Impact of age integration on the well-being of elderly tenants in public housing. The social, psychological, and environmental situations of a national area probability sample of 1875 elderly tenants in 153 public housing sites were studied by means of interviews with tenants and project mangers and direct observation of social and environmental characteristics of the housing. In this report the association between the age mix of the housing and the well-being of the tenants was investigated. With a variety of personal, social, and physical environmental characteristics statistically controlled, age segregation showed small but reliable relationships to on-site activity participation, morale, housing satisfaction, and neighborhood motility. The results are discussed in terms of policy and planning designed to maximize options for the individual.


Stature change with aging in black americans. The study consisted of a sample of 500 black Americans (50-104 years old) to determine whether or not there was a decrease in height among black Americans with increasing age. There is no significant difference between height and arm-span at the start of adult life. In order to study the loss of stature, as a result of senescence, a comparison of height with arm-span measurement was used. It was found that: (1) the black population has a greater decrease in height with aging than does the white population; (2) black males decrease approximately 4.2 cm in height every 20 years compared to 1.2 cm in the white population; (3) the older population sampled had shorter arm-spans as well as shorter stature.


Replication of age and physical activity effects on reaction and movement time. The latency and consistency of simple reaction time, choice reaction time, and movement time of older men who chronically run or participate in racket sports were compared to those of nonactive men of similar age and also to young men of similar characteristics (young runners, young racketsportsmen, and young nonactive men). The findings of Spirduso's (1975) study, of which this investigation was both a replication and an expansion, that older active men physically reacted to stimuli and moved their forearm over a 20 cm distance as quickly as young sedentary men was reported. The older active men were far superior to older sedentary men in all measures. In addition, the older active group was similar to the groups in terms of group homogeneity and within-subject variability, unlike the older nonactive group, who revealed the commonly reported group heterogeneity and within-subject inconsistency.


Spectrophotofluorometric and electron microscopic study of lipofuscin accumulation in the testis of aging mice. Lipofuscin accumulation in the testis of C57BL/6J mice ranging in age from 4 to 39 mo. was investigated by spectrophotofluorometric and electron microscopic techniques. Chloroform-methanol extracts of the whole organ contained fluorescent substances which increased linearly until about 24 mo. Thereafter, no further increases could be observed. Electron microscopy showed spermatogonia which were completely free of lipofuscin, in striking contrast with both Sertoli and interstitial cells of Leydig, which, in old animals, had accumulated very large amounts of pigment. In the Sertoli cells, a process of mitochondrial vacuolation and densification was apparently linked with the genesis of lipofuscin. On the other hand, in the interstitial cells, densification of lipid droplets played a role in the formation of most pigment granules.


Dermatoglyphics and aging.

Dermatoglyphics and aging. The objectives of the present study were to compare the frequencies of various dermatoglyphic features among male adults of four different age groups (30-44 years of age, 45-59, 60-74, and 75 years of age and older) and to compare the dermatoglyphic frequencies of a sample of normal 7-year-old males with those of each of the four adult groups. The results indicated that, for the most part, the four adult groups had very similar dermatoglyphic frequencies. The dermatoglyphics of the 7-year-olds were also found to be very similar to those of the 30- to 44-year-old adults; however, they showed, progressively, more significant dermatoglyphic differences as they were compared with succeedingly older age groups.


The response of arginine vasopressin to intravenous ethanol and hypertonic saline in man: the impact of aging. The effect of age on the hypothalamic-hypophyseal-renal axis in normal man was determined by assaying plasma arginine vasopressin (AVP) responses to inhibitory and to secretory stimuli. Nine young (21-49 years) and 13 old (54-92 years) subjects received IV ethanol (375 mg/m2 per min). AVP levels fell progressively during the infusion in the young group, but fell for only 30 min in the old group and then rose paradoxically despite the continuing increase in blood ethanol. Eight young (22-48 years) and 8 old (52-66 years) men were provided identical osmolal loads by a 2-hour IV infusion of 3% NaCl at 0.1 ml/kg per min. Serum AVP rose 2.5 times the baseline in the young and 4.5 times the baseline in the old men despite identical free water clearances. Osmoreceptor sensitivity (the slope of AVP on osmolality) was greater in the old subjects. The heightened sensitivity to hyperosomolality helps examine the paradoxical response to ethanol, since osmolality increased during that time. This increased AVP response may severe to compensate for the reduced renal ability to conserve salt and water in aging man.


A study on serum lipids of the elderly.

A study on serum lipids of the elderly. The present survey studies the triangular association of serum lipid levels, atherosclerosis, and age in an elderly (50 to 80 + years) population of 469 subjects with various clinical manifestations of atherosclerosis as well as "healthy" elderly subjects. In general, the average concentration of serum lipid constituents were not influenced by sex, age, differences in nutritional habits, or by atherosclerotic manifestations. Lipid levels were found to be within the normal range of the entire adult population. These results emphasize that lipid-lowering diets should start in young rather than in elderly people.


Illness and health behavior in septuagenarians. A random sample of septuagenarians was obtained by taking 400 consecutive names from a city birth register. Information regarding survival and present residence was acquired. The investigation comprised those septuagenarians who were still alive and had not moved abroad. The results showed that one-third reported no physical disease. Only half of those with physical disease considered themselves ill. Hypochondria was observed only in 3.9%, which contrasting with the high proportion of hypochondria in studies based on voluntary subjects. Active interest in physical exercise and a restrictive attitude to smoking and drinking correlated with health.


Quantitative evaluation of joint motion sensation in an aging population. Fifty-two neurologically normal subjects from 61 to 84 years in age were evaluated for sensitivity of perception of joint motion. Right and left metacarpophalangeal and metatarsophalangeal joints were passively moved in an ever-increasing amplitude in a sinusoidal flexion-extension mode. Precise measurements of the amplitude of the angle of deviation where the subjects felt motion were made and stored with the help of a computer. A younger cohort 19 to 34 years in age was also tested. The older subjects did less well in perceiving motion at the lowest frequency in the metatarsophalangeal joints. When the older cohort was separated in semidecades and compared to each other, as well as the younger cohort, all differences of motion threshold perception lost significance. It is concluded that there is no major decline in joint motion sensation with aging.


Examination of stimulus persistence as the basis for superior visual identification performance among older adults. Visual identification performance of sequentially presented corresponding word-halves was studied in 12 young (mean 18.9 years, range 18-21) and 12 old (mean 68.0 years, range 59-78) male and female subjects. Corresponding word-halves were composed of straight horizontal and vertical line segments and when superimposed tachistoscopically formed clear, fully closed 3-letter words. Stimulus duration and interstimulus interval (ISI) were systematically varied. Correct word recognition was found to be an inverse function of ISI and stimulus duration for both young and old subjects. An interaction was found between age, sex, and stimulus duration. Recognition scores were significantly higher among older subjects, an effect which was particularly prominent at greater ISIs. The data offer strong support for the stimulus-persistence model as applied to age differences in the sequential integration of form.


Principles for identifying structural differences. Some methodological issues related to comparative factor analysis. Several recent articles published in the Journal of Gerontology have been concerned with changes in factor structure of various psychological, social, and medical fitness measures. The present article reviews four principles for comparing structures and evaluates several recent articles in terms of these principles. The four principles are concerned with resolving: (1) problems of metric, (2) problems of rotation to similarity, (3) the number of factors problem, and (4) problems related to different extraction or rotational procedures across comparison groups. Utilization of a different metric in each correlation matrix implies that results may be a simple artifact of a different metric for each group. Failure to rotate to similarity and insufficient care with regard to the number of factors problem may result in artificially dissimilar structures. Finally, in comparing results across studies, differences in extraction or rotational procedures across different studies may result in differing results as artifacts of the methods employed.


Age differences in processing relevant versus irrelevant stimuli in multiple-item recognition learning. Age differences in the processing of relevant stimuli were examined under two levels of irrelevant stimulation. The relevant stimuli were the right words of a multiple-item recognition learning task; the two levels of irrelevant stimulation were provided by the pairing of one wrong word (two-alternative items) versus three wrong words (four-alternative items) with each right word. Elderly subjects were inferior to young adults in the learning of four-alternative items, but not in the learning of two-alternative items. This finding supports the hypothesis, derived from previous research on perceptual tasks, that elderly adults direct greater amounts of attention to irrelevant stimuli than do young adults, thus reducing the amount of processing available for the accompanying relevant stimuli. However, despite their presumed greater attention to irrelevant stimuli, elderly subjects recognized fewer individual wrong words on a subsequent memory test than did young adults. This age-related effect was interpreted in terms of depth of processing theory.


Cautiousness and verbal learning in adulthood. Twenty-two young (age 17-21)and 22 old (age 60-74) men and women participated in an investigation designed to determine the extent to which age differences in omission errors and performance in a serial learning task are accounted for by cautiousness. Age differences were found on the measures of cautiousness, and verbal learning, with young adults making more correct responses and proportionately fewer omission errors on the learning task and taking greater risks on the risk-taking tasks. The results indicated that cautiousness measures accounted for age differences in omission errors but not in performance.


Age perceptions and evaluative reactions toward adult speakers. This study was designed to assess listeners' ability to judge a taped speaker's age and to measure the extent to which personality ratings are affected by perceived age. In two experiments, undergraduate subjects demonstrated that speaker age can be reliably estimated over a wide range for both female and male voices. Furthermore, female speakers perceived to be older were viewed to be more reserved, passive, out-of-it, and inflexible than younger ones; males sounding older were viewed as less flexible than those sounding younger. In the light of these results, the experimental procedure employed appears to provide a promising approach to the indirect assessment of age stereotypes.


Concanavalin A and ricinus communis receptor sites in normal human oral mucosa. Fluorescein conjugates of concanavalin A (Con-A) and Ricinus communis fraction 120 (RCA120) were shown to bind to the cell surfaces of basal and spinous cell layers in oral buccal mucosa. Palatal epithelium showed distinct binding to basal and spinous cells; cell membranes in the granular layer occasionally bound Con-A and always RCA120. The ultrastructural localization of Con-A binding sites on exfoliated buccal cells was detected by the Con-A peroxidase staining method. The Con-A receptors were seen on the cell surface in association with the outer leaflet of the plasma membrane. The reaction products appeared as a homogeneous, electron-dense layer containing irregularly distributed globules.


