Specificity of acquired clonal chromosome abnormalities in New Zealand Black mice. New Zealand Black (NZB) mice, an inbred strain characterized by immunological dysfunction and lymphoreticular malignancy, also develop populations of aneuploid spleen cells. In detailed cytogenetic analyses performed on 10 NZBs, the chromosomally abnormal cells were found to be clonally related within each mouse. Moreover, the karyotypic changes observed were highly non-random, usually involving the 15 (10/10 mice), 2 (8/10 mice), 16 or 17 (9/10 mice), and sex (6/10 mice) chromosomes. These observations suggest an important relationship between chromosomal alterations and tumorigenesis in NZB mice and emphasize the role of chromosome 15 in murine abnormal lymphoreticular proliferations.


Accelerated growth of syngeneic tumors in mice treated with methylcholanthrene. BALB/c and C3H- mice were given a single injection of methylcholanthrene (MCA) and were tested at various times thereafter for immunologic reactivity and resistance to syngeneic tumor challenge. MCA treatment did not affect the rejection of H-2-incompatible tumor allografts, the rejection of H-2-compatible skin allografts, or the induction of delayed hypersensitivity to DNCB as measured by footpad challenge. In contrast, mice treated with MCA exhibited an increase susceptibility to challenge with several syngeneic ultraviolet-induced and MCA-induced fibrosarcomas. These studies demonstrate that in the autochthonous host the measurement of host immune status by in vivo cell-mediated immune responses to exogenous antigens does not necessarily predict the host response to tumor growth.


Abnormalities of chromosome No. 1 in human solid malignant tumours. Marker chromosomes involving chromosome No. 1 were studied with banding techniques in 10 primary solid tumours. Structural or numerical aberrations of chromosome No. 1 were found in nine of these. Two major types of rearrangement of chromosome No. 1 were observed: translocation of the long arm (partial trisomy) and an isochromosome of of 1q. Earlier chromosome studies and the present cases suggest that regions near the centromere and q21 are vulnerable points on human chromosome No. 1, and that region q21-32 is important for development of certain tumour types.


Quantitation of serum complement components and plasma C3d in patients with malignant lymphoma: relation to the stage of the tumor and circulating immune complexes. Total hemolytic complement activity (CH 50) and complement component levels were measured in 27 patients with Hodgkin's disease and 31 patients with non-Hodgkin malignant lymphoma. CH 50 values were higher than normal in almost all the patients. Increased levels of serum C4, C3 and factor B were observed in 62%, 31% and 19% of these patients, respectively. However, plasma concentration of C3d, a breakdown product of C3, was elevated in 29% of the cases. The hypercatabolism of C3 was not closely associated with the presence of circulating immune complexes, as assessed by the C1q binding assay, nor with the presence of general symptoms in the patients. On the contrary, it appeared to be in relation with the extent of the malignant disease.


Chromosome 14q+ in a retinoblastoma.

Chromosome 14q+ in a retinoblastoma. A chromosome 14q+ was found in the tumor cells of a patient with sporadic, bilateral retinoblastoma. Eighty-six per cent of the metaphases contained the marker. Some metaphases showed a chromosome 6q--in addition. The question of the specificity of such markers in lymphoid malignancies is raised.


Reproductive factors and risk for breast cancer in Iceland. A previous publication has shown that there has been a great increase in the incidence of breast cancer in Iceland. The present study was undertaken to evaluate the importance of known risk factors connected with the reroductive history of the women. In a prospective investigation of a cohort of 31,453 women we confirmed previous findings of the increased risk following higher age at first pregnancy and for nulliparous women. The age at first pregnancy and the proportion of nulliparous women have decreased with time in the Icelandic population so that these factors should have tended to decrease the risk, making the found increase still more important. The effect of parity is that the risk decreases with larger number of children and this effect is independent of the effect of age at first pregnancy. Lower age at menarche increases the breast cancer risk, but the contribution of that factor to the overall risk is negligible.


