External labeling of galactose in surface membrane glycoproteins of the intact myelin sheath. The molecular organization of surface galactose residues in glycoproteins of the intact myelin sheath was investigated using the enzymatic membrane probe, galactose oxidase. Rat spinal cords treated under physiological conditions with this nonpermanent probe were labeled specifically in galactose residues by reduction with tritiated sodium borohydride. The enzymatically modified proteins from isolated myelin were analyzed electrophoretically and their specific radioactivities determined. Results indicated tritium label associated with a surprising variety of high molecular weight proteins. The most extensively labeled peak corresponded to the major myelin glycoprotein as indicated by the coincidence of tritium label with that of [14C]fucose used as an internal marker for the glycoproteins. The radioactivity associated with this protein was 1.1 to 2.7 times higher after treatment with galactose oxidase when compared to reduction in the absence of the enzyme and 1.4 to 4.8 times higher when oxidized and reduced after prior treatment with neuraminidase. The results suggest a complex heterogeneity of minor glycoproteins associated with isolated myelin. It is concluded that from this complexity of glycoproteins, a major glycoprotein is at least partially localized on the external surface of either the intact myelin sheath or the closely associated oligodendroglial plasma membrane. Such a localization of this glycoprotein and the probable localization of the other glycoproteins enhances their potential role in specific interactions in the process of mpyelination or myelin maintenance.


Chemical and biological properties of synthetic, sulfur-free analogues of parathyroid hormone. Several analogues of the biologically active fragment of bovine parathyroid hormone (bPTH), based on the sequence of the NH2-terminal 34 amino acids, were prepared by solid phase synthesis and bioassayed in the in vitro adenylyl cyclase assay to provide further information concerning structure-activity relations in parathyroid hormone. In two analogues both methionines of the natural hormone were replaced with the sulfur-free and closely isosteric amino acid norleucine (Nle). The synthetic analogue [Nle-8, Nle-18]bPTH-(1-34) was highly active in the in vitro rat adenylyl cyclase bioassay, thus demonstrating that neither of the methionines, found in the native sequence, is indispensable for biological activity. Tyrosine was substituted for phenylalanine at position 34 in the synthesis of two other hormone analogues, [Try-34]bPTH-(1-34) and [Nle-8,Nle-18,Tyr-34]bPTH-(1-34). Both derivatives were exposed to conventional iodination procedures involving use of the oxidant chloramine T. Although iodination of [Try-34]bPTH-(1-34) resulted in virtually complete loss of biological activity, [Nle-8,Nle-18,Tyr-34]-bPTH-(1-34), which lacks methionine, could be exposed to oxidants and labeled efficiently with iodine with retention of nearly complete biological activity. These findings confirm that the loss of biological activity after oxidation of bPTH, as previously observed with the native hormone, is indeed attributable to the oxidation lability of methionine rather than to any other modifications. This sulfur-free, radioiodinated, biologically active analogue of parathyroid hormone may prove useful in studies of interaction of the hormone with the membrane receptors of target tissues and in studies of the metabolism of parathyroid hormone.


Bromopyruvate inactivation of glutamate apodecarboxylase. Kinetics and specificity. A number of halo carboxylic and dicarboxylic acids were substrate-competitive inhibitors of glutamate decarboxylase, with bromosuccinate, 3-bromopropionate, and iodoacetate having the highest affinity for the enzyme. Some of the halo acids also inactivated the apoenzyme. Bromopyruvate at relatively low concentrations inactivated the apoenzyme irreversibly. The rate of the inactivation of the apodecarboxylase was proportional to bromopyruvate at low concentration and approached a constant rate of inactivation at high bromopyruvate concentration. These data are consistent with a two-step inactivation process in which an enzyme-bromopyruvate complex is formed followed by inactivation. The concentration of bromopyruvate giving the half-maximum rate of inactivation was 6.9 mM, and the maximum rate of inactivation was 1.75 min-1 at pH 4.6 and 23 degrees. Much faster rates of inactivation were obtained at pH 5.96 and 6.44. Phosphate, an inhibitor of pyrisoxal-P binding to the apoenzyme, competitively inhibited the inactivation of the apoenzyme by bromopyruvate. In addition, bromopyruvate inhibited the rate of pyridoxal-P binding to the apoenzyme. Kinetics of the incorporation of bromo[2-14C]pyruvate indicated that complete inactivation was obtained when 1.2 mol of radioactive residue were covalently bound per subunit of apoenzyme. Amino acid analyses demonstrated that a cysteinyl residue was alkylated by the bromopyruvate. The bromopyruvate was evidently interacting nincovalently with a cationic group at or near the pyridoxal-P-binding site, and then was alkylating a nearby cysteinyl residue.


Horse liver aldehyde dehydrogenase. Purification and characterization of two isozymes. Two isozymes of horse liver aldehyde dehydrogenase (aldehyde, NAD oxidoreductase (EC 1.2.1.3)), F1 and F2, have been purified to homogeneity using salt fractionation followed by ion exchange and gel filtration chromatography. The specific activities of the two isozymes in a pH 9.0 system with propionaldehyde as substrate were approximately 0.35 and 1.0 mumol of NADH/min/mg of protein for the F1 and F2 isozymes, respectively. The multiporosity polyacrylamide gel electrophoresis molecular weights of the F1 and F2 isozymes were approximately 230,000 and 240,000 respectively. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis gave subunit molecular weight estimates of 52,000 and 53,000 for the F1 and F2 isozymes, respectively. The amino acid compositions of the two isozymes were found to be similar; the ionizable amino acid contents being consistent with the electrophoretic and chromatographic behavior of the two isozymes. Both isozymes exhibited a broad aldehyde specificity, oxidizing a wide variety of aliphatic and aromatic aldehydes and utilized NAD as coenzyme, but at approximately 300-fold higher coenzyme concentration could use NADP. The F1 isozyme exhibited a very low Km for NAD (3 muM) and a higher Km for acetaldehyde (70 muM), while the F2 isozyme was found to have a higher Km for NAD (30 muM) and a low Km for acetaldehyde (0.2 muM). The two isozymes showed similar chloral hydrate and p-chloromercuribenzoate inhibition characteristics, but the F1 isozyme was found to be several orders of magnittude more sensitive to disulfiram, a physiological inhibitor of acetaldehyde oxidation. Based on its disulfiram inhibition characteristics, it has been suggested that the F1 isozyme may be the primary enzyme for oxidizing the acetyldehyde produced during ethanol oxidation in vivo.


Resolution of erythrocyte membrane proteins by two-dimensional electrophoresis. A two-dimensional electrophoresis method has been developed which solubilizes erythrocyte membrane proteins, and which resolves the components of the band that migrates in detergent gels as if its molecular mass were 95,000 daltons. This method uses gel electrophoresis with sodium dodecyl sulfate in the first dimension and phenol, aqueous urea, and acetic acid in the second dimension. The 95,000 dalton band is known to contain several different membrane proteins, including those associated with anion transport, glucose transport, and (Na+,K+) transport. Two-dimensional electrophoresis resolved this band into one major spot and several minor ones. Pronase digestion of whole erythrocytes, followed by preparation of ghosts and two-dimensional electrophoresis, showed that only the major component of this band was digested by pronase.


Mechanism of 3-mercaptopicolinic acid inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP). The hypoglycemic agent 3-mercaptopicolinic acid inhibits gluconeogenesis from lactate by isolated, perfused livers from fasted rats and guinea pigs. A 3-mercaptopicolinate concentration of 50 muM caused a sharp decrease in glucose synthesis, with virtually complete inhibition at 100 muM. This inhibitory effect was reversed completely when 3-mercaptopicolinate was removed and the rate of glucose synthesis returned to normal values within 2 min. Oxygen consumption was not altered, even at the highest concentration of inhibitor. Gluconeogenesis from glycerol by guinea pig liver was blocked completely by 100 muM 3-mercaptopicolinate but was inhibited only partially in rat liver. After removal of the inhibitor glucose synthesis returned to levels higher than noted before the addition of this compound. The formation of P-enolpyruvate bu isolated guinea pig liver mitochondria metabolizing alpha-ketoglutarate (State 3) was inhibited markedly by 3-mercaptopicolinate, but malate conversion to P-enolpyruvate was considerably less sensitive. Kinetic studies with purified P-enolpyruvate carboxykinase from rat liver cytosol indicate that 3-mercaptopicolinate is a noncompetitive inhibitor with respect to both oxalacetate and MnGTP2-, and that simulataeous saturation with both substrates does not diminish this inhibition. The inhibitory effects of 3-mercaptopicolinate occur primarily by decreasing the rate of product formation while having relatively minor effects on the apparent Michaelis constants for substrates. Inhibition constants for slope and intercept effects ranged from 3 to 9 muM 3-mercaptopicolinate, and the inhibition patterns were dependent on the concentration of free Mn2+ present. Comparison of the inhibition constants with the observed inhibition of gluconeogenesis in livers perfused with 3-mercaptopicolinate supports the contention that P-enolpyruvate carboxykinase is the site of action of this inhibitor. The possibility that 3-mercaptopicolinate inhibition occurs by binding either free or bound manganese was eliminated by determination of the dissociation constant of 0.51 mM for the manganese-3-mercaptopicolinate complex. In addition, no tightly bound, slowly exchanging metal was bound to purified enzyme protein. These results suggest that 3-mercaptopicolinate inhibits by the removal of a tightly bound, rapidly exchanging metal ion other than Mn2+.


Ligand binding properties of horse hemoglobins containing deutero- and mesoheme. The reactions of horse globin reconstituted with proto-, deutero-, and mesoheme have been examined by equilibrium and kinetic methods. In virtually all reactions studied, mesohemoglobin displays the more extreme functional behavior, whereas deuterohemoglobin exhibits behavior which is either very similar to native hemoglobin or intermediate between the two. Our kinetic and equilibrium results indicate that the primary effect of heme modification on the functional properties of hemoglobin is to alter the intrinsic reactivities of the deoxy and liganded conformations. Heme modification does not, however, result in substantial alterations in the conformational equilibrium between the two states. Simple inductive electronic effects of the 2- and 4-substituents of the heme moiety in deutero- and mesohemoglobin are apparently not sufficient to explain the observed equilibrium and kinetic properties completely, which indicates that steric effects of these substituents may also play a role in determining the functional behavior of the hemoglobin molecule.