UV-induced unscheduled DNA synthesis in guinea pig skin melanocytes isolated in culture. Pigmented melanocytes isolated in culture from the epidermis of guinea pig ears were used to study the unscheduled DNA synthesis (UDS) induced by ultraviolet (UV) irradiation at 254 nm. After irradiation, the cells were labeled for 6 hr with 3H-thymidine (3HTdR), fixed, dehydrated, and flat embedded in Epon. Radioautographs were made on serial 0.5-1 micrometer thick sections of the cultures in order to distinguish silver grains from pigment granules. Cells irradiated with 5, 10, or 50 joules (J) m-2 showed a 3HTdR uptake due to UDS, whereas their proliferative ability, measured by the 3HTdR uptake due to scheduled DNA synthesis, was very low. For the same UV doses, UDS was lower in melanocytes than in guinea pig fibroblasts and keratinocytes.


5-S-cysteinyldopa excretion after treatment with 8-methoxypsoralen and UVA light. The excretion of the specific melanocytic metabolite 5-S-cysteinyldopa was studied in patients with psoriasis treated by 8-methoxypsoralen and UVA light. A pronounced increase was found after only 2 days treatment, although no increase in pigmentation could yet be observed. Peak values for urinary 5-S-cysteinyldopa were noted after 1 or 2 weeks treatment. Increase in pigmentation persisted after the excretion maxima for 5-S-cysteinyldopa.


Two tris urea mercaptoethanol extractable polypeptides found uniquely in scales of patients with psoriasis. This study was designed to chemically characterize the principal structural proteins of psoriatic scales. Cornified cells were obtained from 40 patients with psoriasis, 21 patients with other scaly diseases, and 13 normal individuals. Cells were washed with Tris-HCl buffer and incubated in 8 M urea containing 2-mercaptoethanol (pH 9.0) at 30 degrees C for 7 hr. Extracted proteins were subjected to SDS polyacrylamide gel electrophoresis and protein patterns from normal and diseased scales were compared. The 67,000 dalton constituent of normal cornified cells could not be identified in protein from psoriatic scale and instead, a pair of polypeptides of approximately 54,000 and 57,000 daltons appeared. These extra bands were not found in protein extractions from other skin diseases, uninvolved skin of psoriasis patients, or normal skin. In order to analyze further normal and psoriatic scale proteins, the immunoreaction of rabbit antisera to human 67,000 dalton polypeptide with extracted psoriasis protein and with frozen biopsy sections, was studied using immunoprecipitation tests and indirect immunofluorescence microscopy. Both techniques demonstrated the existence of the 67,000 dalton protein in psoriasis, but as a minor component. These results indicate that additional unique urea mercaptoethanol soluble proteins are formed in psoriatic lesions, and this unusual protein synthesis may reflect the morphological changes in this disease.


The effect of antimicrobial agents on leukocyte chemotaxis. The effects of several chemotherapeutic agents on the chemotaxis of human leukocytes were studied in an in vitro system using a Sykes-Moore chamber and a double-filter technique. Chemotactic factor was generated by the interaction of normal human serum and zymosan. At concentrations comparable to and below therapeutic blood levels, tetracycline HCl, erythromycin base and clindamycin HCl were all inhibitory, causing marked suppression of leukocyte chemotaxis and slight reduction of random migration. Penicillin G-Na, dapsone, and sulfapyridine did not alter white cell motility at the concentrations of drug tested. It is postulated that the capacity of some of these agents to inhibit leukocyte chemotaxis may account, in part, for their efficacy in inflammatory skin diseases such as acne vulgaris.


Quantitation of 25-hydroxycholecalciferol in human serum by high-pressure liquid chromatography. An HPLC method for assaying 25(OH)D3 in extracts of human serum is described. The method involves extraction of serum with methanol-dichloromethane and chromatography on a column of Sephadex LH-20 prior to HPLC with quantitation by UV absorbance. Comparison with a CBP assay for 25(OH)D3 showed no difference between the two methods.


Platelets from "giant platelet syndrome (BSS)" are discocytes and normal sized. A comparison is made between the shape of human platelets obtained from nine normal donors and two BSS donors. Sizes are evaluated from a cinematographic analysis of freely rotating, unfixed, and glutaraldehyde-hardened platelets in citrated PRP and of platelets on blood smear. On blood smeae, the mean diameters of BSS platelets are 1.7 to 1.8 times larger than those of normal platelets, with a major fraction having a diameter greater than 2.5 micrometer. As for normal donors, 80% to 90% BSS platelets in PRP are in the disc form (discocyte). In addition, they are essentially indistinguishable from a normal discocyte. Echinocytes (spherical forms with pseudopods) for BSS have a main body diameter (i.e., excluding pseudopods) 1.6 times larger than normal and in addition a reduced number of pseudopods. The results demonstrate that the giant size of BSS platelets results from abnormal behavior of these platelets during the preparation of the blood smear. It is suggested that this disorder is associated with a defect in the mechanism of platelet shape change.


Humoral regulation of thrombopoiesis in man. Plasma was obtained before and after plateletpheresis-induced thrombocytopenia from two healthy male subjects during periods of ethanol ingestion and abstinence. Autologous reinfusion of these plasmas was performed at a later date when both subjects were hematologically normal. Eight thrombopoietically active plasmas produced an increased percent of immature megakaryocytes 24 hr after reinfusion and a peak rise in platelet count (averaging 148% of baseline values) at 5.8 days. Similar changes were not found with inactive plasmas, plasma collected at the end of a "sham" plateletpheresis, or plasma collected after 8 hr of ingestion of 296 gm of ethanol. A transient increase in TSA was found in plasmas collected at the end of plateletpheresis during abstinence, but this activity was not detected 12 hr later. The rapid disappearance of TSA, despite persistent thrombocytopenia, coincided with the appearance of an increased percent of immature magakaryocytes in the bone marrow. Elevated TSA was also noted at the end of plateletpheresis during ethanol ingestion but, in contrast to events during abstinence, remained elevated as long as ethanol ingestion continued.


A noninvasive method for the evaluation of tissue iron deposition in beta-thalassemia major. DXS, a noninvasive method for the analysis and quantitation of trace elements in different tissues, was applied to quantitate the degree of iron overload in the skin of 19 patients with beta-thalassemia major. The duration of the test is short, it is not associated with inconvenience to the patient, and it can be repeated at different times at different locations on the outer surface of the body. In patients who receive numerous repeated blood transfusions, there was a close correlation between the dermal iron content and the rate of transfusions when they exeeded 6 units of packed RBC per year. In three patients with the spleen in situ, the dermal iron content was lower than in corresponding splenectomized patients. The rate of dermal iron accumulation was found to be similar to the rate of iron deposition in the liver, as assessed in a similar group of patients by repeated liver biopsies. The monitoring of the degree of iron accumulation in individual patients as a function of time and the effect of treatment with iron chelating agents can be determined noninvasively with the aid of DXS.


Heterogeneity of human factor VIII. I. Characterization of factor VIII present in the supernatant of cryoprecipitate. Recent observations suggest that plasma F VIII consists of a series of molecules with different molecular weights. The data described in this paper suggest that sup F VIII represents the molecules with relatively low molecular weights whereas the molecules with the highest molecular weights appear in cryo F VIII. Sup F VIII was associated with VIII:C and VIIIR:Ag, but ristocetin cofactor activity was lacking. Although the immunoprecipitation characteristics of sup F VIII with rabbit antifactor VIII were different from those of cryo F VIII, immunological identity was observed in immunodiffusion and crossed immunoelectrophoresis. In 0.8M NaCl sup F VIII dissociated into VIIIR:Ag of relatively high molecular weight and VIII:C of low molecular weight. No indications were obtained that the presence of sup F VIII was the result of proteolytic degradation of factor VIII. VIII:C of sup F VIII was more labile in vitro than VIII:C in plasma. It could be activated by traces of thrombin in a way similar to plasma F VIII. In patients with classic von Willebrand's disease relatively more VIII:C remained in the supernatant after cryoprecipitation of plasma.


Interaction of human platelets with heparinized agarose gel. Platelet interaction with surfaces to which heparin had been covalently bonded was investigated with a chromatographic technique employing agarose gel beads heparinized via a cyanogen bromide reaction. Heparinization significantly increased platelet retention by the gel. Platelet retention was unchanged after pretreatment of the heparinized gel with albumin but increased after pretreatment with fibrinogen. Pretreatment with plasma or purified AT III decreased platelet retention. Reduction in platelet retention was correlated with the amount of AT III removed from plasma. Plasma with decreased levels of AT III was less effective in surface passivation. Pretreatment of heparinized gel with PF4 or protamine sulfate did not decrease platelet  retention, but subsequent exposure to plasma did. The results suggest that a surface with covalently bonded heparin is reactive toward platelets but can be passivated by formation of a heparin/AT III complex.


Uremic hyperstannum: elevated tissue tin levels associated with uremia. Previous work has shown that the concentration of the essential trace element tin is elevated in several tissues of dialyzed uremic patients. Analysis of 80 postmortem liver samples from controls and nondialyzed uremic and dialyzed uremic patients now shows that nondialyzed uremic patients also have abnormally high tin concentrations, averaging about three times that of controls. It is concluded that these elevated tin levels are associated with uremia rather than with dialysis. Abnormally high tin levels were also found in the kidneys of uremic patients at autopsy. This may have special importance, since tin has been shown to be a powerful inducer of heme oxygenase activity in rat kidney. The urinary excretion of tin by nondialysed uremic patients was measured and found to be normal.


Thrombin binding to thrombasthenic platelets. Platelets from two patients with Glanzmann's thrombasthenia showed decreased iodination of surface glycoproteins GPIIb and GPIII. Despite these changes, the binding of [125I] alpha-thrombin to the thrombasthenic platelets was normal. Binding was linear up to a thrombin concentration of 0.1 to 0.2 U/ml, at which point a change in the slope of the binding curve was observed. At lower concentrations of thrombin, 1,000 to 2,000 molecules of thrombin were bound per platelet, with an apparent Kdiss of 0.1 to 0.3 U/ml. With high concentrations of thrombin, thrombasthenic platelets bound 30,000 to 65,000 molecules of thrombin per platelet at saturation, with an apparent Kdiss of 5 to 10 U/ml. The release of [14C]serotonin by thrombasthenic platelets as a function of thrombin concentration was also similar to release by normal platelets. These studies indicate that the receptor(s) for thrombin on the plasma membrane of platelets from patients with Glanzmann's disease are intact and that membrane glycoproteins GPIIb and GPIII play little or no role in either the initial binding of thrombin to platelets or the transmission of this surface stimulus to release-inducing mechanisms.


