high early case-fatality ratio. Late deaths in SCI are principally the direct or indirect result of the neurogenic bladder. With treatment in comprehensive spinal cord injury centers, more than 4 of 5 traumatic SCI patients will survive ten years with an average of almost 18 years. Median survival may be almost 14 years for complete quadriplegia, 17 for complete paraplegia, 19 for incomplete quadriplegia, 20 for incomplete paraplegia and 28 for cauda equina lesions. Prevalence is likely to be some 50 per 100 000 population with about 20 per 100 000 completely paralyzed (3 quadriplegic and 19 paraplegic). Some 4 out of 5 survivors of traumatic SCI should be able to live at home and perform gainful work after such treatment.


A new method for the examination of language in aphasics: internal and external reliability coefficients. A new method is presented to test language, worked out by one of the authors (R.R.L.). Briefly, it consists of the systematic and ordered exploration of the functions from the cortical sensory and motor areas, the interchange of the sensorial information from the sensory to the motor areas. Nine patients with different aphasic syndromes were examined independently from each other. The test was divided in two ranks; the sensory interchange and the motor-oral-manual. The Spearman Correlation Coefficient and its statistical meaning was calculated for each rank. For the internal reliability tests, the results achieved by two successive examination on the same patient were compared by the same explorer. For the external reliability, the results from two sucessive tests on the same patient were compared by two different explorers. The Spearman Correlation Coefficient rate in all the cases varied between 1 and 0.88 with a probability of more than 0.0005 and high statistical significance, with exception of the motor rank of case 4, where it was 0.87 with a probability of more than 0.005 and less than 0.0005 with still some statistical meaning.


Some descriptive epidemiologic features of central nervous system (CNS) neoplasms in childhood, in Manitoba, Canada. In an attempt to describe epidemiologic features to generate etiological hypotheses and to study natural history, 121 cases of childhood CNS neoplasms under 15 years of age, occurring during 1950-66 in Manitoba, were analyzed. The incidence of CNS neoplasms in childhood (2.4/100 000 per annum) ranks second only to leukemia in Manitoba. For both sexes somewhat elevated incidences were noted for both extreme age groups; i.e. 0-4 and 10-14. Such peaks were more prominent for gliomas, which may indicate differential factors operation in the genesis of gliomas between early and late childhood. The former may be related to genetic and/or perinatal environmental factors and the latter, to environmental factors, in early childhood. Excess occurrences of gliomas among Irish, Scottish and Icelandic offsprings were observed, which possibly indicates the importance of either genetic or environmental factors peculiar to these ethnic groups. There was no evidence of time clustering (i.e. season and year) by estimated conception or by birth. Further investigation into the relative role of genetic and environmental factor in the genesis of childhood gliomas are in order.


An estimate of the true prevalence of epilepsy in a rural Appalachian population. Relationship between reported and true prevalence of seizures in communities are often confounded by such factors as: availability of appropriate diagnostic and therapeutic resources, sophistication of medical records and disease reporting systems, a uniform definition of cases the social implications of the disease in that area. Through applications of an epidemiologic survey, monitored to take these factors into account, we have developed data which are considered an accurate estimate of the true prevalence of seizures in the school age population of a relatively isolated mountain community of 19 000. Analysis suggested a 50% greater prevalence of seizures than expected from other studies of similar age groups. Although exact comparison of these data with data from other studies is hampered by variation in definitions, there is a strong suggestion that a high rate of seizures does exist in this community. Some possible explanations are examined and plans for further investigation are described. The methodology employed in the survey is presented as a potential model for consideration.


The spectrum of myopathies in the city of São Paulo. A fifteen-year study was made in the neurologic clinic of the school of medicine, of the City of Sao Paulo; 466 patients were examined clinically and with EMG determination of enzymes, biopsies and genetic counsel. The diagnosis varied much and some important findings at heart level, with overload, were discovered in some cases. In the cases in which the diagnosis was not confirmed; CPK was determined, which was increased in all cases, but was not so with GOT, GPT and LDH. A family pattern was found in the Duchenne Becker distrophy, limb-girdle syndrome, fascioscapulohumeral and oculopharyngeal. The biopsy exposed 15 of the 18 polymyositis cases. Genetic counsel was given to heterozygotes with PMD genes of great risk of presentation. An acute stage, detected by CPK dosage, was foreseen for adolescent heterozygotes.