Studies on the mechanism and stereochemical properties of the oxalacetate decarboxylase activity of pyruvate kinase. When cod fish muscle oxalacetate decarboxylase catalyzes the decarboxylation of oxalacetate in the presence of NaBH4, L-lactate results from the reduction of enzyme-bound pyruvate. However, D-lactate results when borohydride reduces the binary enzyme-pyruvate complex formed by adding pyruvate from solution, as reported by others. This observation suggests that there are alternate mechanisms for reduction that are either kinetically or sterically determined for the E-pyruvate forms produced in the two directions. In the process of investigating the mechanism of reduction, the cod fish muscle decarboxylase was discovered to be identical with pyruvate kinase. Decarboxylase activity appears to take place at a site which overlaps the phosphoenolpyruvate binding site on this enzyme, as discussed in the following paper. Crystalline rabbit muscle pyruvate kinase also contains significant decarboxylase activity indicating that the two reactions may be structurally related functions. In the presence of K+, orthophosphate, or ATP the rabbit muscle enzyme catalyzes the detritiation of enzyme-bound pyruvate formed during decarboxylation before release of pyruvate from the enzyme, in analogy with the detritiation of pyruvate formed from P-[3-3/]enolpyruvate in the kinase reaction. This observation is consistent with the formation of an enolpyruvate intermediate common to the kinetic pathways of both reactions. Since the decarboxylase reac.tion is completely stereospecific, within the limits of detection, going with retention of configuration, the protonation of the enolpyruvate intermediate is completely determined by the enzyme as is the case with the enolpyruvate intermediate generated from P-enolpyruvate in the kinase reaction.


Oxalacetate decarboxylase activity in muscle is due to pyruvate kinase. The enzyme from cod fish muscle that catalyzes the irreversible decarboxylation of oxalacetate and is homogeneous by several criteria contains very significant pyruvate kinase activity. For every unit of decarboxylase activity (0.90 unit/mg) there are 235 units of pyruvate kinase activity (212 units/mg). The inability to separate the two activities by a variety of physical techniques indicates that both are due to a single enzyme protein. Improtantly, the two activities appear to take place at the same or overlapping sites on the enzyme. Phosphoenolpyruvate and 4-ethyloxalacetate are strong linear competitive inhibitors of the decarboxylase activity with respect to oxalacetate having dissociation constants of 3.2 and 10.2 muM, respectively, while 4-ethyloxalacetate is a linear competitive inhibitor of the pyruvate kinase activity with respect to phosphoenolpyruvate, Ki - 13.5 muM. In addition, both activities exhibit sigmoidal kinetics for substrates. The differential influence of effectors on substrate cooperativity for the two reactions indicates that the decarboxylase reaction may be an important tool for studying allosteric mechanisms in this enzyme.


Differential control of rat microsomal "aryl hydrocarbon" monooxygenase and epoxide hydratase. A growing body of evidence implicates epoxide metabolites of mutagenic and carcinogenic polycyclic hydrocarbons as either the only species, or one of the contributing species responsible for these adverse effects. Selective induction of epoxide hydratase(s) catalyzing the transformation of epoxides to electrophilically unreactive dihydrodiols, under conditions not leading to increases in monooxygenase(s) responsible for epoxide formation would, therefore, be of interest. All inducers of rat hepatic epoxide hydratase (determined with [7-3H]styrene oxide as substrate) which have been discovered also induced monooxygenase (determined with benzo(a)pyrene as substrate) suggesting a possible common biosynthetic control of these enzymes. The enzyme levels observed in different sexes and at different stages of the ontogenetic development, possibly dependent on endogenous inducers, strengthened this view. No sex difference is epoxide hydratase activity was observed in young rats (1 to 5 days old) while epoxide hydratase levels were about 3-fold higher in adult males than in females, which was remarkably similar to the behavior of monooxygenase. Moreover, the prenatal development of epoxide hydratase and monooxygenase appeared to be similar--although the low enzyme levels precluded accurate determinations of the latter. Although different types of known monooxygenase inducers all led to epoxide hydratase induction in adult rat liver, their effect of epoxide hydratase and monooxygenase could be dissociated by transplacental treatment. Dissociation was clearest with inducers of the polycyclic hydrocarbon type which led to great induction of monooxygenase while epoxide hydratase remained unchanged. The increases in monooxygenase activity were very different when determined by two methods based on different principles, demonstrating that at least two monooxygenases are involved in oxidative metabolism of benzo(a)pyrene, and that the control of epoxide hydratase is not under common control with either of them.


An electron microscopic study of the neuromuscular junction in the myotomes of larval lamprey, Lampetra japonica. The neuromuscular junction in the myotomes of larval and adult lampreys, Lampetra japonica, was studied with the electron microscope. In larval lampreys of 26 days after artificial insemination, the myotome consists of triangular lamellae of muscle cell with their bases laterally and apexes medially oriented and placed one on the other. The lateral aspect of the myotome is covered by a layer of flattened cell, and the other aspect is covered by an external lamina which does not extend into the intercellular space between adjacent cells within a myotome. A bundle of thin axons was found in a depression at the middle of medial edge (apex) of each muscle lamella of the myotome and neuromuscular junction was formed here. No nerve endings were found at the myoseptal ends or at the lateral borders of the muscle lamellae. Enlarged axon terminals contained numerous clear vesicles with a few cored vesicles, mitochondria and neurofilaments. The presynaptic axolemma was separated from the postsynaptic sarcolemma by an interspace (50-55 mmu wide) with an interposed external lamina. In the trunk musculature of adult lampreys, nerve endings were found on the surface of the parietal fibers whereas they were seen on both the myoseptal ends near the myotendinous junction along the medial border of each central fiber. Thickening and enhancement in the electron density and accumulation of filamentous material on the sarcoplasmic surface of the postsynaptic sarcolemma were noted in both the larval and adult lampreys. Any other specific alterations were not found on both the pre- and postsynaptic membrane in the neuromuscular junctions of larval and adult lampreys. A brief comment was made on the relationship in development of the characteristic muscle units and patterns of the motor innervation in the larval and adult lampreys. The significance of the neuromuscular junction in the very young larvae reported here was also discussed in respect to the evolution of the neuromuscular junction, particularly in lower chordates, and it was presumed to be the most primitive pattern of innervation in the vertebrate skeletal muscle.


Tectal efferents in the blind cave fish Astyanax hubbsi. Suction lesions were placed in the optic tecta of 36 blind cave fish. Three main bundles of tectal efferents were observed. A large, caudally directed fascicle distributes to the ipsilateral torus semicircularis, nucleus isthmi, and lateral tegmental areas of the mesencephalon and pons via the ipsilateral tectobulbar tract. Contralaterally, this fascicle descends to pontine levels as the contralateral tectobulbar tract. A second, rostrally directed bundle exits from the tectum at two levels. A small fascicle leaves from the caudal tectum and ascends rostrally as the commissura transversa. This bundle then joins with more rostrally exiting fibers and the combined fascicles collect in the area of the medial optic tract. They remain in this position until the level of the postoptic commissure where they decussate. Subsequently, this bundle moves caudally and enters the contralateral tectum at its most rostral extreme. The third bundle of tectofugal efferents leaves the tectum medially, at the level of the lesion, and enters the tectal commissure, through which it is distributed to the ipsilateral torus longitudinalis and contralateral optic tectum.


Experimental reorganization of the cerebellar cortes. V. Effects of early x-irradiation schedules that allow or prevent the acquisition of basket cells. In neonate and infant rats the area of cerebellum was irradiated with different schedules of single or multiple doses of low-level X-ray. One set of schedules allowed the early recovery of the external germinal layer and the differentiation of all the postnatally-forming cell types while the other selectively prevented the acquisition of basket cells. The first schedule did not interfere with the development of normally oriented and arborizing Purkinje cells. The second schedule led to the growth of twisted and entwined stem dendrites even when, in association, with the recovered granule cells, parallel fibers were present in the molecular layer together with Purkinje cell spiny branchlets. Evidence was presented that the alignment of Purkinje cell perikarya in a monolayer does not guarantee the normal growth of Purkinje cell stem dendrites which may be dependent on the presence of basket cells. The problem was discussed whether cell differentiation in the cerebellar cortex is governed by a chronological or sequential principle.


Experimental reorganization of the cerebellar cortes. VI. Effects of x-irradiation schedules that allow or prevent cell acquisition after basket cells are formed. In Long-Evans rats the area of the cerebellum was X-irradiated with two schedules beginning on day 8 by which time the bulk of basket cells were formed. The shorter schedule of four successive daily doses of 200 r between 8-11 days was designed to allow some cell recovery, the longer schedule between 8-15 days was expected to prevent it. Neither of the schedules interfered with the differentiation of basket cells. Purkinje cells remained aligned in a monocellular layer and formed singularly long, upright stem dendrites which were surrounded by the descending collaterals of basket cell axons. This supported the hypothesis that the directed growth of Purkinje cell stem dendrite is promoted by morphogenic interaction with basket cells. The upright stem dendrites had few or no smooth branches where cell recovery was prevented or had few such branches where recovery occurred. It was postulated that the out-growth of smooth branches is dependent on interaction with stellate cells which form after the acquisition of basket cells. The absence or scarcity of smooth branches did not prevent the formation of spiny branchlets which grew downward to establish synaptic contacts with the spared parallel fibers of granule cells formed before the start of irradiation. In the group with some granule cell recovery, spiny branchlets grew to a limited extent upward into the pile of parallel fibers formed after the irradiation.


Experimental reorganization of the cerebellar cortex. VII. Effects of late x-irradiation schedules that interfere with cell acquisition after stellate cells are formed. In Long-Evans rats the area of the cerebellum was irradiated with multiple doses of low-level X-ray beginning on day 12 after the bulk of stellate cells were acquired. The treatment spared basket, stellate and early-forming granule cells but led to a substantial reduction in the total granule cell population and a correlated miniaturization of the cerebellar cortex. Nevertheless most Purkinje cells had normally shaped planar dendritic arbors, with an upward directed stem dendrite, several smooth branches and a multitude of spiny branchlets. The frequency piling up of spiny branchlets near the surface was attributed to the truncation of the bed of parallel fibers by this radiation schedule. In this last paper of the series the accumulated results are summarized and evaluated. The hypothesis is offered that while the growth of the Purkinje cell perikaryon is an autonomous process, the oriented perpendicular growth of a single stem dendrite depends on the presence of basket cell axons, the outgrowth of smooth branches on the presence of stellate cell axons, and the proliferation of spiny branchlets on interaction with parallel fibers. The parallel fibers are responsible for the orthogonal, planar growth of the dendritic arbor and a hypothesis is offered about the mechanisms involved.