Effects of Corynebacterium parvum and cortisone on the primary Lewis tumour and its metastases. The effects of Corynebacterium parvum and cortisone acetate (CA) on the primary Lewis lung carcinoma and its pulmonary metastases were investigated. C. parvum given IV either on the same day or 7 days after tumour inoculation, reduced primary tumour growth, while 2.5 mg CA (high-dose) given SC 4 and 11 days after tumour, alone or in combination with C. parvum, administered on day 0, reduced primary tumour growth to the same extent as C. pravum alone. High-dose CA given on days 2 and 6 had no effect on primary tumour growth or the action of C. parvum, administered on day 7, while 0.05 mg CA (low-dose) given on days 4 and 11 did not alter tumour growth or the action of C. parvum given at the same time as tumour. High-dose CA given 4 and 11 days after tumour caused a significant enhancement in metastases. C. parvum given to these mice on the same day as tumour significantly reduced the pulmonary nodules but only to the level found in control, saline-treated mice. In mice given C. parvum alone, metastases were significantly reduced when compared with controls. Similarly, high-dose CA given on days 2 and 6 significantly enhanced metastases, and C. parvum on day 7 reduced their level to that found in control mice. Low-dose CA had no effect on the number of metastases or the antimetastatic action of C. parvum. The relevance of these results to the clinical situation is discussed.


Psychopathology and nonmedical drug use: a comparison of patient and nonpatient drug users. This investigation examined the hypothesis that high-rate drug use is not always related to high levels of psychological discomfort. High-rate drug users who were actively involved in treatment are compared to a group of high rate drug users who had never been in treatment nor did they desire it at the time of the investigation. Although both groups used drugs with high frequency, actual patterns of drug use differed. Comparison of MMPI and CAPPS data suggested that the patients were experiencing significantly more distress than were nonpatients. The data further suggest that the patient group had a poorer premorbid level of adjustment. Based on these data patterns of drug use, possible implications for treatment are discussed.


Compulsive heroin use and interpersonal orientation. This research attempt to clarify and quantify the ways in which heroin addicts deal with interpersonal relations. A sample of heroin addicts on a methadone maintenance program were given the Fundamental Interpersonal Relations Orientation-Behavior (FIRO-B) scale. An accidental sample consisted of 35, approximately one-half, of the clinic's population. A mean interpersonal orientation profile is established and interpreted. An analysis of variance was performed for each of the six FIRO-B scores. Patients needs based on FIRO-B scores are discussed with regard to the descriptions of addicts life-styles as described in the literature. The possible etiological basis for these interpersoanl orientations is also discussed. Several therapeutic approaches, as indicated by FIRO-B scores, are explored.


The validity of reported drug use: the randomized response technique. A working outline is provided of the "randomized response model" which offers an alternative indirect procedure for obtaining estimates of drug use. Evidence obtained from an experimental study demonstrated significant underreporting of drug use when estimates were obtained by standard direct methods of inquiry when compared to those obtained by randomized response technique.


Gateway Houses: effectiveness of treatment on criminal behavior. Arrest rates for the year preceding admission to and the year following discharge from the Gateway Houses program were determined for three groups of former residents: Group 1, early dropouts; Group 2, late dropouts; and Group 3, persons who completed treatment. Data were obtained from police records. Results showed that arrest rates for the groups were comparable prior to admission but significantly different following discharge. Group 1 showed no change in arrest rates from the year prior to admission to the year following discharge, Group 2 showed an 81% reduction in arrest rates, and Group 3 showed a 97% reduction in arrest rates. It is argued that change in criminal behavior occurred as a function of treatment.


Pharmacotherapy of drug abusers: adjunctive psychopharmacologic management of nonopiate mixed substance abusers in an outpatient setting. Conventional practice in treating nonopiate mixed substance abusers have avoided the use of pharmaceuticals because of the strong drug orientation of this patient population. The author's impressions are that this is a maladaptive treatment polarization, and that psychopharmacotherapy of this group of patients is not only sometimes useful but necessary for some individuals. Diagnostic syndromata and problems specific to this patient population are delineated along with our experience in pharmacotherapy.


Induction of alcohol withdrawal symptoms by nalorphine in chronic alcoholic patients. The effect of nalorphine on eliciting symptoms of either alcohol or narcotic withdrawal was studied. Five male alcoholics were challenged with nalorphine and saline, both while sober and during alcohol ingestion. After nalorphine, pulse rate decreased in patients when sober, but increased when they were ingesting alcohol. Nalorphine administration resulted, during alcohol ingestion, but not in the sober state, in lacrimation, a symptom of narcotic withdrawal, in one patient, and in the following symptoms of alcohol or narcotic withdrawal in one or more patients: weakness, anorexia, insomnia, disorientation, and tremor. These findings suggest that morphine-like alkaloids play a role in the mediation of alcohol withdrawal symptoms.