Determination of prekallikrein in human plasma: optimal conditions for activating prekallikrein. A method for the assay of human plasma prekallikrein in which a chromogenic synthetic tripeptide, PPAN, is used as a substrate for kallikrein is described. The conversion of prekallikrein to kallikrein is achieved by cold activation (0 degrees C) with water-soluble dextran sulfate. Conditions for obtaining optimal amounts of free kallikrein with respect to concentration of dextran sulfate, activation time, inhibitors (C-1-inactivator), and requirement of factor XII have been determined. The activation procedure is compared to other known procedures. The assay system was worked out for pooled normal plasma and is applicable to any plasma sample not liable to unwanted preactivation or incomplete inactivation, as revealed by control experiments. A survey in 15 apparently health individuals showed a mean activity of 476 +/- 58 (S.D.) mU/ml with a range of 385 to 586 mU/ml.


Stressful life events and community mental health center patients. This paper reports on the occurrence of stressful life events prior to treatment and at a follow-up timepoint in a general sample of community mental health center patients. Life events scores from the patients, at both timepoints, are compared with scores from a nonpatient sample drawn from the community. Results indicate that patients before entering treatment tend to experience more events (particularly undesirable ones that could be confounded with psychological condition) than nonpatients. The result is no longer true at the follow-up time point. Findings regarding life events and patienthood are basically the same whether all events are used (i.e., the change score) or undesirable events alone. If, however, only events judged to be unconfounded with psychological condition are considered, we find no difference between patients and nonpatients at either timepoint. Implications of the study's results for the direction-of-effect issue with respect to the stress-psychological disorder relationship are discussed.


Social functioning and self-care in hospitalized psychogeriatric patients. Evaluations of social disability have been found useful in determining factors of diagnostic,  therapeutic and prognostic significance in the management of psychogeriatric patients. A random sample of 100 psychogeriatric patients aged 65 or over admitted to three Toronto hospitals were studied prospectively. Standardized clinical and social interview schedules were used to assess patients' mental state, self-care capacity, social isolation, burden on the family and household contribution before admission. These assessments were carried out to determine their significance with respect to diagnosis and outcome. Self-care capacity, as measured by the Activities of Daily Living Performance Test or by informant report, was related to diagnosis and outcome measures in this sample. Social isolation was significantly correlated with length of hospital stay. Burden on the family was not found to be significantly associated with diagnosis or outcome although there was a tendency for patients with organic disorders to present more difficulties for their families. The severe burden imposed on relatives suggests the need for utilization of community social and medical services to provide relief for families of psychogeriatric patients. The implications for management are considered in the light of the above findings.


Drug dependence: a study of the relationship between motivational, cognitive, social and historical factors, and treatment variables. The question of why addicts seek and remain in treatment has received very little attention. In the present study, 40 addicts requesting inpatient treatment for drug dependence were interviewed prior to admission about cognitive, motivational, social, and historical factors. These factors were investigated in relation to their association with certain treatment variables--whether or not the individual subsequently presented for admission, the manner in which inpatient treatment was terminated, and the length of stay. The factors most potent as predictors included the addict's evaluation of the drug unit itself, and social pressures from the family. Forensic factors were found to be positively related to length of admission; and motivation for treatment--a problematic concept which has frequently been regarded as tautologous--is also discussed. The results point to the complex interaction of factors associated with the addict's decision to seek treatment.


Course and prognosis of the syndrome of doubles. The course and prognosis of 20 patients with the syndrome of doubles (syndrome of Capgras, syndrome of Frégoli, syndrome of intermetamorphosis, syndrome of subjective doubles) were studied. The onset of the syndrome occurred either synchronously or at a later stage than the onset of the associated psychosis. The syndrome failed to remit in seven of the 20 cases, and in the others remission occurred either synchronously with or later than the remission of the basic psychosis. In all cases of depression, the syndrome cleared shortly after remission of the depressive illness. It was, however, more persistent than the accompanying psychosis in the schizophrenic patients with the Capgras variety. Relapse of the basic psychotic condition in the setting of which the syndrome had originally developed was invariably accompanied by reappearance of the syndrome.


Some issues in research on stressful life events. This paper is concerned with the kind of work that is needed in order to provide a more solid scientific foundation for the belief that life stress causes illness. Although indirect evidence from controlled laboratory studies and from extreme situations provides strong indications of the general relationship between stress and illness, the evidence concerning the effects of naturally occurring and more ordinary stressful life events is less clear. Although we have a body of research indicating that life events are associated with a wide range of disorders and distress, it does not provide a clear picture of the nature and strength of this relationship. In order to clarify our understanding of how stressful life events affect health and illness, we will need to deal with methodological issues that have emerged from research to date and to tackle a major substantive problem that has been largely neglected. The methodological issues are three: a) definition of the populations of life events to be studied; b) measurement of the magnitudes of the life events; and c) use of a research design appropriate to the question to be answered. The substantive issue concerns factors that mediate the impact of life events. Each of these issues is examined in turn in this paper.


Morphologic and metabolic studies in a case of oculo-cranio-somatic neuromuscular disease. A case resembling the syndrome of "ophthalmoplegia plus" or "oculo-cranio-somatic neuromuscular disease" is reported. A biopsy of deltoid muscle showed that 23% of the fibers were "ragged-red fibers" and were all type 1. Study of their ultrastructure revealed clusters of abnormal skeletal muscle mitochondria in subsarcolemmal and intermyofibrillar spaces. A liver biopsy also revealed a considerable increase in the number and size of the mitochondria. In some instances the mitochondria contained osmiophilic rounded inclusions surrounded by myelin-like structures. Metabolic studies revealed an increase of blood lactate concentration after very light exercise, while the O2 consumption was increased within the expected range. It is concluded that: a) the association of ophthalmoplegia and ultrastructural alterations of the mitochondria in muscle fibers may represent a specific nosographic entity: b) mitochondrial abnormalities are not limited to the skeletal muscles and c) the dysmetabolic basis of such a clinico-pathological entity might lie in an alteration of the mechanism which regulates the mitochondrial oxidative phosphorylation.


Dystopic myelination with hypertrophy of pyramidal tract. In a case of hypertrophy of the pyramidal tract the cross section of the hypertrophic pyramids was 174% of controls with an increase  (148%) in the total population of myelinated fibers. However, there was no commensurate increase in the density of Betz cells. Confined to the hypertrophic tract there was a peculiar anomaly consisting of tubes of thick myelin sheaths that encompassed columns of glial nuclei instead of axons. This type of change, along with the clinical data, may indicate that the lesion originated in the perinatal period when myelin formation is in progress and is susceptible to derangement.


Pathogenesis of the Arnold-Chiari malformation: the significance of hydrocephalus and aqueduct stenosis. In 24 cases of spina bifida, correlations were made comparing the degree of hydrocephalus with the cross-sectional area of the supratentorial compartment, posterior fossa, hindbrain prolapse, size of myelocele, and degree of fibrovascular reaction at the base of the brain. The size and postion of the aqueduct and fourth ventricle were compared with the degree of hydrocephalus. The results demonstrate that the aqueduct stenosis is usually due to external compression of the mesencephalon. The results also suggest that the size of the posterior fossa and hindbrain prolapse are secondary to hydrocephalus. It is postulated that the hydrocephalic process may be initiated by fibrovascular occlusion of the basal subarachnoid space.


A critical comparison of neurosurgical and otolaryngological approaches to acoustic neuromas. Neurosurgeons have traditionally advocated the transmeatal suboccipital craniectomy as the procedure of choice in treating acoustic neuromas of all sizes. With this technique, complete tumor removal was achieved in 91% of our patients. Facial motor activity was fully preserved in 59% and it was only partially deficient in an additional 29%. Conversely, recent otological reports have proposed a more flexible attitute in which the size of the tumor dictates the form of surgical therapy. In that scheme, the universally applicable and clinically proven suboccipital craniectomy is replaced by a series of procedures (translabyrinthine, middle fossa, transsigmoidal), each of which differs in its anatomical and technical requirements. This necessity for several operations seems to stem from the failure of any particular approach either to provide adequate visualization of the entire pathological process, or to afford maximum opportunity for complete tumor removal. By employing these various techniques, total capsular removal has been generally achieved in only 71% of cases. A careful comparison and analysis of these individual procedures reaffirms the superiority of the posterior fossa approach.


Extrapyramidal disorder with pineal germinoma. Case report. Space-occupying lesions of the basal ganglia are a rare cause of extrapyramidal dysfunction in children. Metastatic pineal germinoma in both basal ganglia produced dystonia in a 12-year-old boy. The literature is reviewed. Extrapyramidal manifestations in the child are compared with previously reported cases of basal ganglia neoplasms.


Bilateral carotid-cavernous fistulae of mixed types with unusual radiological and neuropathological findings. This report describes a case of bilateral post-traumatic carotid-carotid-cavernous fistulae (CCF), of both typical and atypical types, with delayed clinical deterioration. Unusual neuropathological lesions, distinctive from those due to direct cerebral trauma, are related to combined arterial ischemia and venous hypertension. Atypical CCF is not necessarily a benign disorder. Radiological monitoring is essential to detect spontaneous progressive intracranial shunting, to predict areas that are at risk from venous hypertension, and to identify remote sites of circulatory vulnerability.


Herniated thoracic disc at T1-2 level associated with Horner's syndrome. Case report. A case of symptomatic herniation at the first thoracic disc level is reported. The patient presented with hand weakness, Horner's syndrome, and pain radiating along the medial aspect of the upper extremity. Myelography demonstrated a smooth lateral defect at T1-2. Three sequestrated epidural disc fragments were removed with postoperatvie relief of pain. A slightly miotic pupil remains.


Spinal cord vasculitis presenting as a spinal cord tumor in a heroin addict. Case report. Progressive quadriparesis in a heroin addict was diagnosed on the basis of clinical and myelographic findings as an intramedullary cervical spinal cord tumor. A biopsy of the enlarged cervical spinal cord showed myelomalacia, vasculitis, and many doubly refractile bodies in the parenchyma and vessel walls.


Mobile schwannoma of the cauda equina. Case report. A patient with a mobile schwannoma of the cauda equina is described. The wide discrepancy between the myelographic and surgical locations of the tumor is most unusual. Awareness of the possibility of such an extreme degree of motility is important when dealing with cauda equina tumors.