A comparative neuroanatomic study of retinal projections in two fishes: Astyanax hubbsi (the blind cave fish), and Astyanax mexicanus. Retinofugal projections in the blind cave fish A. hubbsi and in the highly visual A. mexicanus were studied with both reduced silver and autoradiographic methods. Contrary to what has been reported for other teleosts, ipsilateral, as well as the generally accepted contralateral, projections were found in A. mexicanus. Bilateral retinofugal projections were traced to the dorsolateral thalamic nucleus and area pretectalis. Contralateral projections were traced to the lateral geniculate nucleus, nucleus pretectalis, accessory optic nucleus, nucleus corticalis, nucleus opticus hypothalamicus and the superficial layers of the optic tectum (strata opticum, fibrosum and griseum superficiale, and the cellular zone of griseum centrale). Retinal efferents in the blindfish, A. hubbsi, are sparse and totally crossed. Areas receiving a retinal projection include nucleus opticus hypothalamicus, lateral geniculate and the superficial layers of the medial third of the optic tectum. Preliminary behavioral studies are described and discussed in relation to the possible visual potential of this teleost.


Practices and problems in HANES. Dietary data methodology. Between April 1971 and June 1974, the first attempt to assess the nutritional status of the non-institutional population of the U.S. was carried out by the DHEW. The survey is known as "HANES" (U.S. Health and Nutrition Examination Survey). Preliminary findings have been released, and further data are expected to be available soon. In this report, dietary collection methods, training and evaluation of interviewers, types of data collected, and data processing procedures of the survey are described, as well as some of the problems encountered.


Dietary regulation of serum lipids in healthy, young adults. When healthy medical students and their wives were fed a diet providing 2,375 kcal per day, 33 per cent of which was derived from fat, and received a cholesterol intake of less than 250 mg. per day, their serum cholesterol levels were significantly reduced. Differences in the change in the phospholipids of the students and their wives suggest a different response of the sexes to the diet. Since increasing the P:S ratio from 0.3 to 1.2 produced comparable lowering of serum lipids, data suggest that cholesterol intake and caloric balance are of prime importance in maintaining the level of serum cholesterol.


Prevalence and awareness of hyperlipoproteinemia in physicians and their spouses. A survey of the prevalence of hyperlipoproteinemia was conducted on physicians and their spouses. For those who were classified as having hyperlipoproteinemia, 84 to 88 per cent of the men and 94 to 96 per cent of the women were unaware that they possessed this risk factor. The implication of this lack of awareness among physician is discussed, and the need for further physician education is stressed.


Nutritive content of college meals. II. Lipids. Two samples, each consisting of two breakfasts, two lunches, and two dinners as offered to college students, were collected for seven consecutive days from each of fifty colleges. Two samples of the composited meals from each college were analyzed for fat and fatty acids. The fat content of the meals averaged 125.58 gm., with a range of 96.96 to 163.74 gm. This provided an average of 42.33 per cent of total calories, (range, 36.68 to 47.67 per cent). No college served meals with as little as 35 per cent of calories derived from fat. The meals contained an average of 46.3 gm. saturated fatty acids; 48.98 gm. mono-unsaturated fatty acids, of which 48.19 gm. were oleic acid; and 18.25 gm. polyunsaturated fatty acids, of which 17.22 gm. were linoleic acid. Four fatty acids--palmitic (C-16); stearic (C-18); oleic (C-18:1); and linoleic (C-18:2)--contributed approximately 92 per cent of the total fatty acids. The average ratio of polyunsaturated fatty acids to saturated fatty acids was 0.39 (range, 0.22 to 0.69). Six colleges served meals with a P:S ratio of 0.30 or below; five colleges had a P:S ratio of 0.50 or above.


Some cerebral proteins and enzyme systems in Alzheimer's presenile and senile dementia. The water-soluble proteins of the cerebral gray matter and some enzyme systems (cholinesterase, acetylcholinesterase, lactate dehydrogenase, malate dehydrogenase, acid phosphatase) were studied in 9 autopsy cases of Alzheimer's presenile or senile dementia, 1 case of Pick's disease and 1 case of cerebral arteriosclerosis. The proteins and enzyme patterns were visualized on polyacrylamide gradient gels after electrophoresis. In all patients studied, the profiles of cerebral gray-matter proteins were normal. In the patients with advanced dementia, the enzyme patterns usually were abnormal. Particularly in Alzheimer's disease, the activity of malate dehydrogenase was markedly increased.


A psychogeriatric assessment program. III. Clinical and experimental psychologic aspects. Variables stemming from standard psychologic tests, psychophysiologic tests, and operant conditioning procedures were employed in assessing the status of 80 psychogeriatric patients with either organic brain syndromes or functional psychoses. Differences were observed in the responses between the two groups. In general, the performance of the patients with organic brain syndromes was more deviant than that of the patients with functional psychoses, and the performance of the hospitalized geriatric patients (regardless of diagnosis) was worse than that of the normal control groups.


Treatment of the aging skin by dermatologic methods. Adverse physiologic and biochemical changes in the aging skin are aggravated by unprotected, continuous or repeated exposure to the harmful rays of the sun. Waning hormonal activity contributes to these changes. The associated clinical entities are skin dryness, accentuation of facial lines and wrinkles, hyperpigmentation, and multiple benign or malignant growths. The skin should be protected by sunscreening and sunblocking agents. Overexposure to the sun must be avoided. Repeated applications of moisturizing creams, vegetable oils, and appropriate hormonal cosmetics may be helpful in hydrating the skin and thus improving its external appearance. Chemosurgery (peeling) and dermabrasion may reduce hyperpigmentation and fine facial lines and wrinkles. New growths can be removed by various surgical methods. Biopsy should be performed to determine the presence of a malignant lesion requiring additional x-ray therapy.


Incidence of murmurs in the aging heart. One hundred patients aged 60 or older were studied clinically after excluding those with cardiac enlargement, definite valvular lesions or electrocardiographic (ECG) evidence of left ventricular hypertrophy. In 30 of the the 100 patients a significant systolic murmur was heard on auscultation. Phonocardiograms (PCGs), mitral echograms and pulse tracings were obtained in 28 of these 30 patients (2 had died meanwhile), and the ECGs and chest roentgenograms were reviewed. In 23 PCG patients there was an early or midsystolic murmur, best recorded at the base of the heart and often transmiteed to the apex. Mitral valve echograms and carotid and jugular pulse tracings were normal in all cases. Chest roentgenograms revealed aortic enlargement in 83 percent of the 23 patients. In the elderly with no evidence of organic heart disease, a basal systolic murmur is probably an aortic flow phenomenon caused by either moderate aortic dilatation or minimal fibrotic fusion of one or more commissures of the aortic valve.


Paraesophageal hiatus hernia in the aged. A review of the records of Granada Hills Hospital revealed 4 documented cases of paraesophageal hiatus hernia. One of these geriatric patients presented with incarceration of the gastric fundus, and required an emergency thoracotomy for relief. Paraesophageal hiatus hernia, unlike sliding hiatal hernia, often gives rise to acute surgical problems secondary to incarceration, obstruction, gangrene, perforation or hemorrhage. The approach to the repair operation, may be either abdominal or thoracic, dependent upon the need to correct other associated gastrointestinal pathologic lesions. Unless severe debilitating medical diseases are present, operative intervention is recommended.


Determinants of a positive attitude toward retirement. This research investigates the possibility that attitude toward retirement is better understood as resulting from the worker's realistic appraisal of the type of retirement experience which he can expect than as part of a general value orientation stressing the worker role. Questionnaire data collected from 70 older industrial workers indicate that workers who can expect a positive retirement experience in terms of finances, friends, social activity, and level of preparedness are likely to have a positive attitude toward retirement. No relationship was found between commitment to work and attitude toward retirement.


Calendar life-span versus fission life-span of Paramecium aurelia. The hypothesis that paramecia use fissions, not days, to measure length of cell life-span was investigated. Parallel cell lines were grown at 27 C and at 24 C. The daily fission rate of the cells at 24 C was lower than at 27 C. If the cells count fissions, not days, the life-span in fissions should remain unchanged, whereas the cell life-span in days should increase in the lines with reduced daily fission rate. The results showed a significant increase in cell life-span in days when the cells were cultivated for 70-100% of their life cycle at 24 C. The life-span as measured by fissions, however, remained unchanged regardless of the time of the life cycle when cells were shifted to 24 C. The data indicate that, as a model system for cellular aging, paramecia are comparable to cells which use cell doublings to measure life-span.


Effects of hyperbaric oxygen on behavioral and physiological measures in elderly demented patients. This study tested the effects of repeated exposures to hyperbaric oxygen (HBO) on psychological, electroencephalographic, and cerebral blood flow measures in 8 patients with cerebrovascular disease and 13 patients with cortical atrophy. Patients were exposed to 100% oxygen at 2.5 atmospheres absolute twice daily for 90 min. for 15 days. No significant changes were observed in any of the measures in either group. Level of initial functioning was not associated with change due to treatment. Results suggest that HBO has no therapeutic effect in patients with moderate to severe dementia.


Visual short-term memory and aging.

Visual short-term memory and aging. Short-term memory (STM) functioning of young and older adults was studied in two experiments in which recall and recognition tasks were used. The stimuli consisted of simple and complex visual patterns which were subject paced (Exp. I) or paced (Exp. II). Sex and response delay were the other independent variables. Age-related decrements in visual STM were observed. They interacted in a complex manner with the other variables suggesting age-related deficits at the encoding and post-encoding but not the retrieval phases. The results were discussed with reference to the locus of age related STM deficits.


Age differences in aversively motivated visual discrimination learning and retention in male Sprague-Dawley rats. Rats 3, 7, 12, and 24.5 mo. old were trained to an 11/12 correct initial response criterion on a shock-motivated light-dark discrimination. Eight days later they were retrained to the same criterion. Original learning and relearning rates were not correlated, but both decreased linearly with increasing age. Ray and Barrett (1973) recently reported that, while year-old rats made fewer avoidances than younger animals on a shock-motivated discrimination, they appeared to have learned equally well, since there were no differences in number of correct initial responses. They suggested that avoidance scores may reflect performance factors and that learning decrements with age might not occur if the correct initial response measure were used. The present study demonstrates that this is not the case; when rats as old as 24.5 mo. are tested there are clear age-related deficits in number of correct initial responses.