The Defense Mechanism Inventory and alcoholics. The utility of the Defense Mechanism Inventory (DMI) with alcoholic patients was evaluated by reviewing previous research and presenting new data concerning the test characteristics and the relationships between the DMI and various demographic, cognitive, and personality variables. In general, the defense mechansims of projection and turning against others was associated with greater anxiety, depression, and psychopathology. Utilization of the mechanisms of intellectualization and denial were related to lower levels of psychopathology. The construct validity of the DMI was questioned in view of the results obtained, and the utility of the measure for the prediction of treatment response of alcholics was discussed.


Heroin addiction as an occupation: traditional addicts and heroin-addicted polydrug users. This paper discusses work aimed at exploring the possibility that heroin addiction is a form of work, i.e., it is an occupation no different in social or psychological value than any other vocation. The question of whether or not a heroin addict in treatment is "out of work" is also explored.


Iatrogenic addiction and its treatment.

Iatrogenic addiction and its treatment. Iatrogenic addictions, in contrast to illicit drug addictions, are commonly maintained for years before being brought to the attention of mental health professionals. Typically, by the time treatment is sought, both the physiological addiction and its related psychological problems have encapsulated the patient's life-style. The case histories described here illustrate some of the problems which typify treatment of the iatrogenically drug-dependent patient. Psychotherapeutic strategies utilizing life review, assertion training, and didactic teaching of alternative pain relief methods are often useful. The use of methadone for brief or more extended periods is sometimes helpful as an adjunct to psychotherapy.


Multiple drug abuse: examination of drug-abuse patterns in male prisoners. Preincarceration drug-use patterns were investigated  retrospectively in 58 male prisoners, average age 18.6 years, of whom 50% were White, 43% Black, and 7% Hispanic. Fifty-five percent were classified as drug-dependent, 36% as regular, and 9% as casual users of at least one drug. Classification according to numbers of "hard" drugs used regularly gave equal percentages of subjects using none, one to two, or more than two (polydrug users). The polydrug users were predominantly White and often used amphetamines or hallucinogens, while those using one to two "hard" drugs regularly were predominantly Black, eschewed hallucinogens, and preferred narcotics.


Patient improvement, measured by the MMPI and Pyp, related to paraprofessional and professional counselor assignment. This study examined the treatment efficacy of professional and paraprofessional counselors with similar caseloads of narcotic addicts stabilizaed on methadone. The patients assigned to a professional counselor showed a statistically significant decrease on the D and Sc scales of the MMPI. The patients assigned to paraprofessional counselors did not demonstrate statistically significant decreases on the scales of the MMPI. On the basis of examined patient variables, the two groups of patients appeared comparable in terms of demographic characteristics prior to admission and there did not appear to be a bias in the assignment of patient to counselor.


Exercise, induced bronchospasm in asthmatic children as a dose-response model for theophylline. Efficacy and dose-response activity of oral theophylline were evaluated in 21 asthmatic children, using inhibition of exercise-induced bronchospasm (EIB) as a therapeutic marker. An aqueous theophylline suspension free of alcohol, sugar, and dye was found to be effective for prevention of EIB when given in usual maintenance doses of 4 to 6 mg/kg every 6 hours for 3 weeks, following single loading doses of 8 mg/kg. Pulmonary function measurements (FEV1, FEF25%-75%, PEFR) following standardized treadmill exercise stress were signifcantly improved during both acute and chronic theophylline administration compared to pre-drug control evaluations. There were no signs of developing tolerance to theophylline. The drug produced at least 50% inhibition of EIB in 16 to 21 patients treated. Individualized adjustment of maintenance dosage resulted in optimal theophylline serum concentrations of 10 to 18 microgram/ml in 17 patients. Signs of drug toxicity were observed only when serum levels exceeded 20 microgram/ml following loading doses in 6 patients. Although some children required higher maintenance dosage because of variability in theophylline pharmacokinetics, no child experienced adverse effects after dosage adjustment. Serum half-life ranged between 86 and 351 minutes (mean, 259 minutes); mean peak serum concentration of theophylline after 3 weeks of treatment was 14.9 microgram/ml.


Methylergometrine (methylergonovine) concentrations in the human plasma and urine. There were no significant differeneces in the radioimmunologically determined plasma concentrations of methylergometrine, nor in its 32-hour cumulative urinary excretion after a sinlge 0.250-mg p.o. dose of Methergin (Sandoz) or Myomergin (Leiras). Peak plasma concentrations were obtained as early as 0.5 hours after the drug administration. Approximately 3% of the 0.250-mg p.o. dose was excreted in the urine during a period of 32 hours. In two subjects, after a single 0.20-mg i.v. injection, the beta phase half-life in the plasma was 1.9 hours. From the ratio of the area under the plasma curve after p.o. and i.v. administration in these two subjects, it was estimated that 64% and 63% of the p.o. dose reached the systemic circulation. No cumulation in the plasma was observed after repeated p.o. doses of 0.125 mg of methylergometrine given thrice daily to the two subjects.