Risk factors in stroke in a Mexican-American population (Houston). To date, there is little information available on stroke risk factors in a major ethnic minority such as Mexican-Americans (M-A) in the USA. Forty-three M-A patients were admitted to The Methodist Hospital and Ben Taub General Hospital (Houston) for a 12-month period, with diagnosis of atherosclerotic stroke. Thrombosis was diagnosed in 31 patients (72%), embolism from atherosclerotic sources in seven (16.4%), and parenchymal hemorrhage in five (11.6%). Hypertension was a common risk factor in all groups, being higher in hemorrhage followed by thrombosis and embolism. Arteriosclerotic heart disease was a common risk to all stroke types. TIAs, hyperlipidemia, diabetes, associated atherosclerotic lesions, smoking, obesity, erythrocytosis and sedentary life were significantly associated with embolism; less so with thrombosis or hemorrhage. Gout was only associated with thrombosis. These results indicate similar risk factors for Anglo-saxons and M-A in the USA with some minor differences between the Mexican and the USA stroke series.


[Epidemiologic study of 500 adult epileptics from a hospital population]. An epidemiology analysis is carried out in a hospital population of 500 epileptic patients older than 14 years of age, pertaining to the outpatient department of the Instituto de Neurología, Hospital de Clínicas, Monevideo". This information gathered, corresponds to the period, 1966-1975. Specially formulated records of precoded-type data were used for this research and the data was processed by automation. This work deals fundamentally with a descriptive study in which the character of the population and of its epilepsy is studied by means of 20 items. Analyzed from within the social aspects, the school attendance and the occupation of the patients, amounts, similar to those of the general population of the country, were found. An elevated incidence of family epilepsy antecedents (17%) in the group and also of perinatal pathology (19%), is emphasized. An analytic study of the clinical type of crisis and of the factors unleashed by the attacks is made. Dividing the population into two groups, according to the beginning of epilepsy, before or after the 25 years, the different etiology for both groups is specially pointed out, the juvenile epilepsy predominating in the unknown etiology, genetics and that which is produced by perinatal pathology, while in the tary epilepsy, the vascular and tumoral etiology, above all, is most frequent.


[Medicosocial aspects of epilepsy in Latin America]. This paper justifies the consideration of epilepsy as a social problem and an important public health problem in Latinamerica. It comments on the lack of proper statistical studies and the particular composition of the Latinamerican population where epilepsy has no clear differences according to age, in reference to mortality. It considers the labor structure of the population with low income and exposed to morbility and malnutrition for different causes, making notice that the social problems of epilepsy are by and large going along with the economic deficits and the unequal social system. The article mentions the problem of neonatal anoxia and other perinatal hazards so much influenced by poor hygiene and ignorance, going along with other poorly understood or non existing hygienic prevention problems. Among other points it touches on human and material resources in relation to epilepsy.


Anticonvulsivant-induced depression of clotting factors in children. A few neonates born to mothers receiving anticonvulsant drugs during pregnancy have shown defects in vitamin K dependent clotting factors with or without clinical bleeding. Experimentally, phenytoin (diphenyl hydantoin, DPH) has induced clotting defects in cats and inhibited production of clotting factors in rat liver slices. Phenobarbital has produced similar but milder defects. Anticonvulsants have been observed to produce clotting defects in 9 children, 2 weeks to 8 years in age. Elevated levels of phenytoin or other anticonvulsants, or a combination of anticonvulsants were measured in the children. Six patients were on drug combination including two or more of the following: phenytoin, phenobarbital, primidone, carbamazepine, diazepam, ethosuximide. Clotting defects included: elevated prothrombin time, elevated partial thromboplastin time, diminished factors V, VII or X. All children had neurologic symptoms of anticonvulsant toxicity, but the only hematologic problems were oozing from venipuncture sites and increased bruising in 3. All patients were on normal diets and had normal liver function tests. By lowering the level of anticonvulsants, clotting factors returned toward normal. Elevated levels of anticonvulsants can potentially produce clotting defects in neonates and young children.