Perceptions of onsets of young adulthood, middle age, and old age. Male and female undergraduates and older community volunteers were asked their opinions as to the age of onset of young man- and womanhood, middle-age man- and womanhood, and old man- and womanhood. Data indicated that older respondents generally judged onsets of both middle and old age to occur significantly later than did young respondents and that women retarded middle- and old-age onsets, compared with men respondents. Men were generally seen as reaching transition points at a somewhat later age than women. Both sex and age of perceiver, as well as sex of the perceived, are variables in the perception of onsets of middle and old age, with onset of young adulthood a relatively fixed age for all respondents. The results were not considered compatible with interpretation of sex differences in stage onsets based upon sex-related occupational-role discontinuities.


Auditory temporal summation in presbycusis and noise exposure. Threshold-duration functions were obtained at 250, 1000, and 4999 Hz by Brief-Tone Békésy Audiometry. Results for an older group (51-57 yrs.) with no otological abnormalities showed the presence of depressed threshold-duration functions with a decreased constant of temporal summation when compared to a young normative group. The effect is frequency dependent and is most pronounced at 4000 Hz. The older group, divided into noise exposed and non-noise exposed subsamples, showed identical threshold-duration functions and resembled those for a young noise exposed group. Auditory temporal summation appears to be affected by the neuorphysiological disturbances of presbycusis and at least from 51 to 57 years is independent of noise exposure.


Aging and effect of physical-mental practice upon acquisition and retention of a motor skill. The purpose of the study was to determine the effectiveness of physical-mental practice upon two age groups (65-79 and 80-100) in the acquisition and retention of a motor skill. The subjects (140) were randomly assigned to one of the following conditions:  physical practice, one-half physical practice, physical-mental practice, or a control group engaging in no practice. Eight trials of 15 sec. each on a pursuit rotor were administered prior to and imme-iately following the practice conditions and 8 weeks later. Analyses of data indicated that for both age groups physical-mental practice was as effective as any other type of physical practice.


Reduction of adolescent misperceptions of the aged. Forty adolescent girls simulated the responses of an elderly woman on Jackson's Personality Research Form (PRF, Form A) in pre-test and were then randomly assigned to one of four training conditions involving items of PRF Form B. In Specific training, feedback information of the actual self-endorsements of 10 elderly women was given with regard to the three PRF scales which showed largest misperceptions during pre-test simulation; under General Training, feedback information was given with regard to all PRF scales; two further conditions (No Feedback Training, No Training) served as controls. Training was partially effective. Increased accuracy of perception was observed during post-test for the most misperceived personality dimension (dominance) both immediately after specific training and after 2 weeks in a delayed post-test.


Feedback effects on spatial egocentrism in old age. In literature on egocentrism, a decline in the ability to decenter with advanced age is indicated. In the present study, the extent to which perspective-taking feedback and practice reduce the egocentric performance of elderly individuals was examined. Eighteen men (X = 68.9 years, sd. = 7.14) and 18 women (X x 72.4 years, sd. = 3.65) were each assigned to one of three treatment conditions: feedback, practice, or control. Either immediately or 2 weeks after training, subjects were post-tested on measures of spatial egocentrism, fluid intelligence, perceptual speed, and volume conservation. The effect of perspective-taking feedback was to improve scores on the spatial egocentrism task, but this influence did not directly generalize to the other ability measures. Emphasis was placed on the importance of enviromental/experiential variables in the acquistion and maintenance of cognitive abilities in old age.


A morphometric study of age-dependent changes in mitochondrial population of mouse liver and heart. Mitochondria in sections of liver and heart (wall of left ventricle) from C57BL/6J mice, 8, 30 and 43 to 44 mo. old, were analyzed, using sterological techniques. The mitochondrial volume density decreased with age in both tissues: in liver the value estimated as 43 to 44 mo. of age was 65% the value estimated at 8 mo. of age; in the heart the 43 to 44 mo. value was 84% of the 8-mo. value. In both tissues, the decrease in mitochondrial volume density was the result of a decrease in the mitochondrial numerical density; the average volume of the mitochondrion remained constant throughout life.


Psychological and social correlates of life satisfaction as a function of residential constraint. Two questions were addressed in the present study: Do residential setting of varying levels of constraint influence life satisfaction? Do such settings involve different correlates of life satisfaction? A total of 129 male and female ambulatory residents were surveyed in settings of high and low constraint on the following measures: life, satisfaction, developmental task resolution, self-acceptance, perceived autonomy, activity level, health and educational level. Stepwise regression, covariance, and t-test analyses indicated: (1) life satisfaction and developmental task accomplishment were greater in the lower constraining setting; (2) the selected correlates resulted in multiple correlations of .675 and .590 with satisfaction; (3) differing sets of correlates significantly predicted satisfaction in each setting; health the most important in the high constraining setting and perceived autonomy and self-concept important to the low constraining setting; (4) developmental task success significantly predicted satisfaction in both settings.


Remarriage probability after widowhood: a retrospective method. A technique was devised to estimate age specific remarriage probabilities for newly widowed persons utilizing North Carolina marriage certificates plus informatiom from the 1970 U. S. Census. Remarriage probabilities are very high for persons widowed before age 35. Remarriage probabilities decrease faster for widows than widowers. Less than one-fourth of men widowed after age 65 ever remarry. Less than 5% of women widowed after age 55 ever remarry. Age specific intervals to remarriage were also calculated. Men remarry more quickly than women. The median interval to remarriage was 1.7 years for men and 3.5 years for women.


Inhibition of lymphocyte trapping by a passenger virus in murine ascitic tumors: characterization of lactic dehydrogenase virus (LDV) as the inhibitory component and analysis of the mechanism of inhibition. Cell-free fluid from several ascites promoting tumors inhibits lymphocyte trapping. Lactic dehydrogenase virus (LDV), a common passenger virus in many mouse tumors, was found to be a trapping inhibitor component in these fluids. Procedures used to eliminate infective LDV, such as dilution, passage of the tumor through irradiated rats, ether fractionation, and ultraviolet (UV) irradiation abolished the trapping inhibitory capacity of the fluids. LDV, dissociated from tumors, was inhibitory. Lymph nodes in mice with acute, but not chronic, LDV infections were inhibited from trapping. LDV does not appear to inhibit the capacity of circulating cells to be trapped, and as measured by mitogen responsiveness, the virus does not directly interfere with T-cell function. LDV may inhibit trapping by indirectly affecting the T cell or directly affecting the macrophage in which it replicates. The known characteristics of LDV infection may explain a number of reported immunosuppressive attributes of tumor-associated ascitic fluids.


Immunologic properties of bacterial lipopolysaccharide (LPS). III. Genetic linkage between the in vitro mitogenic and in vivo adjuvant properties of LPS. The mechanism was investigated underlying the activity of bacterial lipopolysaccharide (LPS) as an adjuvant of antibody formation as assessed by its capacity to modulate the induction of tolerance in mice to the antigen human Ig G (HGG) into a state of immunity to HGG. The adjuvant activity of LPS was found to be closely correlated with its ability to function as a B-cell mitogen. This correlation was revealed by an analysis of the genetic control of the mitogenic and adjuvant properties of LPS utilizing the refractory state inherent in the C3H/HeJ mouse strain to these activities of LPS. Thus, mice that were the progeny of a backcross between the nonresponder C3H/JeJ parent and the responder (C3H/HeJ X CWB) F1 hybrid were individually typed for responsiveness to LPS, as an adjuvant and as a B-cell mitogen. It was found that LPS interfered with tolerance induction to HGG in vivo only in those backcross progeny whose spleen cells were also capable of responding mitogenically to LPS in vitro, demonstrating that the adjuvant and B-cell mitogenic properties of LPS are genetically linked. In contrast, these properties were observed to segregate independently from either H-2 or heavy chain allotype loci, and were not sex linked. These results are compatible with the concepts that, in this system, (a) the cellular site of action of LPS as an adjuvant is confined to B cells, and (b) the subcellular mode of action of LPS as an adjuvant may involve the delivery of a "signal" to B cells which is a stimulus for mitogenesis.


Lymphopoiesis and lymphocyte recirculation in the sheep fetus. The production and the circulation of lymphocytes has been examined in the sheep fetus where neither foreign antigen nor immunoglobulins occur. It was found that as the lymphoid organs increased in size during fetal life, the numbers and the output of lymphocytes in the thoracic duct lymph increased. The recirculating pool of lymphocytes was estimated to be 5.5 +/- 1.5 X 10(8) cells in fetal lambs 95-100 days of age, 5.7 +/- 1.2 X 10(9)  cells in fetuses 130-135 days of age, and 1.2 +/0 9.3 X 10(10) cells in fetuses near to term. The rate of addition of lymphocytes to the recirculating pool was 3.2 +/- 1.9 X 10(6) cells/h in fetuses of 100 days and 3.4 +/- 0.9 X 10(7) cells/h in fetuses of 130 days of age. Lymphocytes recirculated from blood to lymph in fetuses; labeled cells injected into the blood stream reappeared in the thoracic duct lymph promptly and reached maximum levels around 12-18 h after they were injected. Labeled lymphocytes were detected subsequently in greatest numbers in the lymph nodes, particularly in the mesenteric lymph nodes and in the interfollicular areas of the Peyer's patches. Chronic drainage of thoracic duct lymph from fetuses in utero for periods of up to 36 days had no obvious effects on the growth or development of the fetus and only minimal effects on the content of lymphocytes in the various lymphoid tissues even though the number of cells in the blood and lymph were reduced to between 20-30% of normal levels. Thymectomy done in fetuses about 2 mo befor cannulation of the thoracic duct reduced the output of cells in the thoracic duct to about 25% of normal levels and caused a significant reduction in the content of lymphocytes in the various lymphoid tissues. Thymectomized fetal lambs subjected to thoracic duct drainage for periods up to 2 wk in utero had a similar complement of lymphocytes in their lymphoid tissues to intact thymectomized fetal lambs. Lymphocytes obtained from the thoracic duct lymph of lambs thymectomized 2 mo previously recirculated from blood to lymph when they were injected intravenously, although they did this at a significantly slower rate than did lymphocytes from normal lambs.