Enhanced 5-F.U. mortality in rats eating definded formula diets. Rats eating nutritionally adequate defined-formula diets (D.F.D) before and following lethal i.p. injection of 5-fluorouracil exhibit increased mortality and shorter survival time than rats eating conventional Purina rat chow. Neither the presence of proteins in hydrolyzed form nor the nitrogen level in the D.F.D appear to be the crucial factor of enhanced lethality. The possible mechanisms and implications of the phenomenon are discussed.


The distribution of sulfamerazin between plasma, cerebrospinal fluid, and bile in humans. The concentration-time curves of sulfamerazin were determined in plasma, cerebrospinal fluid (c.s.f.) and bile in two groups of patients (ventricle drainage and Kerr's T-tube drain). In plasma, a half-life of 13.6 hours as well as an invasion and evasion constant of 0.145 hours -1 and 0.051 hours -1, resepectively, were observed. The distribution of half-life times showed a bimodal behavior in these patients. The unbound part of sulfamerazin was 12% and the acetylated products 14%. Unlike plasma in c.s.f. and bile the influx is delayed up to steady state. The decreases of concentration in all three compartments are the same. The concentration ratio of sulfamerazin between C.S.F. and bile and plasma water amounted to 1 and 2.5, respectively. Of the given dose of sulfamerzin, 0.87% was eliminated by bile within 24 hours. The therapeutic conclusions are discussed with regard to the bimodal distribution of half-lives, the minimal inhibition concentrations and the unbound part in the plasma.


Intramuscular absorption of dihydroergotamine in man. In order to prevent hypotension, 1.0 mg of dihydroergotamine (Vasogin) was injected intramuscularly to 10 patients 5 minutes before spinal anaesthesia. The peak plasma concentrations were measured by a radioimmunoassay as early as at 30 minutes after drug administration, indicating a fast intramuscular absorption. According to the plasma levels the drug has to be given 15-30 minutes before spinal anaesthia.


Pharmacokinetic investigations with 3H-penta-acetyl-gitoxin in volunteers and patients with respect to the occurrence of drug latentiation. After oral administration of 3H-penta-acetyl-gitoxin (Pengitoxin W.H.O., Pentagit) 1.5 mg to four volunteers, serum radioactivity diclines with a half-life of 62 +/- 10 hours. After an oral maintenance dose of 0.4 mg pengitoxin in five digitalized patients, four of them with a cannulated bile duct, serum radioactivity declines with half-life of 56 +/- 8 hours. In volunteers within 4 days 50.7% of the administered radioactivity is excreted in urine; in the patients 52.3% in urine and 28.0% in bile. By thin-layer chromatographic studies, 16-acetyl-gitoxin was charactrized as the main metabolite in serum, bile and urine. Furthermore, in the first 8 hours after administration, two additional metabolites occur in urine.


Hemodynamic effects of cutaneously administered isosorbide dinitrate ointment. With a view to testing the hemodynamic effects of a 10% isosorbide dinitrate ointment, about 40 mg of the drug was applied to the skin of nine cardiologically healthy volunteers. The ensuing hemodynamic changes were followed up for six hours by means of noninvasive techniques including echocardiography. As early as 30 min after drug application, significant decreases in heart rate, cardiac output, systolic blood pressure and intracardiac diameters were recorded. Only systolic blood pressure had returned to initial values by the end of the observation period. Isosorbide dinitrate ointment diminished myocardial oxygen consumption for a duration beyond six hr, by reducing pressure and heart-rate work of the left ventricle.


The pharmacokinetics of digoxin in patients with manifest hyperthyroidism and after normalization of thyroid function. The pharmakokinetic data (elimination half-life, apparent distribution volume, total and renal clearance and cumulative urine excretion) were determined after intravenous administration of 1 mg digoxin in 9 female patients with an average age of 52 +/- 15 years with manifest hyperthyroidism. The study protocol was repeated after normalization of thyroid function by means of conventional thyrostatic therapy. Digoxin was determined by radioimmunoassay.