Camurati-Engelmann disease (progressive hereditary craniodiaphyseal dysplasia). Case report. In a patient with Camurati-Engelmann disease, orbital and optic nerve decompression resulted in improvement of papilledema. Subsequent x-ray films of the optic canals, however, revealed reconstitution of osseous optic canals bilaterally, and papilledema has returned in one eye. Definitive treatment of this dysplastic metabolic bone disorder rests in the control of rapid abnormal bone formation.


Inferior vena cava and hepatic vein thrombosis as a rare complication of ventriculoatrial shunt. Case report. A case is reported of hepatic vein thrombosis (Budd-Chiari syndrome) complicating ventriculoatrial shunt for tumoral hydrocephalus. The diagnosis of hepatic vein thrombosis requires specific radiographic investigations that are unlikely to be undertaken unless the condition is specifically suspected. An awareness of this rare and frequently fatal complication is essential for proper diagnosis and treatment.


Migration of ventriculoperitoneal shunt into the chest. Case report. A case is presented of a baby in whom the abdominal catheter of a ventriculoperitoneal shunt entered the thoracic cavity. It is believed that the catheter migrated along the xiphocostal margin beneath the rectus abdominis muscle.


Coexisting pituitary adenomas and partially empty sellas. seventeen cases of coexisting secreting pituitary adenomas and partially empty sellas are presented. The location of the cisternal invagination into the sella was not helpful in predicting the location of the tumor. In patients with endocrine indication of a secreting pituitary neoplasm, the finding of a partially empty sella should not contradict the diagnosis.


SEM evaluation of endothelial damage following temporary middle cerebral artery occlusion in dogs. Microsurgical clips and tourniquets were used to occlude middle cerebral arteries of dogs for 45-minute periods. Scanning electron microscopy and light microscopy studies revealed significant endothelial damage in many of these arteries. Less traumatic microsurgical clips are needed for temporary small vessel occlusion.


Ultrastructural changes in feline arterial endothelium following subarachnoid hemorrhage. Scanning electron microscopy of feline basilar arterial endothelium 4 hours, and 1, 3,5, and 7 days after subarachnoid hemorrhage (SAH) showed longitudinal furrows that correlated with angiographically demonstrated vasospasm. These ridges persisted after fixation at physiological pressure, and probably reflected medial contraction with undulation of the underlying elastic lamina. No change in endothelial cell morphology or thrombogenesis was observed as long as 7 days after SAH. There is no evidence from this study to suggest that ischemia from vasospasm is a product of thromboembolism from damaged endothelial surfaces.


Pathological changes from acute to chronic in experimental spinal cord trauma. The pathological changes occurring in the thoracic spinal cords of 41 cats were studied by light microscopy at 4 hours, 4 weeks, and 4 months after graded transdural trauma. Alterations characteristic of a vascular injury proportionate to the magnitude of the original trauma which results in tissue hypoxia, destruction, and reparation were identified at each interval studied. In more severely injured animals these changes consisted of an initial hemorrhagic infarction followed by the removal of necrotic parenchyma and the development of an adhesive arachnoiditis and intramedullary carvitation. A comparison of the findings in the present investigation with what has been described in postmortem studies of spinal cord injured patients indicates that the response of the spinal cord to non-disruptive trauma is similar in both cases.


Pineal and suprasellar germinomas. Results of radiation treatment. The results of radiation treatment of 52 patients with a tumor in the pineal region or a suprasellar germinoma are analyzed. The overall 5-year survival rate was 59%. Ten patients in whom initial biopsy confirmed pineal germinoma were all alive 2 to 121 months from diagnosis, although two developed meningeal seeding at 2 and 7 months. Twelve of 15 patients 25 years old or younger with an unbiopsied tumor in the pineal region were alive 12 to 225 months after irradiation, with a 5-year survival rate of 81%. In comparison only five of 16 patients older than 25 years with a pineal region tumor survived, a 5-year survival rate of 37%. This marked age dependence in survival rates was attributed to a high proportion of germinomas in the younger patients and gliomas in the older patients.


Influence of different levels of dietary pyridoxine on milk composition in the rat. The effects of five different levels of dietary pyridoxine on milk composition were studied in the rat. Sprague-Dawley strain rats received diets containing 1.2, 2.4, 4.8, 9.6 or 19.2 mg pyridoxine-HCl/kg diet throughout growth, gestation and lactation. Milk samples obtained on days 10, 11, and 12 of lactation were similar in concentrations of total fat, solids-not-fat, carbohydrate, casein and non-casein protein for rats fed the five levels of pyridoxine. The level of vitamin B-6 in milk was significantly higher for rats fed 9.6 or 19.2 mg pyridoxine.HCl/kg diet compared to values for rats fed the three lower levels of vitamin. A higher level of dietary pyridoxine (9.6 mg/kg diet) was required to increase the levels of the vitamin in mammary gland and milk than was needed for maternal liver (4.8 mg/kg) or muscle tissue (2.4 mg/kg). The findings indicated that as the level of pyridoxine was decreased in the diet from an apparently adequate level, the concentration of the vitamin in milk decreased before that in liver or muscle tissue. This suggested that the concentration of the vitamin in milk was an indicator of marginal deficiency of vitamin B-6.


The effect of litter size on weight gain in mice. The body weights of rodents at weaning are generally believed to be inversely related to the number of animals in the litter during the birth-to-weaning period. Quantitative data for rats have been published, but not for mice. Using carefully matched litters, we have measured the average body weights of mice raised in litters containing 2, 4, 6, and 12 pups relative to the average body weight of litters of eight pups. Except for the 2 pup litters, the inverse relation was found to hold. It is also shown that the pattern of average weaning weight as a function of litter size is the same as previously published by two other groups using rats.


Influence of dietary potassium on lysine metabolism in the chick. High levels of dietary cations have been reported to spare the arginine requirement of chicks fed a diet containing excess lysine. The present studies were conducted to determine the nature of this effect, using potassium as the variable cation. The inclusion of 1.8% potassium in a high lysine diet improved growth but did not affect consistently the efficiency of feed utilization, nor did it have a significant effect on arginine metabolism as measured by renal arginase activity, urea excretion or arginine excretion. Lysine catabolism was markedly increased, however. Chicks fed the potassium supplemented diet converted approximately 23% of an oral loading dose of 14C lysine to respiratory 14CO2 over a 6-hour period, in contrast to approximately 9% of the dose in chicks fed the unsupplemented diet containing 0.4% potassium. The activity of hepatic lysine-alpha-ketoglutarate reductase, an initial enzyme in the catabolism of lysine, was increased in response to potassium or arginine supplementation. It is proposed that high levels of potassium or other cations may improve the growth of chicks fed diets containing excess lysine by increasing lysine catabolism. The effect on growth may be mediated primarily by increasing food intake and to a lesser extent by alleviation of the other metabolic manifestation of the lysine-arginine antagonism.


Iron deficiency hyperlipidemia in 18-day-old rat pups: effects of milk lipids, lipoprotein lipase, and triglyceride synthesis. Three levels of iron (5, 29, 307 ppm iron) were fed to rats from conception through the 18th day of lactation. Dams in the 5 ppm iron group and pups in the 5 and 29 ppm iron groups developed anemia characterized by lower hemoglobin and hematocrit values than control animals. Liver and spleen levels of iron in dams and pups in the 5 and 29 ppm iron groups were lower than in the 307 ppm iron groups. Milk iron was lower in the 5 ppm iron group than in the 29 and 307 ppm iron groups. Pups in the 5 ppm iron group had hyperlipidemia characterized by elevated serum triglycerides, cholesterol, and phospholipids. Milk lipids and post-heparin plasma lipoprotein lipase levels in pups did not differ among experimental groups. Triglyceride and CO2 production from [U-14C]glucose were significantly greater in the iron-deficient pups than in control pups. Hyperlipidemia in 18-day-old iron-deficient rat pups appears to be related to increased endogenous production of triglycerides.


Threonine metabolism in vivo: effect of threonine intake and prior induction of threonine dehydratase in rats. The metabolic fate of threonine was investigated in young male rats fed 15% amino acid diets containing from 0.15% to 0.85% of L-threonine. Liver serine-threonine dehydratase (S-TDH) activity did not increase with increasing dietary threonine content. The level of threonine required for maximum weight gain was not greater than 0.55% of the diet (or about 600 mumoles/day). Tissue free threonine content of rats fed the diets with 0.15% or 0.3% of threonine was very low but increased sharply with increasing dietary threonine content above 0.3%. During ad libitum feeding of these diets containing L-[U-14C]threonine, rate of oxidation of threonine was low when intake was in the range of the requirement for maximum growth, but increased, thereafter as threonine intake increased. A 30-fold induction of liver S-TDH, by prior feeding of an 80% casein diet, did not result in increased oxidation of threonine when dietary threonine content was 0.15%. When dietary threonine content was increased to 0.5%, oxidation of threonine increased slightly but significantly. With 3% of threonine in the diet, rats previously fed a 15% casein diet had extremely high tissue threonine concentrations whereas those with high S-TDH activity, due to the previous feeding of the 80% casein diet, oxidized threonine rapidly and tissue threonine concentrations were elevated much less.


Thiamin requirement of channel catfish fingerlings. In separate 20 and 12 week feeding studies, channel catfish fingerlings were fed semipurified diets containing five levels (0, 2.5, 5.0, 10.0 and 15.0 mg/kg) and six levels (0, 0.5, 1.0, 2.5, 5.0 and 10.0 mg/kg) of supplemented thiamin hydrochloride respectively. The dietary thiamin level required to provide maximal growth and prevent deficiency symptoms in channel catfish fingerlings was found to be approximately 1 mg/kg of diet. Fish fed unsupplemented diets (thiamin content of less 1 mg/kg diet) demonstrated anorexia, extremely poor growth, dark coloration of the skin and increased mortality rates. Neurological symptoms were not observed. Histological examinations of the heart, hepatopancreas, kidney, lateral muscle, gastrointestinal tract and gills of deficient fish revealed no abnormalities.