Immunosuppressive activity of a subline of the mouse EL-4 lymphoma. Evidence for minute virus of mice causing the inhibition. Filtered culture fluids from the early in vitro passages of a subline of the C57BL/6 mouse EL-4 lymphoma, EL-4(G-), were strongly inhibitory for BABL/c vs. C57BL/6 mixed lymphocyte cultures (MLC). The inhibitory activity could be preserved by storage at -75 degrees C or 4 degrees C, thus allowing its further characterization. The inhibitory factor was particulate (nondialyzable, sedimentable at 100,000 g for 1 h), very small (recovered after 0.10 mum filtration), sensitive to UV irradiation, but heat stable (56 degrees C, 1 h) and resistant to chloroform. It was infectious, since later, noninhibitory passages of EL-4(G-) tissue culture cells became strongly inhibitory upon inoculation with the culture fluid. This data was consistent with the inhibitory factor being an infectious virus. Virus analysis by mouse antibody production tests revealed that viruses were indeed present in EL-4(G-) ascites cells and in the culture fluid, and not in a late passage of EL-4(G-) tissue culture cells which were not inhibitory. Neutralization of the inhibitory factor was achieved by pretreatment with ascitic fluid or with the sera raised against those (EL-4(G-)-derived materials which contained viruses. Mouse reference immune sera against minute virus of mice (MVM) completely neutralized the inhibitory factor in the culture fluid or in EL-4(G-) ascites cells. Two prototype MVM strains, and one Kilham rat virus preparation, did not inhibit the mouse MLC. Thus, the possibility exists that a variant of MVM, or an unidentified virus, has been grown and selected for in EL-4(G-) cells and recognized, due to its immunosuppressive characteristics. In any event, immunosuppression by EL-4(G-) cells was not mediated by the tumor cells, their metabolic products, or associated endogenous type C viruses, but by an exogenous virus, most likely a variant MVM with immunosuppressive characteristics. This adds weight to a parallel observation from our laboratory on the immunosuppressive effects of Kilham rat virus in rat lymphocyte cultures.


Cell-mediated lympholysis of trinitrophenyl-modified autologous lymphocytes. Confirmation of genetic control of response to trinitrophenyl-modified H-2 antigens by the use of anti-H-2 and anti-Ia antibodies. Splenic lymphocytes from B10.A and B10.D2 mice were sensitized in vitro to trinitrophenyl (TNP)-modified autologous spleen cells. The effector cells generated were assayed in a 51Cr-release assay on TNP-modified syngeneic or congenic spleen target cells. Effector cells from B10.A donors lysed TNP-modified H-2Kk- but not H-2Dd-region products, whereas B10.D2 effectors reacted with modified products of both the H-2Kd and H-2Dd regions. As an independent confirmation that this selective K-end lysis by B10.A effector cells is due to an H-2-linked responder cell defect (4), anti-H-2Kk but not anti-H-2Dd sera were shown to inhibit the lysis of B10.A-TNP targets by B10.A effectors. In contrast, anti-H-2Dd sera inhibited the lysis of B10.A-TNP targets by B10.D2 effectors. Anti-Ia antibodies had no detectable effect on lysis. Anti-TNP-keyhole limpet hemocyanin sera blocked the lysis of TNP-modified targets, irrespective of whether the effector cells were directed against TNP-modified autologous H-2 products or H-2 alloantigens. These results independently verify that B10. A responding lymphocytes do not generate effector cells to TNP-modified H-2Dd products, whereas B10.D2 lymphocytes do (4), and suggest that some TNP groups are sterically close to (or part of) the serologically defined H-2K- and H-2D-region antigens.


Differential effects of chlorpromazine on the in vitro generation and effector function of cytotoxic lymphocytes. Allograft rejection represents a cytotoxic response mediated to a large degree by thymus-derived T lymphocytes (1). The study of such cell-mediated cytotoxic phenomena has been greatly facilitated by the discovery first noted by Hayry and Defendi (2) and Wunderlich and Cany (3), that a natural consequence of allogeneic stimulation in an unidirectional mixed lymphocyte culture (MLC) was the appearance of cytotoxic lymphocytes specific for antigens present on the stimulator cells. Subsequent studies have shown that such in vitro generation of cytotoxic lymphocytes was dependent on the proliferative response in an MLC (4), was genetically determined (5), and possibly required the interaction of several subpopulations of T cells (6). We now report that the surface active agent chlorpromazine: (a) inhibits allogeneic stimulation of the proliferative response in an MLC; (b) inhibits the MLC generation of cytotoxic lymphocytes, (c) has no effect on the recognition, binding, or lysis of target cells by already sensitized lymphocytes; and (d) blocks a postproliferative membrane-mediated event, independent of proliferation, and necessary for the MLC generation of cytotoxic lymphocytes.


A common cell-type specific surface antigen in cultured human glial cells and fibroblasts: loss in malignant cells. Fibroblast surface antigen (SFA) is a high molecular weight protein antigen, first shown on the surface of cultured fibroblasts in fibrillar structures. It is shed to the extracellular medium and also present in the circulation (serum and plasma). Fibroblasts transformed by tumor viruses produce SFA but do not retain it on cell surface. In this report we show that SFA is also present in cultured nonestablished astroglial cells. The glial and fibroblast SFAs are immunologically indistinguishable. Glial cells (three different nonestablished lines) contain more SFA per milligram cellular protein than fibroblasts. SFA was located on cell surface in fibrillar striae that frequently extended out from the cell body. Fluorescence was also found intracellularly in the cytoplasm. Malignant gliomas (astrocytomas) established to grow in culture from human tumor material produced SFA into the growth medium but had very little (lines U-105 MG and U-343 MG) or no detectable (lines U-118 MG, U-251 MG, and U-343 MG-a) cell surface SFA. In cultures of the glioma cells many cells, in particular those that appeared to be in the telophase stage, stained strongly positive for intracellular cytoplasmic SFA. These data demonstrate that similar to fibroblasts transformed experimentally by oncogenic viruses, cells grown from naturally occurring human tumors (glioblastomas) produce SFA but lose ability to retain it on cell surface.


Studies on the role of the host immune response in recovery from Friend virus leukemia. I. Antiviral and antileukemia cell antibodies. The humoral immune response to Friend virus leukemia was studied in congenic F1 mice differing in their incidence of recovery from leukemia. Antiviral neutralizing antibodies rose in titer in vivo concurrently with disappearance of viremia and fall in spleen virus levels. Cytotoxic antileukemia cell antibodies also appeared at this time. Passive transfer of these antibodies could inactivate low numbers of leukemia cells in vivo; however, mice of both high and low recovery genotypes produced antibodies in equal titer and recovered from viral infection in spite of striking differences in recovery from leukemic splenomegaly. Mice lacking C57BL genes did not produce antibodies or recover from viremia except in rare instances. Recovery from splenomegaly was found to be influenced by three or more C57BL genes independent of the H-2 complex.


Aneurysm of the inferior gluteal artery causing sciatic pain. Case report. The authors describe a case with sciatic pain caused by a large extrapelvic aneurysm of the inferior gluteal artery. Differential diagnosis and treatment are discussed.


Intracranial epithelial cysts. Report of two cases. The authors report two cases with large unilocular intracerebral epithelial cysts. Diagnosis was facilitated in both patients by computerized tomography (EMI scanner). The clinical and diagnostic aspects of previously reported cases are reviewed, and the etiology and pathogenesis of these cysts discussed.


Medical modification of sensation.

Medical modification of sensation. The authors describe the sensory examinations of 3 patients who had undergone cervical rhizotomy alone and in combination with trigeminal tractotomy and section of the nervus intermedius, the glossopharyngeal nerve, and the upper portion of the vagus nerve. Following administration of L-dopa there was an increase in their pain and a decrease in the area of clinically anesthetic or analgesic skin. When methyldopa was given, the subjective and objective changes were the opposite of those elicited by L-dopa. These observations support the existence of a wider dorsal root cutaneous distribution than is usually accepted as well as significant control of cutaneous sensation by suprasegmental areas of the central nervous system. Part of the suprasegmental bias supplied to the area in the spinal cord that processes sensory information apparently occurs by way of an aminergic descending reticulospinal tract. These findings are discussed in terms of attempts totally to denervate restricted cutaneous areas of the body for treatment of pain-producing states.


Monitoring optic nerve function during craniotomy. During surgical removal of a pituitary adenoma, conduction in the anterior visual pathways was monitored by continuous recording of visual evoked responses (VER). The method employed a scleral contact lens with an embedded flashing diode for delivery of visual stimuli. Evoked potentials of nearly normal latency, amplitude, and form were recorded from occipital scalp electrodes immediately after the optic nerves were decompressed. Restoration of the VER was correlated with restoration of normal vision.


Cerebrospinal fluid creatine phosphokinase in acute subarachnoid hemorrhage. The author measured the level of creatine phosphokinase (CPK) in 35 cerebrospinal fluid (CSF) specimens from 30 patients with acute subarachnoid hemorrhage, and correlations were sought with 17 other clinical and laboratory parameters. Elevations of CSF CPK have no diagnostic specificity. However, they do dhow a statistically significant correlation with the existence of any destructive process in cerebral tissue (hydrocephalus, infarction, intraparenchymal hemorrhage, or intraventricular clot). Yet arterial spasm without infarction does not raise the CSF CPK level. During the preoperative management of ruptured aneurysms and vascular malformations, a significant elevation of the CSF CPK level can thus provide a clue to the presence or significance of one or more of these destructive processes.


Anatomical features of the straight sinus and its tributaries. The authors report a variety of arrangements of the venous channels comprising the straight sinus (sinus rectus) and its connections during a continuing study of the cerebral sinuses and their tributaries. In approximately 85% of 131 specimens of dura mater with enclosed venous sinuses derived from fresh cadavers, the straight sinus was represented by a single midline tentorial channel whereas in the remaining 15%, segments of it were doubled and in a few, tripled. In addition to these aberrations in the development of the main trunk of this sinus, the venous patterns at the junctions of the inferior sagittal sinus, vein of Galen and straight sinus showed comparable developmental inconstancies. Also in no specimens were the patterns of venous channels in the leaves of the tentorium cerebelli alike. The course, size, and connections of all the tributaries of the straight sinus have been studied and consideration given to their potentials as collateral pathways in the event either the vein of Galen or the straight sinus itself were occluded.


Management of depressed skull fracture in the newborn. The authors describe 3 cases of neonatal depressed skull fracture subsequent to difficult delivery, treated without surgical elevation. None of the patients developed neurological deficits, cosmetic deformity or electroencephalographic signs of epileptiform activity. Neonatal depressed skull fractures not associated with focal neurological signs may not require surgical therapy; we are not certain what the absolute criteria for operation should be.