Clinical localization of tubular transport of exogenous substances exhibiting urine flow dependence excretion. The proposed method is based on the assumption that a fluid flow dependent tubular transport process in the distal (diluting) segment of the nephron can be influenced by water diuresis as well as osmotic diuresis. If the fluid flow dependent transport process is localized in the proximal part of the nephron only, the urinary excretion of such a substance can be increased by proximal osmotic diuresis but not by water diuresis. By means of this method the localization of fluid flow dependent tubular transport processes of chloramphenicol and its metabolites (arylamines and total nitro compounds) has been studied in 17 healthy volunteers. The results indicate that the flow dependent transport processes of substances under study may be localized in the diluting segment.


Bioavailability of digoxin in capsules.

Bioavailability of digoxin in capsules. The authors have studied the bioavailability of a commercially available digoxin solution in capsule. Data obtained were different from that reported by other authors using experimental preparations. Single-dose and steady-state studies evidenced a similar bioavailability for capsules and standard tablets. These results introduce the new problem of the inadequate bioavailability of capsules.


Variable inhibition of human hepatic drug metabolizing enzymes by disulfiram. In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.


The distribution of lithium into cerebrospinal fluid, brain tissue and bile in man. The concentration of lithium was determined in plasma, cerebrospinal fluid (CSF) and bile in two groups of 5 and 6 patients after oral administration of lithium carbonate (0.2 mVal/kg b.w.) in  each group. In a third group of 7 patients the lithium concentration in the brain and also in the CSF and the plasma was determined in the steady state. The influx into CSF was delayed in contrast to that into plasma and bile. The elimination was biexponential. The mean plasma half-life of lithium carbonate was 21 hours. The concentration ratio between CSF and bile, respectively, and plasma was 0.44 +/- 0.03 and 1.48 +/- 0.36 in steady state. Two percent of the given dose was eliminated with the bile within 24 hours. There was no concentration difference in steady state between that for CSF and both white and grey brain matter. It is suggested that the concentration of lithium in CSF represents the brain concentration.


Uptake of noradrenaline by human erythrocytes. If human red cells are incubated with either noradrenaline or isoprenaline, these catecholamines are adsorbed to the cells surface first in a fast reaction. In a second, slower reaction they enter the cell membrane and are accumulated against the concentration gradient by the cells. It is supposed that the catecholamines enter the cells by simple diffusion and that they are reversibly bound to hemoglobin within the cells. It is  possible that this binding plays an important role in the transport of catecholamines in the blood stream where, it is assumed, they are protected from oxidation.


beta-Endorphin: synthesis and analgesic activity of several analogs modified in positions 2 and 5. The solid-phase syntheses of [Sar2]-, [Ala2]-, [D-Leu2]-, [D-Lys2]-beta-endorphins and [Pro5]-, [Leu5]-, [D-Leu5]-, [D-Ala2, D-Leu5]-beta-endorphins are described. The synthetic peptides were purified by chromatography on carboxymethylcellulose and partition chromatography on Sephadex G-50. They were characterized by partition chromatography on agarose, thin-layer chromatography, paper electrophoresis, and amino acid analyses of acid and enzymic hydrolysates. Bioassay of the synthetic analogs for analgesic activity by the tail-flick method showed the D-Leu2 analog to be 48% as potent as betah-endorphin while the Ala2, D-Lys2, Leu5, and [D-Ala2, D-Leu5] analogs were 8 to 17% as active. The Sar2, D-Leu5, and Pro5 analogs were less than 1% as potent.


[52-Homoserine]-basic pancreatic trypsin inhibitor. Preparation and properties of a protein analog. Treatment of basic pancreatic trypsin inhibitor (BPTI) with cyanogen bromide smoothly cleaves the polypeptide chain at the single methionyl residue. The newly formed homoserine lactone and alpha-amino functions are held in proximity by a disulfide linkage, and in neutral aqueous solution react together spontaneously to re-form the peptide chain. The resulting analog, [52-homoserine]-BPTI is very similar to the native molecule in most properties measured. The rate of formation of this analog from the chain-cleaved intermediate has been determined. It is apparent that the facility of analog synthesis is due in large part to the retention of the native protein conformation in the cyanogen bromide-cleaved intermediate.


Graphical refinement of the amino acid molar ratio and of the molecular weights of peptides and proteins on the basis of amino acid analyses. Corrected analysis results are handled graphically to find the most probable molar composition of polypeptides and proteins and to refine the molecular weights, even if only approximate molecular weights are available. The principle and properties of the graphical representation of idealized analyses are discussed first. Examples are given of the solution for a polypeptide consisting of 25 amino acids and for its not quite precise analysis and for a concrete protein - extracellular alkaline protease from Aspergillus flavus. The general character of the method is discussed.