[Chromosomal in study patients treated with anticonvulsant drugs]. Selected at random from a special consultation in a general teaching hospital in the City of La Habana, 10 epileptic patients were studied. They were clinically, as well as electroencephalographically diagnosed; followed by treatment with different anticonvulsant drugs for a period not less than 3 months and not greater than 5 years. 100 metaphases of each one of the patients were analyzed without finding any deviation in the normal diploidy number of chromosomes (2n = 46), nor alterations in the morphology of the same. We consider this work a preliminary report which does not permit us to arrive at definite conclusions at this moment; but in subsequent work, which we are already carrying out, we hope to issue some considerations with respect to the use of anticonvulsant drugs and their effects in the human chromosomes.


Stabilization of the thalamocortical motor system by cerebellar stimulation. Epilepsy typifies instability in a complex control system. We have previously identified parameters of the thalamocortical motor system of the cat which correlate with epileptiform activity and are controlled by common anticonvulsants. This study is concerned with the control of such parameters by cerebellar stimulation, potencially promoting stability within the motor system. Under computer control, stimuli were delivered to both ventrolateral thalamus and cerebellar cortex, with multichannel recording of evoked responses obtained from sensorimotor cortex. Cortical evoked responses were plotted as an excitability curve (mean response amplitude as a function of pulse interval) or a family of threshold curves (mean response amplitude as a function of stimulus amplitude at various fixed intervals). The present study reveals that cerebellar epidural stimulation can reduce both the height and duration of the excitability curve, as well as increase the response threshold and reduce the saturation level of the threshold curve. The degree and direction of these parameter changes are dependent on the frequency, polarity, and amplitude of cerebellar stimulation, with the amount of parameter change exceeding that achieved by monotoxic doses of anticonvulsants. These data suggest that control of parameters related to excitability and threshold in the thalamocortical motor system may be the means by which cerebellar stimulation accomplishes control of clinical seizures.


[Status epilepticus. Study of 105 cases 1972-73]. We have analyzed 105 cases of Status Epilepticus of variable etiology, cared for over a period of 3 years at the "Instituto de Neurología y Neurocirugía". Age, sex, origin, duration of illness before attending the Institute, Conscience variations, clinical crisis types, condition of Status Epilepticus appearance and unleashing factors were considered. Various complementary investigations were performed, although dissimilar in each case. Follow up EEG's were realized in 60% of the patients and pretherapeutic EEG's were done in less than 50%. The necessary time to control the Status was explained, depending on its duration before commencing treatment. Of 93 surviving patients, it was possible to learn the cause of epilepsy only in 43. The necroscopy study of 12 cases demonstrated that death in 9 patients was inevitable for various causes (tumorous, infectious, vascular, etc.) almost always intricate. In other 3 autopsied patients, only signs of cerebral hypoxia and non-neurologic infectious complications were found. In the discussion, the hypoxia-edema-hypoxia mechanism is insisted upon, as well as the need of breaking this circle as an important part of the treatment of these patients.


Is multiple sclerosis an age-dependent host response to measles? A hypothesis is presented that multiple sclerosis (MS) may represent an unusual host response to measles virus, dependent upon when the measles virus is acquired. If acquired late in childhood or near adolescence, the risk of MS is increased. Evidence to support this hypothesis is still meager, but there is ample support from many types of infection for the idea that a host's response may vary with age at the time of infection. As measles virus titers are somewhat increased in MS, evidence for age-dependent alteration in host responsiveness to measles may be taken as further support for the hypothesis. In addition, epidemiologic and clinical data linking MS frequency and average age at the time of measles infection exist. In those areas where MS is rare, measles tends to occur early in life; where MS is common, measles tends to occur later. In case-control studies, measles occurred later in MS patients than in the control groups. Finally mechanisms which might explain an age-dependent alteration in host responsiveness were considered, including maturation of an immune system or maturation of a CNS target cell, e.g. the oligocyte. Additional studies are needed to establish a firmer basis for the concept that risk of MS might be determined, in part, by the age at which a certain infection (e.g. measles) is acquired. If the hypothesis is correct, the mass measles vaccination programs should start to produce a decline in MS frequency. Because the event causing MS is believed to occur before age 15 and MS begins on the average by age 30, a 15-year lag in the effect of measles vaccine on MS frequency is to be expected. Mass measles vaccination was began in 1965, thus by 1980, a decline in MS frequency might be looked for as a test of the hypothesis. Perhaps by the V Pan-American Congress of Neurology, we shall be able to report that MS is disappearing.