Vertebral hydatid disease. Clinical experience with 27 cases. The authors present 27 cases of vertebral hydatidosis with clinical and laboratory findings. The most frequent location of the lesion was the lumbar spine. Principal neurological symptoms were paraparesis, sphincter disturbances, paresthesia and paraplegia. The average number of surgical interventions per patient was 2.6; the most common procedure was laminectomy with extirpation of the cyst and surgical toilet. The results of surgical treatment were generally good in the immediate postoperative period, but long-term results were poor.


Intracranial ectopic pituitary adenoma. Case report. The authors report a unique case of ectopic intracranial pituitary adenoma, associated clinically with generalized seizures and aggressive behavior. The lesion presumably arose from cells in the pars tuberalis and did not involve the sella turcica.


Evaluation of the posterior flow study in brain scintigraphy. To evaluate the usefulness of the posterior cerebral flow study, a prospective study was instituted. Of 32 adult patients examined for presumed posterior disease, 17 were found to have a positive posterior flow study that yielded information not available from the anterior study. Indications for posterior flow studies include posterior parietal, occipital, and posterior fossa tumors, posteriorly located arteriovenous malformations, Paget's disease involving occipital bone, posterior cerebral infarcts, and sagittal sinus occlusions. Our experience indicates that the posterior flow study is a valuable adjunct in those patients carefully screened for suspected posterior cerebral disease.


Differentiation between malignant and benign solitary thyroid nodules by fluorescent scanning. A quantitative fluorescent technique has been developed for making in vivo iodine content determinations of the total thyroid gland or of selected parts. In solitary thyroid nodules "cold" to radionuclide studies, the ratio of iodine content in the nodule to that in a corresponding area of the contralateral lobe has proven to be a good indicator of malignancy. In a preliminary study of 42 surgical patients, an iodine content ratio (ICR) below 0.60 (chosen a posteriori) proved to be an excellent indication of malignancy with a sensitivity of 100%, a specificity (predictive value) of 79%, and an overall accuracy of 90%. Further definitive studies are needed to verify these preliminary observations.


Thyroid carcinoma presenting as a pertechnetate "hot" nodule, but without 131I uptake: case report. A 24-year-old woman presented with a mass on the right side of the neck; this proved to be a hyperfunctioning or "hot" nodule on pertechnetate scan. Because of the firmness of the area, the study was repeated with 131I, but the region did not accumulate radioiodide. The tissue showing this discrepant handling of pertechnetate and radioiodide was surgically removed and identified as a follicular carcinoma with papillary foci. A brief review of the literature data on the disassociation of thyroid trapping and organification functions, and hence of possible discrepancies between pertechnetate and radioiodide uptake, is given.


Vertebral artery fistula detected by radionuclide angiography: case report. A vertebral artery fistula was detected as increased neck vessel activity by rapid-sequential scintigraphy.


Abnormal radionuclide angiogram in cervical lymphadenitis: case report. We have observed increased activity over the neck on radionuclide angiograms of two patients with cervical lymphadenitis. This incidental findings should not be confused with other causes of locally increased perfusion.


False-positive liver scan in a patient with hepatic amyloidosis: case report. A case of secondary hepatic amyloidosis exhibiting a large liver and multiple defects on the radiocolloid scintigraph is presented. Biopsy and angiographic studies indicated that the areas of reduced colloid uptake represented heavy amyloid deposition, and the area of the left lobe with contrasting high activity most probably represented compensatory hypertrophy.


Technetium-99m-pyridoxylideneglutamate, a new agent for gallbladder imaging: comparison with 131I-rose bengal. Two agents used for hepatobiliary studies, 131I-rose bengal and 99mTc-pyridoxylideneglutamate, have been compared in rabbits. The 99mTc radiopharmaceutical is rapidly cleared from the blood by the liver and rapidly excreted through the common bile duct into the duodenum. Because of its rapid removal from the liver, visualization of the gallbladder and biliary passages was obtained within 15 min after injection in experimental animals.


In vivo behavior of 99mTc-fibrinogen and its potential as a thrombus-imaging agent. We have investigated the in vivo behavior of 99mTc-fibrinogen, prepared by a mild and efficient electrolytic method employing tin electrodes. The clearance mechanisms of this agent were studied, and its efficacy for imaging deep-vein thrombi in dogs with an Anger camera was determined. The 99mTc-fibrinogen preparations, which are stable in vitro, undergo partial rapid exchange of the technetium with other plasma proteins and with anions of the blood buffer system in vivo, resulting in an early drop in the percent of radioactivity associated with clottable protein. However, very little or no oxidation to pertechnetate occurs. The nonclottable material is much more rapidly cleared from the blood than the remaining 99mTc-fibrinogen, and the proportion of clottable protein activity increases with time. The fraction of 99mTc-fibrinogen that remains intact in vivo is biologically active and will incorporate into thrombi. Higher thrombus-to-blood activity ratios are obtained with 99mTc-fibrinogen than with radioidinated fibrinogen when both agents are injected into dogs 4 hr after induction of femoral vein thrombosis. Clearly delineated images of the thrombi are obtained, beginning about 2.5 hr after injection. Thus, 99mTc-fibrinogen may be of clinical use as a thrombus-imaging agent in patients under-going active thrombosis, especially in regions of high blood pool.


Technetium-99m-human serum albumin: evaluation of a commercially produced kit. Results are reported on the use of a commercial kit for the labeling of human serum albumin with 99mTc. One-hour blood levels obtained in 20 subjects undergoing gated cardiac imaging were found to be 46.0 +/- 10.5% (s.d.) of the administered dose. The highest labeling efficiencies (94.2 +/- 9.3%) were obtained when human serum albumin 25% (salt-poor) was used. Satisfactory nuclear cardiac ventriculographic images were obtained in patients receiving the radiopharmaceutical when the labeling efficiency was at least 85%. Occasional batches were milky in appearance, contained black particulate matter, were acidic, or contained a high percentage of unbound 99mTc activity. Although this kit makes 99mTc-human serum albumin accessible to most nuclear medicine facilities for general clinical use, an active quality control program is required prior to use in patients.


Optimized collimators for scintillation cameras. The use of commerically available tantalum or lead tubes permits convenient fabrication of collimators optimized for specific imaging studies.


Unreliability of combined pneumoencephalography and scinticisternography. Evidence is presented that the radiopharmaceutical flow in cerebrospinal fluid may be significantly altered by pneumoencephalography. When both pneumoencephalography and scinticisternography are required in the same patient, the studies should be performed separately rather than as a combined procedure.


Labeling of tin-soaked albumin microspheres with 68Ga. A method is described for the labeling of tin-soaked human serum albumin microspheres with 68Ga. The radionuclide is a short-lived (T 1/2 = 68 min) generator product and a positron emitter; the labeled particles may be used for perfusion studies with a positron camera. The labeling procedure requires 40 min after elution of the 68Ga generator and provides a labeling efficiency of 90 +/- 5%. The in vivo stability of the particles was determined in a series of animal experiments which showed little washout of lung activity over a 2-hr period.


Transient brain scan abnormalities in renal dialysis patients. Two patients on chronic renal hemodialysis developed acute neurologic symptoms and unusual brain scan findings, including very prominent cranial sinuses. Symptoms and scan abnormalities reverted to normal within a few days. The possible mechanisms are discussed.


Alteration of the cerebral bloodflow study due to reflux in internal jugular veins. This paper considers abnormalities of flow patterns in the flow patterns in the cervical vasculature due to varying degrees of jugular venous reflux, and their influence on cerebral bloodflow studies. Two commonly encountered patterns are described. In the first group, the abnormal flow study resulted from reflux of the activity in the left internal jugular vein. In the second group, the observed abnormality resulted from reflux of the activity in the left internal jugular vein, followed by flow into the contralateral jugular vein, most probably through the transverse and sigmoid sinuses.


Infusion cisternography.

Infusion cisternography. A source of error in cerebrospinal fluid (CSF) infusion tests is leakage at the dural puncture site. The addition of a bolus of radionuclide to the infusion fluid was helpful in detecting the existence of leakage as shown by increased infusion pressure in six of eight patients studied with and without scintigraphic evidence of leakage. Comparison of CSF dynamics in 26 patients studied by infusion cisternography and conventional cisternography showed similar patterns, suggesting no alteration of CSF dynamics by the artificial CSF infusion. Combining the two tests, therefore, resulted in simple identification of the leakage and saved the patient time and discomfort.


Cervical venous reflux in dynamic brain scintigraphy. Cervical venous reflux, shown by dynamic brain scintigraphy, was investigated through three avenues of approach: (A) by reviewing 371 randomly chosen routine dynamic intracerebral bloodflow studies to estimate its incidence; (B) by correlative positive-contrast superior venacavography in patients with characteristic cervical venous reflux; and (C) by performing dynamic brain scintigraphy while utilizing various positional and physiologic maneuvers to attempt to produce cervical venous reflux in patients who did not exhibit this phenomenon on earlier examination. Although any obstruction of the superior vena cava or a properly timed Valsalva maneuver in selected patients can produce the scintigraphic picture of cervical venous reflux, in most cases it is a normal phenomenon due to incompetent or absent cervical venous valves.


Alcohol metabolism in American Indians and whites. Lack of racial differences in metabolic rate and liver alcohol dehydrogenase. To investigate alleged racial differences in alcohol tolerance, we measured the rate of ethanol metabolism in 30 American Indians and 30 whites. The mean rates of alcohol metabolism were virtually identical in the two groups: 92 +/- 3 mg of ethanol metabolized per kilogram of body weight per hour for the Indians versus 93 +/- 3 for the whites (mean +/- S.E.M.). Similarly, a comparison of liver alcohol dehydrogenase specific activity and isoenzyme pattern in biopsy specimens from seven American Indians and six whites revealed no racial differences. Biopsy specimens from the Indians demonstrated a mean specific enzymatic activity of 0.073 +/- 0.004 mumoles of ethanol oxidized per minute per milligram of soluble protein and from the whites, 0.082 +/- 0.009. These findings make it unlikely that alleged racial differences in response to alcohol can be explained on the basis of racial differences in the rate of alcohol metabolism.