Effects of dietary corn on hematological response of anemic rats to ferrous sulfate. Anemic rats were fed diets containing adequate quantities of all required nutrients, except iron, which was supplied by ferrous sulfate and/or corn grain. Diets were supplemented with the inorganic salt and corn in such a pattern that regression of hematological response on increments of ferrous sulfate intake could be calculated for 0, 25%, 50% and 75% dietary corn. Corn was added to the diets at the expense of starch which served only as a source of energy. Slopes of the regression lines for response (hemoglobin iron gain or final hemoglobin concentration) to ferrous sulfate intake were not altered significantly by inclusion of up to 75% corn in the diets. Results indicate that corn does not contain an inhibitor of iron absorption. Poor iron absorption from diets or meals in which corn provides a significant portion of the total food supply is probably due to a nutritional inadequacy of the corn, possibly its amino acid imbalance.


Effect of branched-chain keto-acids and dietary protein content on the activity of branched-chain amino acid transferase in rat tissues. Rats fed branched-chain keto-acids in place of branched-chain amino acids exhibited increased specific activity of branched-chain amino acid transferase (BATase) in muscle, intestine, brain and liver as compared with controls fed sufficient diet to achieve comparable weight gain. This increase was observed whether or not methionine and phenylalanine were also replaced by their N-free analogues. Kidney BATase was unaffected. Rats fed a protein-free diet exhibited higher BATase specific activity in kidney, brain, liver and intestine than rats fed diets containing 6% casein; but little change in specific activity in these organs was seen as casein intake was progressively increased from 6% to 18%. Muscle BATase specific activity was the same between 0 and 18% dietary casein. The results show that branched-chain keto-analogues augment BATase in several tissues, including muscle. In contrast, varying casein intake from 6% to 18% had little effect, although protein-feeding augments BATase in some organs.


Protein intake, hepatic purine enzyme levels and uric acid production in growing chicks. Changes in hepatic purine enzyme activities of chicks fed diets containing 11%, 20%, 43% and 80% protein were correlated with protein intake and uric acid production in order to identify those enzymes with activities that parallel closely and may regulate uric acid production. Nucleoside phosphorylase, xanthine dehydrogenase, adenylosuccinate synthetase and adenosine kinase correlated positively with protein intake and uric acid production. Adenosine deaminase, 5'-nucleotidase (AMP), adenylate deaminase and adenine phosphoribosyltransferase correlated negatively with protein intake and uric acid production. Hypoxanthine phosphoribosyltransferase and 5'-nucleotidase (IMP) were unaffected by protein intake and did not correlate with uric acid production. The ratio of adenosine kinase to adenosine deaminase correlated positively with protein intake and uric acid production. The increased activities of adenylosuccinate synthetase and adenosine kinase, along with the reduced activities of 5'-nucleotidase and adenylate deaminase, in liver from chickens fed the 80% compared with the 11% protein diet demonstrate enhanced synthesis of adenine nucleotides. Since adenine nucleotides are essential cofactors for de novo purine synthesis, it is proposed that adenylosuccinate synthetase, adenosine kinase, 5'-nucleotidase and adenylate deaminase are key enzymes involved in the regulation of purine biosynthesis.


Determination of net protein utilization using whole carcass, hind leg or liver of the rat and its relationship with protein efficiency ratio determination. Experiments were conducted to test the simplified NPU method designed by Lachance and Miller with diets of different protein quality and to determine the NPU using the liver nitrogen concentration instead of that in the hind limb. The NPU determination was done after 10- and 21-day periods instead of a 28-day period. The second part of the study was the analysis of the relationship between NPU and PER done with the same rats. The NPU calculated from whole carcass nitrogen concentration showed a high correlation with the NPU calculated from the nitrogen concentration in the leg (r = 0.990) and also with the NPU calculated from the liver nitrogen concentration. The Tukey's "t" test showed that in the 10-day experiment discrimination between the effect of the different diets upon NPU was not as good as was the case at 21 days. However, the NPU values at 10 days were in the same sequence as those at 21 days. For practical purposes it is more reliable and easier to perform the NPU determination using the liver instead of the whole carcass or leg. The statistical analysis of PER and NPU showed the same discriminating value when the test diets were isoenergetic.


The role of transamination in methionine oxidation in the rat. The role of transamination as the initial step in catabolism of methionine in the rat was investigated. [Methyl-14C] or [1-14C]-L-Methionine was added to tissue homogenates and transamination was determined from the counts recovered in a precipitable phenylhydrazone following treatment of the samples with 2,4-dinitrophenylhydrazine. Transamination of methionine was detected in homogenates of liver, kidney, heart, brain, spleen, skeletal muscle, and small intestines. The product of methionine transamination in the liver was identified as alpha-keto-gamma-methiolbutyrate. Approximately the same tissue distribution was observed for the conversion of the methyl or carboxyl carbon of methionine or alpha-keto-gamma-methiolbutyrate to CO2. alpha-Keto-butyrate could be used as a co-substrate for transamination, but inhibited oxidation of methionine apparently by competing for oxidation of alpha-keto-gamma-methiolbutyrate. S-Adenosyl-L-methionine was not a substrate for transamination in the liver homogenate system nor did it inhibit transamination of methionine. Amino-oxyacetic acid inhibited transamination and oxidation of methionine, but not oxidation of alpha-keto-gamma-methiolbutyrate. These observations are consistent with transamination being an initial step in methionine catabolism and an alternate pathway for methionine oxidation which does not involve its activation to S-adenosyl-L-methionine.


Estimation of the fraction of the lactose in a high lactose diet available for fermentation in the cecum and colon of the rat. Experiments were conducted to determine the amount of lactose which passed into the large intestine and the lactase activity in the small intestine of rats (200 g) fed a control diet or a diet containing 30% lactose. The fraction of lactose consumed in a single 1-hour meal that escaped hydrolysis in the small intestine was estimated by measuring the area under a smooth curve of a plot of lactose:marker ratio in the terminal ileum expressed as a fraction of intake, against the fraction of the total marker that passed into the large intestine. This amounted to approximately 30% and 31.5% of the lactose consumed for the rats fed the control and 30% lactose diets, respectively. In another experiment in which the rats were fed a diet containing 30% lactose and the Cr-EDTA marker ad libitum for 1 week, approximately 43% of the lactose consumed became available for fermentation in the large intestine. This work suggests that a substantial fraction of the lactose ingested is available for fermentation in the large intestine. The lactase activity of homogenates of the small intestine of rats fed the control or high lactose diet was 106 +/- 5 or 115 +/- 4 mg lactose/30 minutes/rat (P less than 0.05), respectively. The lactase activity in the small intestine homogenate (mucosa + contents) was significantly higher than that actually available in vivo (110 +/- 7 versus 69 +/- 4 mg/30 minutes/rat).


Human protein requirements: interrelationships between energy intake and nitrogen balance in young men consuming the 1973 FAO/WHO safe level of egg protein, with added non-essential amino acids. Our recent studies have shown that the 1973 FAO/WHO "safe level of intake" of egg protein (0.57 g/kg/day) is inadequate for maintaining protein nutritional status in young men receiving generous energy intakes. Therefore, an experiment was conducted to determine nitrogen (N) balance and the energy intake needed to support it when supplementary N, equivalent to 0.23 g of protein (N X 6.25)/kg/day from a nonessential amino acid mixture, was added to a diet containing 0.57 g of egg protein/kg/day. Four young men, 20 to 21 years old, participated in the 58- to 79-day metabolic N balance study. This group required significantly lower energy intakes to maintain N balance than a previously studied group fed only 0.57 g of egg protein under identical conditions. The energy intakes predicted to maintain N balance were approximately 10 to 15% less than the requirements estimate from body weight and N balance data. Present results, although based on a limited number of subjects, suggest that total N may be the limiting factor in short-term N balance at the 1973 FAO/WHO egg protein intake level for a significant proportion of young adult male populations. Long-term metabolic studies will be necessary before the practical significance of the observations can be determined.


Oral theophylline dosage for the management of chronic asthma. Theophylline dosage requirements to maintain serum concentrations of 10 to 20 microgram/ml among asthmatic patients were examined in 156 children, ages 2 1/2 months to 16 years, and 33 otherwise health adults. Using 100% bioavailable preparations, low doses were used initially and increased, if tolerated, at three-day intervals. Final dosage was based on serum theophylline measurements which were subsequently repeated after six or more months of therapy. Dosage standardized by weight averaged 24.1 +/- 5.5 mg/kg/day (mean +/- SD) among the 77 children under age 9 years. Age-related variability of weight-adjusted doses were not observed for younger children, but average dose requirements decreased progressively beyound age 9 years to 13 mg/kg/day for patients beyoung 16 years of age. Although interpatient variability in dosage was confirmed at all ages, intrapatient variability in requirements over an average eight-month interval were small; dosage changes to maintain therapeutic serum concentration were primarily associated with growth. These data allow age-specific guidelines for dosage recommendations based on the likelihood of optimally effective and potentially toxic serum theophylline concentrations.


Oral antibiotic therapy for skeletal infections of children. I. Antibiotic concentrations in suppurative synovial fluid. To evaluate the feasibility of oral antibiotic treatment for pyogenic arthritis, one or more oral doses of antibiotics were substituted for the drugs being used for parenteral therapy. Synovial fluid and serum specimens obtained at randomized times after an oral dose of ampicillin, cephalexin, cloxacillin, dicloxacillin, or penicillin G were assayed for antibiotic content and antibacterial activity. Seventy specimens from 21 infants and children were studied. Peak synovial fluid concentrations were greater than 60% of peak serum concentrations with all drugs tested and there was adequate inhibitory activity against bacteria commonly causing arthritis. The degree of antibiotic binding to serum protein had no apparent effect on the degree of penetration into pyogenic synovial fluid.


Antibiotic concentrations in pus and bone of children with osteomyelitis. Pharmacologic data are presented on 39 children treated for osteomyelitis with one of the following antibiotics: methicillin, dicloxacillin, cephaloridine, or cefazolin. The concentrations of drug in pus and bone were correlated with serum concentrations, with the susceptibilities of Staphylococcus aureus strains isolated from the patients, and with the degree of drug protein-binding. The penetration of the antibiotics into pus and bone was similar for the two penicillins and for the two cephalosporins despite the disparate protein-binding affinities of these drugs. The agents attained concentrations in tissues that were at least several fold, and often more than tenfold, greater than the MIC and MBC values of the S. aureus stains. These data provide a basis for selection of antimicrobial agents for treatment of osteomyelitis.