Free-living amebic meningoencephalitides: comparative study. Primary amebic meningoencephalitis (PAM) is an infectious disease essentially confined to the central nervous system (CNS) and caused by free-living ameboflagellates of the genus Naegleria (N) and Acanthamoeba (A). N produces an acute fulminant, usually fatal hemorrhagic-necrotizing meningoencephalitis, associated with an inflammatory reaction composed of neutrophils, eosinophils, macrophages and a few lymphocytes. The incubation period is between 3-7 days. Typically, PAM occurs in healthy, young individuals, who frequently have a history of swimming or washing their face in infested waters. The portal of entry into the CNS is through the olfactory neuroepithelium, at the level of the cribriform plate and invasion of the amyelinic submucosal nervous plexus. Trophozoites are the only amebic forms found in the lesions. By contrast, A produces a sub-acute or chronic granulamotous meningoencephalitis (AM) with multinucleated foreign body giant cells, lymphocytes and monocytes. Cysts and trophozoites may be present in the lesions. AM have been reported in chronically ill debilitated individuals, some of them under immunosuppressive therapy, without history of recent swimming. The portal of entry into the CNS appears to be by hematogenous route. The incubation period is unknown, but perhaps more than 10 days. This comparison indicates that infection due to Naegleria produces a clearly defined clinco-pathological entity, which differs significantly from that due to Acanthamoeba, and both species of amebus should be considered in the differential diagnosis of amebic meningoencephalitis.


Histoplasma meningitis with common variable hypogammaglobulinemia. Histoplasma meningitis (HM) has been reported to occur primarily in association with disseminated histoplasmosis (DH). We report a case of histoplasma meningitis occurring in a patient with common variable hypogammaglobulinemia (CVH) in which no manifestations of DH were observed. L. L., a 66-year-old Caucasian male, clerical worker, developed occasional episodes of dizziness and tinnitus in mid-1971. During 1972, increasing frequency of these episodes and gradually progressive confusion were noted. In January 1973, vomiting, forther confusion, obnubilation, and a left central facial paresis developed and he was hospitalized. Physical examination revealed no pulmonary abnormalities, lymphadenopathy or hepatosplenomegaly. Over the ensuing 6-week evaluation, there was occasional fever to 38.5 degrees C. Chest roentgenogram was normal. Cerebral angiography suggested a mass in the left cerebellar hemisphere. EEG was diffusely slow. Multiple CSF examinations revealed: Glucose 7-18 mg/with a normal blood glucose, protein 109-256 mg/and cells 66-140 (95 + % mononuclear). Histoplasma capsulatum was cultured from CSF but not from sputum, urine, blood or bone marrow. Skin tests for PPD, histoplasmosis, coccidiodomycosis, blastomycosis, mumps, dinitrochlorobenzene and streptokinase-streptodornase were negative then and 6 months later. Histoplasma serum antibody was absent. Immunoglobulin analysis revealed IgG 430 mg %, IgA 46 mg %, and IgM 35 mg %, which with the history and skin test results suggested CVH. Treatment with 2.51 gm of amphotericin B given intravenously over a 3-month period resulted in complete reversal of all neurologic signs and clearing of the confusion. The remission has been maintained for two years. This case represents a primary infection of the CNS by histoplasma. The relationship between the HM and the CVH will be discussed.


Cerebrospinal fluid immunoglobulins in cysticercosis of the central nervous system. Investigation on the behavior of immunoglobulins IGG, IGA and IGM in the CSF, in cases of cysticercosis of the CNS, based on data pertaining to two different series of cases. The first series comprises 30 samples of CSF, and the second one, 5 samples. It was demonstrated that IGG is the one representing the largest contingent. IGG concentration keeps in proportion with the gamma globulin concentration, of which it represented an 88% average in the cases studied. Participation of IGG in the protein profile of the CSF is greater than the usually referred; the results for the material analyzed showed 16%. It was verified a proporcionality also between IGG concentration and the titer of positive complement fixation test for cysticercosis; there is a positive correlation, whose numerical expression was found to be significant in the samples studied.