Psychotherapeutic control of hypertension. We conducted a six-month trial to determine the effect of psychologic relaxation on blood pressure. Alterations of peripheral sympathetic-nervous-system activity, as reflected by changes of dopamine-beta-hydroxylase in plasma, were evaluated,  and plasma volume and plasma renin activity were measured. Treated patients exhibited significant (P less than 0.05) reductions of blood pressure when supine and upright, and of plasma dopamine-beta-hydroxylase activity, and furosemide-stimulated renin activity when upright. Blood-pressure changes after six months correlated best with differences in plasma activity of dopamine-beta-hydroxylase with patients supine (r = 0.54; P less than 0.05) and upright (r = 0.62; P less than 0.05). These results suggest that reduction of peripheral adrenergic activity contributes importantly to the improvement of hypertension observed with this form of therapy. Furthermore, the decrease of furosemide-stimulated plasma renin activity suggests that alterations of the renin-angiotensin system may help lower blood pressure in certain patients.


The cost of fetal research: ethical considerations. The purpose of this essay is to examine some ethical and legal aspects of nontherapeutic experimentation with living human fetuses, especially in the context of abortion. Key questions about such research subjects are the status of the fetus, the problem of consent, and the relations between means and ends. The case for considering the fetus a member of the human community, and therefore as endowed with certain rights, is based upon an appeal for consistency with the general evaluation of fetal life. Secondly, consent for nontherapeutic procedures cannot be based upon the analogy of parental rights, and, with rare exceptions, cannot be justified on any other grounds. Thirdly, both humanistic and religious traditions would object to nontherapeutic research with such subjects on the ground that a human being should never be a mere means to the needs of others. The conclusion, therefore, is that such experimentation with living human fetuses is morally unjustifiable.


Subacute effects of heavy marihuana smoking on pulmonary function in healthy men. To evaluate the subacute effects of heavy marihuana smoking on the lung, pulmonary function was tested in 28 healthy young male experienced cannabis users, before and after 47 to 59 days of daily ad-libitum marihuana smoking (mean of 5.2 marihuana cigarettes per day per subject, 2.2 per cent delta9-tetrahydrocannabinol). Base-line pulmonary-function studies were nearly all within normal limits, but after 47 to 59 days of heavy smoking, statistically significant decreases in forced expired volume in one second (3 +/- 1 per cent, S.E.), maximal mid-expiratory flow rate (11 +/- 2 per cent), plethysmographic specific airway conductance (16 +/- 2 per cent) and diffusing capacity (8 +/- 2 per cent) were noted as compared with the base-line studies. The decreases in maximal mid-expiratory flow rate and specific airway conductance were correlated with the quantity of marihuana smoked. These findings suggest that customary social use of marihuana may not result in detectable functional respiratory impairment in healthy young men, whereas very heavy marihuana smoking for six to eight weeks causes mild but statistically significant airway obstruction.


Cancer incidence in Mormons and non-Mormons in Utah, 1966-1970. Between 1950 and 1969 cancer mortality in white Utah residents was 22 per cent less than that in the entire United States population. The religion of 72 per cent of the State residents (Mormon) proscribes use of tobacco and alcohol. We therefore analyzed the 10,641 cases of cancer identified in Utah from 1966 to 1970 and compared the incidence found in Utah Mormons, in Utah non-Mormons, and in a national survey. Comparison of Utah Mormons with non-Mormons showed that Mormons had a lower incidence of all cancers associated with cigarette smoking (P less than 0.00001). Mormon females had a low incidence of cancer of the breast (P = 0.008), uterine cervix (P less than 0.00001), and ovary (P = 0.04); Mormon males had a lower incidence of stomach cancers (P = 0.003). These findings addevidence to the association between cigarette smoking and certain cancers, but leave unexplained the significant differences between Mormons and non-Mormons for incidence of cancer of the breast, cervix, prostate and nervous system.


Shattuck Lecture--strengths and weaknesses of the committee approach. An analysis of past and present recommended dietary allowances for protein in health and disease. A review of the history of international efforts to establish protein requirements and safe allowances for healthy adults reveals the difficulties of the expert-committee approach to problems of this nature. Although it is preferable to less democratic approaches, the committees involved often acted without sufficient knowledge of the relevant literature and seldom had time to study and evaluate unpublished data presented at the meetings. Moreover, the available data are still inadequate for the purpose, even though each meeting report has stimulated additional relevant research. Research since the 1971 meeting of the FAO/WHO Expert Committee on Energy and Protein Requirements has already cast doubt on its recommendations. Recent evidence suggests that the "safe allowance of protein" that it proposed is inadequate for long-term maintenance of healthy in young adults even when energy intakes are wholly adequate or even excessive.


Myeloma with xanthoderma due to an IgG lambdamonoclonal anti-flavin antibody. When yellow skin and yellow hair developed in an elderly patient with multiple myeloma, we ruled out the usual causes of such pigmentation but identified a monoclonal IgGlambda (lgGGar) with anti-flavin antibody activity. Purified IgGGar was bright yellow, and the acid-dissociated chromophore was identified as riboflavin by chromatography and absorption spectroscopy. Native IgGGar contained 1.45 moles of flavin per mole of IgG, and increased to 2 moles with addition of riboflavin to saturation. The flavin was localized to the Fab fragment and was bound to IgGGar with high affinity. IgGGar showed strongest affinities for riboflavin, flavin mononucleotide and flavin adenine dinucleotide, and lower affinities for dinitrophenyl derivatives and naphthoquinone. The demonstration of hapten bound to the circulating monoclonal immunoglobulin in this case suggests the possibility of bound but colorless haptens on other myeloma proteins as well as on normal immunoglobulins.


The dialysis encephalopathy syndrome. Possible aluminum intoxication. The aluminum content of muscle, bone and brain was measured in control subjects and in uremic patients on dialysis who had been maintained on phosphate-binding aluminum gels. The mean muscle aluminum was 14.8 ppm, and the trabecular-bone aluminum 98.5 ppm in the patients on dialysis, as compared with 1.2 and 2.4 in control subjects (P less than 0.05). Brain gray-matter aluminum values in a group of uremic patients on dialysis who died of a neurologic syndrome of unknown cause were 25 ppm as compared with 6.5 ppm in a group of uremic patients on dialysis who died of other causes and 2.2 ppm in control subjects. The fact that brain gray-matter aluminum was higher in all patients with the dialysis-associated encephalopathy syndrome than any of the control subjects or other uremic patients on dialysis suggests that this syndrome may be due to aluminum in intoxication.


Effects of oral contraceptives on the gallbladder bile of normal women. In view of the reported association between use of oral contraceptives and gallbladder disease, the effects of contraceptive steroids on the lipid composition of gallbladder bile were studied in 22 healthy women. Each subject was studied during routine use of oral contraceptives and also during normal menstrual cycles on no medication. Gallbladder bile was significantly more saturated with cholesterol during contraceptive therapy than during normal menstrual cycling (125 versus 92 per cent, P less than 0.001). Chenodeoxycholic acid accounted for a significantly smaller proportion (35 versus 42 per cent P less than 0.001) and cholic acid a significantly greater proportion (50 versus 41 per cent (P less than 0.001) of total bile acids during contraceptive steroid therapy. These findings show that exogenous sex steroids in doses and formulations routinely prescribed induce important alterations in the composition of human gallbladder bile, and suggest a biochemical basis for the increase in gallbladder disease observed among women using oral contraceptives.


Carrier detection in Duchenne muscular dystrophy. We measured endogenous phosphorylation of peak II (apparent molecular weight of 220,000 daltons) of the erythrocyte membrane in 21 mothers of patients with Duchenne muscular dystrophy. The mean values of mothers with affected sons were significantly increased over those of matched controls (77.0 and 55.8 pmoles per milligram of 15-minute incubation; P less than 0.01). Detailed testing of mothers of affected sons revealed proximal muscle weakness. Seven mothers of isolated patients who had normal levels of creatine phosphokinase and no daughters with elevated levels were identified as carriers, because their mean value of peak II phosphorylation was increased (75.9 pmoles per milligram per 15 minutes) and equivalent to the level demonstrated in the 14 acknowledged carriers. Our results suggest that cases of Duchenne muscular dystrophy previously considered to be new mutations are much less common than estimated.


Adjuvant immunotherapy with BCG in treatment of regional-lymph-node metastases from malignant melanoma. Despite current surgical therapy, about 80 per cent of patients with malignant melanoma metastatic to lymph nodes succumb to systemic metastatic disease. To determine if postoperative adjuvant immunization with BCG was an effective systemic treatment in these patients with microscopic subclinical metastatic disease, the clinical course of 42 patients treated by operation alone was compared with that of 84 treated by operation and BCG. At two years, the incidence of metastasis in BCG-treated patients was half that of the control group. BCG was more effective in patients with a smaller tumor burden at the time of initial surgical treatment. In patients receiving BCG adjuvant therapy, 90 per cent with microscopic disease in one lymph node appeared free of disease as compared to 40 per cent with macroscopic disease in multiple nodes. In patients with recurrences, an immunotherapeutic effect was demonstrated by a delay of six months in the time to recurrence. Thus, BCG immunotherapy appears to have an inhibiting effect on the "micrometastases" of malignant melanoma.


Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. To assess the influence of diabetes mellitus on bone metabolism, we measured skeletal mass in the forearms of 35 patients with juvenile diabetes on insulin and 101 stable patients with adult-onset diabetes, on diet alone, insulin, or oral hypoglycemic agents. There was a significant loss of bone mass in both juvenile and adult-onset diabetes (P less than 0.01) as compared to controls matched for age and sex. The decrease was already present in patients with diabetes of less than five years' duration. Bone loss and duration of the diabetes did not correlate; the greatest decrease in bone mass was observed in the patients receiving oral agents. These data are consistent with the hypothesis that the loss of skeletal tissue in diabetes reflects the underlying disease since it occurs early and is not related to severity as evidenced by the need for insulin, to duration, or to treatment with insulin or diet alone.


Saturation-inhibition index as a measure of the risk of calcium oxalate stone formation in the urinary tract. Studies were carried out on multiple urine samples from eight patients with recurrent idiopathic calcium oxalate stone formation and eight normal persons to define an index of the risk of forming calcium oxalate stones. Under the same conditions of dietary and fluid intake the urine samples of the patients with stone formation were more supersaturated with calcium oxalate (P less than 0.001) and had lower concentrations of protective inhibitors of crystallization (P less than 0.001) than those of the controls. However, the best separation between the groups was defined by a discriminant line relating inhibitory activity and urine saturation. A measure of the risk of forming large crystals, the saturation-inhibition index, was defined as the distance of each urine from the discriminant line. The patients with stone formation had a significantly higher mean saturation-inhibition index than the controls (P less than 0.001). Both the percentage of large calcium oxalate crystals excreted (P less than 0.001) and the stone episode rate (P less than 0.005) were significantly correlated with the saturation-inhibition index.