Oral propranolol treatment in infants and children. To determine the effectiveness of oral propranolol in children, we administered 0.5 to 4.0 mg/kg/day of the drug to 64 children (age one day to 20 years); 41 with cardiac dysrhythmias, six with isiopathic hypertrophic subaortic stenosis, and 17 with paroxysmal hypoxemic spells associated with right ventricular infundibular obstruction. A new liquid form of propranolol (10 mg/ml) was administered to 37 of the younger patients, and tablets were given to the other 27. Propranolol improved the dysrhythmia in 31 of 41 patients, being notably effective in supraventricular tachycardia and ventricular tachycardia associated with a prolonged QT interval. The drug also eliminated symptoms attributed to IHSS in six of six patients and abolished hypoxemic spells in 12 of 17. The liquid and tablets were equally effective; and the liquid had the advantage of allowing for accurate dose changes in younger children. We conclude that oral propranolol is an excellent drug for use in pediatric patients with certain types of cardiac disease.


A comparison of four toxicology resources in respect to rates of retrieval and time required. An evaluation was conducted fo four periodically updated poison control resources widely used by pediatricians, emergency room personnel, and poison information/control centers; i.e., Poisindex, ToxiFile, Clinical Toxicology of Commercial Products, and the National Clearinghouse for Poison Control Centers' cards. The frequency of finding entries for substances known to be involved in accidental pediatric ingestions, the extent of the content and management information, and the time required to obtain the information were determined for the four resources. Poisindex was more complete than the other resources. ToxiFile was more useful than the remaining two resources, although the latter should be useful in over 70% of accidental toxic ingestions by children.


Hepatitis B in children. I. Analysis of 80 cases of acute and chronic hepatitis B. From 1971 to 1975, HBV-induced hepatitis was observed in 80 children. The diagnosis was based upon the detection in serum of HBsAg and/or the secondary occurrence of anti-HBs. Thirty-one patients presented with acute viral hepatitis, 16 with severe or fulminant hepatitis, 17 with chronic persistent hepatitis, 12 with chronic active hepatitis, and 4 were asymptomatic chronic carriers of HBsAg. Twenty-nine of 80 children were under one year of age (36%), the peak of frequency occurring from 2 to 5 months. The source of infection, determined in 27 of 29 infants, was administration of blood derivatives in 15 cases and contact with an HBsAg carrier mother in nine instances. In the latter type, the incubation time (103 days) was compartible with an oral route of infection, Persistent antigenemia occurred in only 3 of 29 patients. The overt type of disease developed by most infants, as well as the small number of patients who became HBsAg carriers, suggest that the carrier state, often encountered in neonatally infected infants in other countries, may be related to environmental or genetic factors rather than to immaturity of theimmune system.


Response to experimental challenge in persons immunized with different rubella vaccines. The response to experimental challenge with rubella virus was studied in 113 volunteers, ages 13 to 17 years, immunized with three rubella vaccines: HPV-77-DE-5 and Cendehill (inoculated subcutaneously) and RA-27/3 (administered subcutaneously to one group and intranasally to a second group). The occurrence of side effects ranged from 16% in the Cendehill vaccines to 32% in the RA-27/3-intranasal vaccinees. Antibody response to primary vaccination as measured by CF was significantly lower in the Cendehill vaccines. Challenge by intranasal instillation of RA-27/3 a year later produced no adverse effects. Serologic response was measured by testing for CF, HI, and neutralizing and sensitizing antibodies. Booster response, a fourfold increase in antibody fiter after challenge as evidenced by at least one of the tests, occurred in 67% of the Cendehill vaccinees, in 47% of HPV-77 vaccines, and in only 7 to 11% of RA-27/3 vaccinees. Of 37 subjects exhibiting booster response, 27 had an increase in antibody titer demonstrated by two or more serologic tests; 16 of these 27 were Cendehill vaccinees. These results confirm our previous observations and that of others that the RA-27/3 rubella vaccine has the highest immunogenic potential.


Influenza immunization in immunosuppressed children. Optimal influenza immunization of individuals with malignancy and other immunodeficient states requires and understanding of responses to currently recommended regimens. Children with acute lymphocytic leukemia and other malignancies between three and 17 years of age were immunized with bivalent influenza vaccine containing A/New Jersey/76 and A/Victoria/75. Folowing a two-dose immunization schedule, only 37% (25468) on cancer chemotherapy seroconverted to a hemagglutination inhibition titer greater than or equal to 20 for A/NJ/76; the seroconversion rate in those not on chemotherapy was 92% (68/74, P less than 0.001). The immune response to the A/Vic/75 antigen was also related to a history of recent chemotherapy. There was no correlation between the immune response and the peripheral white blood cell count except at counts less than or equal to 1,000. The optimum time to immunize children with malignancies is when they have been off chemotherapy for one month and have peripheral white blood counts greater than 1,000.


Premature ventricular contractions in normal children. To document the assumed benign prognosis of premature ventricular contractions in children, we followed 17 patients with PVCs and without other heart disease for a mean of seven years (range one to 19 years). Data were collected from the history, physical examination, 15-lead ECG, and treadmill exercise test. Eight of the 17 children still had PVCs at the most recent follow-up. Of these eight children, seven were asymptomatic. The physical examination remained normal in all except one, who developed signs of mitral prolapse. Light exercise abolished the PVCs in all children. We believe that if a careful clinical examination discloses no abnormalities, and if the PVCs are unifocal and disappear with exercise, this dysrhythmia is, in fact, benign in children, and requires no further cardiovascular examination.


Cardiac output measured by thermodilution in infants and children. To determine the accuracy and reproducibility of cardiac output determination by thermodilution (COT) in children, simultaneous outputs were measured by the Fick technique (COF) (using measured oxygen consumption) and thermodilution in 26 children, ranging in age from 8 to 86 months, who were undergoing cardiac catheterization. There was excellent correlation between mean output by thermodilution and by the Fick technique: COT = 1.10 COF -- 0.2 l/minute, R = 0.91. In three-quarters of the patients with COT differed by 15% or less and in none differed by more than 25%. Serial values of thermodilution outputs were reproducible in each patient with a SD of 5.5%. Our observations indicate that COT is accurate, reproducible, and valuable in the care of critically ill infants and children.


The radiolucent esophageal foreign body: an often-forgotten cause of respiratory symptoms. Three children under 2 years of age with a history of respiratory symptoms for one to seven months, secondary to a radiolucent esophageal foreign body, are presented. Delay in diagnosis resulted in an acquired tracheosophageal fistula in two patients and a thoracotomy in all three patients. Physicians alert to the clinical presentation and aware of the proper radiographic investigation of radiolucent esophageal foreign bodies can reduce the morbidity and hospital stay for these patients.


Brain malformations related to prenatal exposure to ethanol. Microcephaly and mental retardation have been principal features of the fetal alcohol syndrome. This article describes the neuropathologic findings in four human neonates who were exposed to large quantities of ethanol at frequent intervals during gestation. The findings suggest that intrauterine exposure to ethanol can result in structural abnormalities of the brain. All four brains displayed similar malformations stemming from errors in migration of neuronal and glial elements. Hydrocephalus was one consequence of the malformations in two of the infants. Futhermore, the brain alterations may be the only distinct abnormality produced by in utero ethanol exposure. Only two of the four subjects were diagnosed as having the fetal alcohol syndrome from external criteria.


Glycohemoglobin (HbAIc): a predictor of birth weight in infants of diabetic mothers. Hemoglobins AIa-c (fast Hb), minor variants of HbA, are elevated in patients with diabetes mellitus. Recent studies indicate a relationship of fast hemoglobins, especially HbAIc (glycosylated form), to chronic hyperglycemia. Since infant oversize has been attributed to maternal hyperglycemia and fetal hyperinsulinemia, the hemoglobin HbAIc fraction was compared to birth weight (actual and relative to gestational age) and to maternal glucose tolerance. Normal (13), probably normal (8), gestational diabetic (10), and insulin-dependent women (14) were studied in the third trimester; women with advanced diabetic vascular disease were excluded. When corrected for gestational age, relative birth weights correlated in a significant linear regression with HbAIc (n = 45, r = 0.57, P less than 0.001). Third trimester maternal glucose tolerance (Kt) of women, not insulin dependent, correlated in a signigicant manner with both HbAIc (P less than 0.05) and birth weight for gestational age (P less than 0.01).


Relationships of mesenteric thromboembolism, oral feeding, and necrotizing enterocolitis. Mesenteric blood vessels were examined in postmortem specimens of 30 selected infants. The infants had had necrotizing enterocolitis (16 cases) or other lesions (14 cases). Mesenteric thromboemboli were observed in 12 of the infants with necrotizing enterocolitis (P less than 0.001). Umbilical vessel catheters were apparently responsible for the emboli. Multiple instances of thrombosis and thromboembolism were detected in other organs. Ninety-four percent of infants with necrotizing enterocolitis were orally fed (P less than 0.001). Mesenteric thromboemboli were more frequent in infants who were fed via the digestive route while an umbilical arterial catheter was in place. Mesenteric thromboembolism in these infants was postulated to have been attributable to increased postprandial blood flow in the mesenteric vessels.


Biosynthesis of morphine alkaloids in Papaver bracteatum Lindl. Administration of 1-3H-N-methyl-14C-(+/-)-reticuline to Papaver bracteatum gave good incorporation of carbon-14 into thebaine and a decrease in the tritium to carbon-14 ratio indicative of racemization. The incorporation of carbon-14 and the extent of tritium loss were the same whether reticuline was administered to the intact plant or to isolated leaves. Carrier dilution with cold codeine, codeinone, and morphine showed only insignificant incorporation of radioactivity into codeine and none at all into codeinone and morphine. When codeinone was administered to the living plant, it was converted to codeine rapidly and efficiently, but no O-demethylation to morphine could be detected. The experimental data indicate that the biosynthesis of thebaine in P. bracteatum proceeds by the same pathway as in the opium poppy. The limiting step in the sequence is the demethylation of the enol ether group of thebaine to neopinone.


Direct and indirect determination of binding constants of drug-protein complexes with microparticles. Albumin can be immobilized in microparticles of poly-acrylamide in such a way that its ligand-binding properties are retained. With radiolabeled salicylic acid, warfarin, and tryptophan, the same characteristics are obtained for binding to albumin in the microparticles as in free solution. The particles can be used conveniently to determine association constants and the number of binding sites directly. The association constant of a competitive displacer can be determined indirectly as well, as shown with diazepam-salicylic acid and tryptophan-salicylic acid.


Polymer-bound carbonic anhydrides in N-acylation of 7-aminocephalosporanic acid. Aminocephalosporanic acid tert-butyl ester was reacted with polystyrene-bound mixed carbonic-carboxylic anhydrides to give the corresponding N-acylated derivatives. Clevage of the tert-butyl protecting group with trifluoroacetic acid gave the corresponding cephalosporanic acid.


High-performance liquid chromatographic assay of isoquinoline alkaloid formation from reaction of biogenic amines and aldehydes. To understand the role that tetrahydroisoquinoline formation may play in alcoholism and drug toxicology, high-performance liquid chromatography with electrochemical detection was used to monitor the overall rate of reaction, in pH 7.4 buffer, between the catecholamines (dopamine, alpha-methyldopamine, dihydroxyphenylpropanolamine, deoxyepinephrine, levodopa, alpha-methyldopa, epinephrine, levarterenol, ans isoproterenol) and acetaldehyde. The observed overall rate of reaction varied from 0.38 to 0.0013 liter/mole sec. In addition, the reaction rate of the neurotransmitter dopamine was measured for various aldehydes (formaldehyde, acetaldehyde, glyoxylic acid, paraldehyde, malonaldehyde, glyceraldehyde, and chloral hydrate). The observed overall rate of reaction varied from 5.3 to 0.0011 liters/mol sec. Penicillamine prevented formation of the tetrahydroisoquinoline alkaloids when initially present in concentrations equal to or greater than the aldehyde concentration.


GLC determination of meperidinic and normeperidinic acids in urine. A GLC procedure for the determination of meperidinic and normeperidinic acids in human urine is described. After the extraction of any interfering meperidine or normeperidine, the urine samples are dried and the acids are reesterified using ethanol-sulfuric acid. The resulting meperidine and normeperidine are then extracted and quantified. With this method, the urinary excretion of these metabolites was followed in five subjects who received a single meperidine dose of 36 mg/m2 im. This method represents an improvement over the previously described methods for meperidinic and normeperidinic acids and can be applied to clinical situations.


Simultaneous GLC determination of phenylpropanolamine and chlorpheniramine in urine using a nitrogen selective detector. A simple, rapid, and sensitive simultaneous quantitative determination of phenylpropanolamine and chlorpheniramine in human urine by GLC, using a nitrogen specific detector, is described. After alkaline extraction from urine, phenylpropanolamine and chlorpheniramine are analyzed directly by GLC, without a derivatization step. Promethazine was used as the internal standard. The total assay time is less than 30 min. The method is useful in studies of pharmacokinetic and pharmacological interactions of drug combinations.


Convenient synthesis of (RS)-4-amino-3-hydroxybutyric acid. A new three-step synthesis of 4-amino-3-hydroxybutyric acid from an inexpensive starting material and under mild reaction conditions is described. Crotonic acid was brominated by the Wohl-Ziegler reaction to 4-bromocrotonic acid, which, in turn, was converted with ammonium hydroxide into 4-aminocrotonic acid. This compound, refluxed in water in the presence of a strong acid resin, afforded 4 amino-3-hydroxybutyric acid in good yields.


Vasodilator activity of adenosine analogs. Various adenosine analogs were evaluated as smooth muscle vasodilators. The compounds were screened ititially using a dog hindlimb preparation. Most analogs were less potent than adenosine. The three most potent compounds were tested for coronary vasodilator effects and duration of action on the isolated rabbit heart. 5'-Deoxy-5'-chloroadenosine and 5'-deoxy-5'-bromoadenosine were equipotent with adenosine but possessed a longer duration of action 2',3',5'-Trideoxy-3',5'-dichloroadenosine, an analog lacking both the 2'- and 3'-hydroxyl groups, had significant vasodilator activity.


Anhydrocannabisativine, a new alkaloid from Cannabis sativa L. Ethanol extracts of the leaves and roots of a Mexican variant of Cannabis sativa L. (marijuana) afforded, after partitioning and chromatography, the new spermidine alkaloid, anhydrocannabisativine. The structure was determined by spectral analysis and semisynthesis.


Synthesis and local anesthetic activity of benzo[b]furan derivatives. Several 2-dialkylaminoethyl 3-methyl-2-benzo[b]furancarboxylates, 2-dialkylaminoethyl 3-methyl-2-benzo[b]furancarbamates, and 3-methyl-2-benzo[b]furancarboxamide derivatives were prepared and tested for local anesthetic activity. Piperidinoethyl 3-methyl-2-benzo[b]furancarbamate, 2-diethylaminoethyl 3-methyl-2-benzo[b]-furancarboxylate, and N-(2-diethylaminoethyl)-3-methyl-2-benzo[b]-furancarboxamide were the most potent.


Determination of ionization constants in mixed aqueous solvents of varying composition by a single titration. A potentiometric titration method is proposed in which only one titration is necessary to obtain pK'a values for different solvent compositions. The method allows the results to be extrapolated to the value for pure water. Examples are given, and the advantages and disadvantages of the method are discussed.


Enhancement of ampicillin partition behavior. Several ion-pair or adduct forming additives tha" enhanced ampicillin partition behavior were identified and evaluated. At pH 3, picric acid and trichloroacetic acid increased the ampicillin aqueous-octanol partition coefficient 250 and 30 times, respectively. At pH 7, quaternary compounds gave the most significant increases in the partition coefficient. Values for an aqueous pH 7 chloroform system increased from zero in the absence of additives to 2.28, 1.86, 1.82, and 1.70 for equimolar amounts of benzalkonium, tetraheptylammonium, benzethonium, and cetalkonium chlorides, respectively. Extraction of ampicillin from aqueous pH 7 solution was possible by adding a quaternary agent in an equimolar amount. However, extraction of ampicillin from plasma required large molar excesses. Tetraheptylammonium chloride was added at a molar concentration 10(3) times greater than that of the ampicillin. Plasma samples spiked at the 3-microgram/ml level gave 93% recovery (CV 6.7%, n = 16) when extracted three times. The extracts were quantitated by TLC.


Solvent deposition method for enhancement of dissolution rate: importance of drug-to-excipient ratio. Dissolution rates and particle sizes of phenylbutazone solvent deposited on lactose, starch, and silicon dioxide, separately, and of norethindrone and digoxin deposited on lactose were investigated. Microparticulate dispersed drugs on the surface of excipients result when drug-to-excipient ratios are low. Fast dissolution rates are observed for such systems. This effect can be extended to higher ratios when silicon dioxide is used as the excipient. Because of adsorption, however, the release from silicon dioxide is more or less limited.


Analysis of tricyclic antidepressants in human plasma by GLC--chemical-ionization mass spectrometry with selected ion monitoring. A method is described for the analysis of amitriptyline, doxepin, imipramine, nortriptyline, desmethyldoxepin, desipramine, and protriptyline in human plasma utlizing GLC-chemical-ionization mass spectrometry with selected ion monitoring. The assay is highly specific and is quantitative to at least 1 ng/ml with a standard error typically less than 5%. Representative concentrations of the parent compounds and their monodemethylated metabolites, as meeasured in plasma samples from patients under treatment with tertiary amine tricyclic antidepressants, are given.


Direct spectrophotometric determination of thebaine in Arya II population capsules of Papaver bracteatum Lindl. A simple spectrophotometric determination of thebaine based on the complexation reaction with bromcresol green was developed. The yellow complex was extracted with chloroform over the pH 1.5--4.5 range. The solution of the complex in chloroform showed the maximum absorption at 415 nm and obeyed Beer's law over the concentration range of 4.0--14.0 microgram/ml. The molar absorptivity of the complex was 1.9460 X 10(4). The ratio of thebaine to bromcresol green in the complex was 1:1. The method was applied successfully to the direct determination of thebaine in the Arya II population capsules of Papaver bracteatum Lindl. The thebaine content of the dried capsules was 3.14%.


Pharmacokinetic model for salicyclate in cerebrospinal fluid, blood, organs, and tissues. The developed pharmacokinetic model, an extension of the Bischoff--Dedrick model, simultaneously predicts the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs, and tissues. The model, which is entirely different from conventional compartment models, is derived from basic considerations of drug distribution with biochemical and physiological meaning. The dog was studied at three different dosages of salicylate: therapeutic, moderate intoxication, and severe intoxication. The predicted kinetics of salicylate in cerebrospinal fluid, blood, plasma, liver, muscle, and adipose tissue by the model agreed well with the experimental data. The effectiveness of hemoperfusion treatment for the severely intoxicated dog by albumin-coated activated carbon and its effect on the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs and tissues were studied. The model was also applied to predict the kinetic changes of salicylate in the body during and after the extracorporeal treatment. The predicted results also agreed with the experimental data.


Frequency distribution of bilirubin intrinsic clearance in adult male sprague--dawley rats. The intrinsic body clearance of bilirubin was determined in 48 adult male Sprague--Dawley rats that received an intravenous infusion of bilirubin. The intrinsic body clearance was calculated from the infusion rate, the steady-state plasma concentration of total (free and protein-bound) bilirubin, and the free fraction of bilirubin in plasma. The intrinsic body clearance of bilirubin ranged from 5.05 to 13.20 liters/kg/min and was bimodally distributed, with half of the animals in each group. The plasma free fraction of bilirubin ranged from 0.00025 to 0.00077 (mean 0.00053) in the 24 intrinsically rapid metabolizers of bilirubin and from 0.00048 to 0.00103 (mean 0.00075) in the intrinsically slow metabolizers of the pigment. Thus, interindividual differences in the total clearance of bilirubin in the rats are due to differences in both intrinsic body clearance and plasma protein binding.


USP dissolution test II: Sigmoid dissolution profiles from directly compressed tablets. The basic steps involved in the dissolution of a directly compressed tablet in a USP basket dissolution apparatus were examined via data generation. The proposed model explains why a dissolution curve can be sigmoid shaped and why the portion past the lag time has a log-linear undissolved mass versus time correlation.


Evaluation of acceptance criteria for particulate limits for small-volume parenteral products. The precision of and correlation between the USP membrane filtration-microscopic method and the instrumental method for sizing and quantifying particulate matter in small-volume parenteral products were determined using simulated products. The total variance for the instrumental counts was lower than the USP method for all products in the 10--25-mum particle range and for most products in the greater than or equal to 25--50-mum range. A linear relationship between the instrumental counts and the USP counts was demonstrated for the 10--25-mum particle range. However, the instrumental reading was higher than the USP method for counts of 10 or more particles/ml. The instrumental and the USP methods failed to correlate on particulate sizes greater than 25 mum. The content of particulate matter in over 100 small-volume parenteral products was sized and quantified by the USP and the instrumental methods. From the instrumental data, a statistical treatment for the analysis of particulate data is presented as an objective method of evaluating acceptance criteria on particulate matter in small-volume parenteral products.