Prinzmetal's variant angina. Coronary arteriogram and left ventriculogram during angina attack induced by methacholine. Recently, in Prinzmetal's variant angina, many cases with normal coronary arteries have been reported. The anginal attacks frequently relapse after aortocoronary bypass grafting. It is frequently possible to induce an anginal attack by parasympathomimetic agents such as methacholine and pilocarpine. In this study, methacholine (0.13 mg per kilogram) was injected subcutaneously in three cases of this disease to induce an angina attack, and coronary arteriograms and left ventriculograms were recorded. In all cases a coronary arterial spasm corresponding to the site of the ST-segment elevation in the electrocardiogram was observed. Complete occlusion due to the spasm was observed even in the normal coronary artery. Asynergy was seen in the left ventricular wall corresponding to the site of the ST-segment elevation in the electrocardiogram.


The significance of extracapillary proliferation. Clinicopathological review of 60 patients. Renal biopsy and clinical data from 60 patients with extracapillary proliferation (crescent formation) in greater than or equal to 50% of glomeruli were correlated. Nephropathy was related to infection (15 cases) malignancy (4 cases) and trichlorethylene exposure (2 cases). Isolated proteinuria was found 0.5-20 years before biopsy in 16 patients. Outcome was significantly related to percentage of crescentic involvement. Oligoanuria and impaired function at presentation were bad prognostic signs but preceding infection was favourable. Diverse histological and immunofluorescent findings indicate that extracapillary glomerulonephritis is not a single entity. The clinical course is not always rapidly progressive.


Relationship between degree of renal failure and impairment of intestinal calcium absorption. The coefficient of true intestinal calcium absorption (a value) was measured by a double radioisotope technique in 29 chronic renal failure patients (serum creatinine levles 2.5-19.5 mg%) aged 20-75 years. The mean log 10 a (+/- standard error) of these subjects (1.197 +/- 0.031) was significantly lower (p less than 0.001) than that of 52 controls (1.532 +/- 0.024), the geometric mean of the renal failure group (15.7%) being approximately half (46%) of that of the controls (33.9%). The decrease of a value of the uremic patients was more pronounced in the younger than in the older subjects as shown by a statistically significant (r = 0.570; p less than 0.001) positive curvilinear, relationship between a value and age. The lowest intestinal calcium absorptions were observed in patients with a serum creatinine level of approximately 11 mg%, the a values increasing progressively with lower or larger than 11 mg% serum creatinine levels, as shown by a statistically significant (r = 0.485; p less than 0.01) parabolic relationship between a value and serum creatinine. The possible mechanism(s) of this relationship are discussed.


Prediction of creatinine clearance from serum creatinine. A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.


Variation of urate excretion with urine flow in normal man. In normal persons, a decrease in urine flow following the injection of small amounts of vasopressin was accompanied by a significant decrease in the clearance and excretion of urate. When vasopressin and a small natriuretic dose of mannitol were administered together, urine flow and urate excretion again decreased. The recovery of urine flow to control values was accompanied by a similar recovery of urate excretion. Because a natriuretic dose of mannitol did not reverse the antiuricosuric effect of the flow decline, it is postulated that the flow effect probably reflects changes in a component of urate efflux distal to the loop of Henle.


Effect of carbohydrate intake on the urinary excretion of magnesium, calcium and sodium in fasting obese patients. The urinary excretion of magnesium, calcium and sodium has been measured in 19 obese patients undergoing 12 days on complete fast (days 1-12) followed by 6 days of carbohydrate supplementation (days 13-18), while receiving no mineral supplements or either calcium, magnesium or sodium supplements. Magnesium and calcium followed different excretion patterns during the 12 days fast. The oral administration of 107 g carbohydrate daily during days 13-19 resulted in a marked decrease in the urinary excretion of magnesium, calcium and sodium by the non-, calcium- and sodium-supplemented patients, but there was no carbohydrate-induced reduction in magnesium excretion in the magnesium-supplemented patients. The kidney appears capable of selectively influencing calcium and sodium reabsorption, without magnesium excretion being affected. It is suggested that involvement in increased renal gluconeongenesis during fasting renders the renal tubule incapable of maximally conserving both divalent and monovalent ions. The increased tubular reabsorption of urinary constituents induced by carbohydrate administration probably stems from the concomitant reduction in gluconeogenesis.


Short duration-high area regular dialysis using two UF 2 coils in series. To increase the number of regular dialysis patients without increasing apparatus, staff or buildings, short time-high area dialysis was undertaken for 3.5 h twice a week or 3 h three times a week with two UF 2 coils in series (2 m2) with dialysis fluid flow of 300 ml/min/kidney in parallel. The biochemical and clinical results were compared with those obtained in a period immediately prior to this using conventional 7-hours dialysis twice a week or 6 h three times a week on UF 145. Urea, creatinine and vitamin B12 clearances, predialysis blood urea and creatinine levels and the clinical state of the patients were satisfactory on short double UF 2 coil in series dialysis. Addition of 1-1.5 liters of saline during dialysis permitted an average net fall in body weight of 1 kg without cramps or hypotension. The merits of rapid dialysis with a large area dialyzer are discussed.


Distribution of intrarenal blood flow after renal denervation in the dog. The effect of acute denervation of the kidney on renal sodium and water excretion, and hemodynamics including intrarenal blood flow, was studied in anesthetized dogs. The intrarenal blood flow was measured by the radioactive microsphere method. In all experiments denervation natriuresis and diuresis was observed without significant change in glomerular filtration rate, renal blood flow and distribution of intrarenal blood flow. There was, however, an associated increase in potassium excretion. We suggest that denervation natriuresis and diuresis may be caused by the elimination of a direct nervous control of sodium and water reabsorption.


Recirculation peritoneal dialysis with sorbent Redy cartridge. Sorbent regeneration of peritoneal dialysate and use of small volume of dialysate for intermittent peritoneal dialysis (IPD) has been shown to be feasible. The present study compares the solute clearance (C) for urea (U) and creatinine (Cr) at varying flow rates in IPD and in recirculation peritoneal dialysis (RPD) utilizing Redy cartridge in ten dogs. Two silastic peritoneal catheters and one Sarns roller pump were used for RPD. CU was 12 +/- 2 ml/min (mean +/- 1SD),18 +/- 2 with IPD and 15 +/- 2,21 +/- 4 with RPD at flow rate of 66 and 100 ml/min, respectively, while CCr was 9 +/- 2,12 +/- 2 with IPD and 10 +/- 2, 13 +/- 3 with RPD. At increasing flow rates of 150,200 and 250 ml/min, CU was 27 +/- 3,31 +/- 4 and 32 +/- 6, and CCr was 17 +/- 2,20 +/- 3 and 22 +/- 3 with RPD. U and Cr were completely removed by the Redy. Glucose was not removed by the cartridge after initial saturation. Serum sodium concentration increased 2-3 mEq/l after 6 h of RPD. The data suggest that at comparable flow rates, RPD is relatively more efficient than IPD (p greater than 0.01). This may be due to continuous exchange across the peritoneal membrane in RPD. At high flow rate in RPD, solute removal is 2-3 times higher than the currently used IPD. RPD with Redy cartridge is mechanically simple, efficient, and may help reduce total peritoneal dialysis time.


Technique for the performance of repeatable renal clearances in the conscious male dog. A preparation for performance of renal clearances in the conscious dog is described. The important aspect of the technique is the use of a Pavlov sling and a specially designed restraining apparatus. Of most importance is the use of a 7 French Swan-Ganz balloon-tipped catheter for urinary bladder catheterization. The use of male dogs obviated the need for an episiotomy. No special training of the animals was required. The animals tolerated long-term and repeated catheterization without any evidence of infection or trauma.


When should maintenance dialysis be initiated? The present trend towared the use of maintenance dialysis in earlier stages of chronic renal failure, and more frequently in association with other morbid illness, raises the question of how well we understand the natural history and prognosis of chronic renal failure prior to total loss of renal function. Survival after serum creatinine exceeds 10 mg/dl is not necessarily very brief and is influenced by many variables. Morbidity and rehabilitation are poorly defined terms that should be approached as objectively and quantitatively as possible if the benefits of dialysis are to be assessed meaningfully.


Residual renal function and effective rehabilitation in chronic dialysis. The results of a 1-7 years follow-up of multiple processed and recorded semiquantitative parameters in 148 cases of chronic uremia on regular dialysis treatment (RDT) are reported. Patients were grouped according to different levels of residual creatinine clearance (CCr) at the beginning of treatment (0-5, 5-15, and 15-21 ml/min). Regardless of a possible return to work and reasonable quality of life, patients on RDT with 0-5 ml/min CCr invariably present a worsening in various subclinical parameters semiquantitatively evaluated (bone biopsies; nerve conduction velocity; glucose A-V, etc.). In patients with 5-15 ml/min CCr better results are found. In patients with residual CCr above 15 ml/min, impairment in several parameters is hardly evident and even after several years of dialysis may still remain minimal. These results seem of importance as far as the effective and not the apparent dialysis rehabilitation is concerned.


Influence of postural changes on the glomerular filtration rate in nephroptosis. The influence of postural changes on renal function was determined in 13 patients with nephroptosis and in 5 normal subjects by measuring GFR in the erect and supine positions. The result indicate that GFR was reduced in the erect position in 10 of 13 patients with either unilateral or bilateral nephroptosis whereas GFR was increased in the erect position in 4 of 5 patients without renal disease. One patient with bilateral nephroptosis and renovascular hypertension was studied before and after surgical correction of his disease. The observations indicate that patients with nephroptosis may have significant reductions in renal function when they assume an upright position, and suggest that GFR measurements in the supine and erect position in patients with nephroptosis can be helpful in evaluating this disease.


Renal trauma and persistent hypertension. A study has been made to assess the incidence of hypertension in patients who have suffered an episode of renal trauma sufficiently severe to cause haematuria. Sixty-three patients were studied and 63 age- and sex-matched controls were also studied. At follow-up, 6-138 months after injury, 13 of the patients who had suffered renal trauma and 12 of the control subjects had a diastolic blood pressure above 99 mm Hg. Three patients showed significant reduction in the size and volume of the previously damaged kidney. In this group, renal trauma did not appear to be associated with an increased risk of permanent hypertension.