Quantitative determination of amitriptyline in blood. An assay was developed and standardized for amitriptyline and its hydroxylated tertiary amine metabolites in blood and other biological tissues. This method is capable of determining 5--15 ng of these compounds/ml and is based on reacting the drug as base with 9-bromomethylacridine to form a quaternary product which, on photolysis, yields fluorescence in a stoichiometric fashion. The precision of the method is usually around +/-5%.


Potential of liquid membranes for drug overdose treatment: in vitro studies. The in vitro removal of six barbiturates from pH 2 donor solutions by liquid membranes with pH control was evaluated. More than 90% of amorbarbital, phenobarbital, and secobarbital were removed within 10 min by the liquid membranes. Drug transport obeyed first-order kinetics initially, and Fick's law was obeyed. The transport rate of phenobarbital by a liquid membrane was temperature dependent. An Arrhenius plot revealed that the activation energy was 10 kcal/mole. The liquid membranes showed some instability in the presence of bile salts.


Three-dimensional molecular illustrations II: Isoelectrostatic energy contour spheres of influence applied to narcotic molecules. A computer-generated method using quantum mechanics was applied to the calculation and subsequent plotting of nonperspective three-dimensional illustrations of molecules in vacuo. The purpose was to generate isoelectrostatic energy contour spheres for larger molecules and current drugs. The molecules chosen, morphine, meperidine, and alphaprodine, possess similar pharmacological properties. Minor configurational manipulation of meperidine and alphaprodine molecules was made to approximate the spatial configuration of the rigid morphine molecule so that direct comparisons were possible. Common areas of reactivity, potential energy minima, net atomic charges, spatial regions, and near neighbor influences are considered.


GLC determination of warfarin in human plasma. A specific and quantitative GLC method for warfarin in human plasma is described. The procedure uses papaverine as the internal standard and involves a dichloroethane extraction of the acidified specimen. The organic extract is evaporated, and the evaporated extract is dissolved in 50 microliter of chloroform. Aliquots of 2-3 microliter are injected into a gas chromatograph equipped with a flame-ionization detector. The sensitivity of the method is such that 0.3 microgram of intact warfarin can be detected in 1 ml of plasma. Statistical analyses indicate a recovery of 97.26 +/- 1.89% SD. The procedure was successfully applied to plasma drug level studies in humans.


Determination of time course of tablet disintegration II: Method using continuous functions. An analysis of the disintegration-dissolution sequence of drug release from a tablet leads to a mathematical expression relating disintegration to the dissolution profile of the tablet and the dissolution rate of the primary drug particles in the tablet. The equation describing the disintegration of an acetaminophen tablet is determined to demonstrate the application of the theory.


Binding of 3-aminoacridinium and 7-aminoquinolinium monocations to double-stranded DNA: evidence for nonlinear binding isotherm in intercalative region. The complexations of the singly charged cations of 3-aminoacridine and 7-aminoquinoline by double-stranded, calf thymus DNA were studied by electronic absorption spectrophotometry. At high ratios of total DNA phosphate concentration to total probe concentration (the region associated with intercalative binding), four DNA phosphate units are associated with each bound monocation. However, a binding isotherm based on four DNA phosphate groups in a single binding site does not yield a reproducible equilibrium constant for the binding process. Rather, the sequestration of the monocations by two binding sites, each containing two DNA phosphate units, yields a satisfactory equilibrium expression. This result suggests that the intercalative mode of binding by DNA is not a simple one-step process, which is in agreement with previous kinetic studies. In the region of low DNA phosphate concentration to monocation concentration (the external binding region), the binding is described adequately by a linear isotherm.


Estimation of dissolution rate of salicylamide in complexing media using a theoretical diffusion model. Dissolution rates of salicylamide in water and caffeine solutions under perfect sink conditions were predicted by theoretical diffusion equations applicable to dissolution in complexing media. Experimental dissolution rates were measured using a compartmentalized rotating-basket apparatus under two sets of conditions. Agreement was found between experimental and predicted rates. Use of the theoretical equation for estimating dissolution rates involves simple calculations of diffusion coefficients and diffusion layer thickness under the operative dissolution conditions. The increase in dissolution rate caused by addition of the complexant can be calculated for diffusion-controlled dissolution directly if the stability constant and the drug solubility in water are known or measured.


The effects of subhypnotic doses of ethanol on regional catecholamine turnover. A 2 g/kg dose of ethanol given intraperitoneally to rats significantly reduced the turnover of dopamine in the substantia nigra and caudate nucleus, increased dopamine turnover in the olfactory tubercle and had no effect on dopamine turnover in the nucleus accumbens, amygdala and hypothalamus. The same dose of ethanol decreased the probenecid-induced homovanillic acid accumulation in the caudate nucleus. The turnover of norepinephrine was also decreased in hypothalamus and increased in the pons medulla region. No change in norepinephrine turnover was observed in frontal cortex, parietal cortex, cerebellum, amygdala, hippocampus and locus ceruleus region. The distribution of ethanol was similar in cortex, caudate nucleus, hypothalamus and pons-medulla. Catecholamine turnover in different brain regions seems to be differentially sensitive to the effects of ethanol, with most regions being unaffected by ethanol.


Effects of d-amphetamine, monomethoxyamphetamines and hallucinogens on schedule-controlled behavior. The effects of 16 drugs were studied in rats responding under fixed-ratio (FR 30) and fixed-interval (FI 2 minute) schedules of food presentation. The drugs tested included lysergic acid diethylamide (LSD), dimethyltryptamine, mescaline, d-amphetamine and 12 methoxylated amphetamines. All of the drugs decreased the average rates of responding under both schedules, but their potencies varied widely. For example, with LSD, the most potent drug tested, doses of 0.1 to 0.3 mg/kg were sufficient to reduce responding while with dimethyltryptamine and mescaline, doses of 10 to 30 mg/kg were required to clearly reduce responding. For the 12 drugs which are known to produce hallucinogenic effects, their potencies in reducing responding were positively correlated with their reported potencies in producing these subjective effects in humans. Although all of the drugs decreased the average rates of responding, alterations in the patterns of responding under the FR and FI schedules varied among the drugs. Analysis of responding under the FI schedule indicated that d-amphetamine, m-methoxyamphetamine, p-methoxyamphetamine, LSD and 3,4-methylenedioxyamphetamine generally increased the low rates of responding occurring at the beginning of each interval and decreased the high rates of responding occurring later in each interval (rate-dependent effects). The other drugs generally decreased responding throughout the interval. These results are discussed in terms of the known neurochemical effects of these drugs.


Phenylbutazone-induced decrease in renal blood flow. Phenylbutazone (Butazolidin), and anti-inflammatory agent, has been reported to decrease renal excretion of sodium and water. Whether or not an alteration in renal hemodynamics could be involved in producing these effects was tested in anesthetized dogs. Renal blood flow (RBF) was monitored with electromagnetic flow probes. After i.v. administration of phenylbutazone, 2 mg/kg, RBF fell by 20%. Glomerular filtration rate, sodium and water excretion were also decreased and blood pressure increased slightly. The reduction of RBF and glomerular filtration rate by phenylbutazone indicates that a hemodynamic mechanism could be involved in the retention of sodium and water induced by this agent. The decreased blood flow was correlated with a depressed renal secretion of prostaglandin E. Also, in animals pretreated with indomethacin, another inhibitor of prostaglandin synthesis, administration of phenylbutazone did not result in any additional changes in renal hemodynamics or excretion of sodium and water. In addition, phenylbutazone antagonized the ability of furosemide to increase RBF, an inhibition which has previously been shown to occur with indomethacin. Thus, phenylbutazone appears to alter renal mechanisms in a manner similar to indomethacin.


Distribution of intracortical renal blood flow induced by bumetanide in the dog. Experiments were performed in hydropenic, anesthetized dogs to investigate the effect of two dose levels of bumetanide on sodium excretion, urinary concentration, total renal blood flow and intracortical distribution of blood flow using the radioactive microsphere technique. Intravenous administration of bumetanide (0.025 mg/kg followed by 0.025 mg/min) did not alter blood flow within the kidney. A higher dose of bumetanide (0.1 mg/kg followed by 0.1 mg/min) significantly increased total renal blood flow and lowered renal vascular resistance. The rise in renal blood flow after bumetanide was due entirely to an increase in perfusion to the midcortical and juxtamedullary regions. A transient rise in plasma renin activity was measured only after the higher dose of bumetanide. Both doses of bumetanide increased sodium excretion and depressed solute free water reabsorption, although natriuresis was greater in response to the high dose. The results indicate that higher dose levels of bumetanide can increase total renal blood flow to the inner cortex. However, changes in renal blood flow were apparently not essential for the diuretic action of bumetanide because a significant natriuresis was observed in a setting where no change in intrarenal hemodynamics could be detected.


Effects of 2,4,6-triaminopyrimidine on the electromechanical properties of guinea-pig myocardium. The effects of 2,4,6-triaminopyrimidine (TAP) were studied in vitro on transmembrane potential and contractility in guinea-pig myocardium. In electrically driven Langendorff-perfused hearts, the addition of 1 and 5 mM TAP produced an initial dose-dependent positive inotropic response with no change in resting tension. The activation process was studied by means of microelectrode and tension recording from isolated electrically driven guinea-pig left atrial preparations. TAP (1-10 mM) produced dose-dependent changes in both electrical and mechanical properties of the tissue. In particular, 1,5 and 10 mM TAP increased the action potential duration by approximately 20, 40 and 60% while also increasing contractile strength by approximately 30, 60 and 90%, respectively. The mechanical effects of TAP were also observed in the presence of 10 muM propranolol. Experiments on catecholamine-restored hearts which were depolarized by potassium indicated that the inotropic action of TAP was associated with slow calcium influx channels. The inotropic effects of TAP were reduced by D600, a calcium antagonistic agent. These data are consistent with a hypothesis that the inotropic actions of TAP result from a decrease in potassium conductance as a result of the inhibition of Ca++-K+ interactions at the inner surface of the myocardial membrane.