Synthesis of some new analogs of the immunoadjuvant glycopeptide MDP (N-acetyl-muramyl-L-alanyl-D-isoglutamine). In our continued efforts to elucidate the relationship between the structure and the immunoadjuvant, antiinfectious or mitogenic activity of N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP), we report the synthesis of 11 new analogs. Five of them present some modifications in the N-acetyl-muramyl moiety.


Preparation of protected peptide hydrazides from the acids and hydrazine by dicyclohexylcarbodiimide-hydroxybenzotriazole coupling. A mild procedure for preparing protected peptide hydrazides directly from the corresponding carboxylic acids and equivalent amounts of hydrazine, N-hydroxybenzotriazole and dicyclohexylcarbodiimide is described. Side reactions frequently encountered in hydrazinolysis are thus totally avoided. The process is especially useful for the preparation of aspartic acid and glutamic acid containing peptide hydrazides. No racemization of the amino acid residue was observed.


Chromosomal proteins. The amino terminal sequence of high mobility group non-histone chromosomal protein HMG 14, showing sequence homologies with two other chromosomal proteins. The amino acid sequence of the first 33 residues of the non-histone chromosomal protein HMG 14 has been determined. The presence of two regions of common sequence between HMG 14 and both the non-histone chromosomal protein HMG 17 and the trout specific protein, H 6, is noted.


Effect of succinylation on the oligomeric structure of arachin. Arachin succinylated to various levels has been studied by the techniques of sedimentation velocity, viscosity, absorption and fluorescence spectra, optical rotation and circular dichroism. Succinylation up to 60% leads to the dissociation of the parent 14S molecule to 9S and 4S fractions; above 60% succinylation, 4S fraction occurs predominantly. The other measured properties also show a gradual change up to 50% succinylation and a marked change above this level. The observed changes suggest that a new organised structure is formed before the 4S fraction is denatured.


Questions we recognize but cannot formulate. The individual response to psychotropic drugs, although dose-dependent, is not stable. In some countries the variations in drug response are more pronounced, indicating a higher level of susceptibility of patients. Factors of importance influencing the response to psychotropic drugs may be subdivided into genetic and environmental ones. In research meant to clarify the difference in relation to the geographic, ethnic and socio-cultural differences among nations and individuals of various ethnic origins in their alien communities, consideration must be given to genetic factors and environmental differences in the daily surroundings. The importance of both social and psychological factors should be recognized in the evaluation of effectiveness of pharmacotherapy.


Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. The life history of melanin and lipofuscin granules of human retinal pigment epithelium (RPE) was studied in 30 human eyes spanning nine decades of life. Autofluorescent granules in the cytoplasm of eye over 30 years of age were shown, ultrastructurally and through lipid solvent extraction, to be lipofuscin granules. Sparse small fluorescent granules in infant eyes were secondary lysosomes containing small droplets of lipid. Flourescent substances in RPE granules of eyes less than 50 years old were more readily extracted with lipid solvents than those in very old eyes (greater than 70). Lipfuscin granules were positive for acid phosphatase and aryl sulfatase activity. Fusions between primary lysosomes and lipofuscin granules were common in older eyes, suggesting that the over-all degradative process involves repeated injection of lysosomal enzymes, i.e., the initial fusion of lysosomes with phagosomes (phagocytized outer segment disks) is only one of several attempts to hydrolyze the membranous material. Some melanin granules showed hydrolytic enzyme reactions. By use of enzyme cytochemistry, fluorescence microscopy, and lipid extraction two types of melanin-containing complex granules were identified: melanin with a cortex of lipofuscin (melanolipofuscin) and melanin with a cortex of nonlipid, enzyme reactive material (melanolysosomes). These findings indicate that  melanin commonly becomes incorporated into the lysosomal system of the RPE cell and suggests that it undergoes modification or degradation there. These studies indicate that a dynamic, complex interrelationship exists between the various components of the phagolysosomal system and the melanin granules in the RPE cytoplasm. Also, the observed variation from one human eye to another in the content and lipid extractability of RPE lipofuscin granules suggests that there may be differences in lipid composition of phagocytized photoreceptor disks and/or differences in the degradation of these lipids in the phagolysosomal system of the RPE cell.


The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Lipofuscin pigment granules (LPG) have been implicated as a marker of cellular aging. We have quantitated the content of LPG in human retinal pigment epithelium (RPE) as a function of age. Furthermore, topographic distribution of LPG within individual eyes was measured. Microspectrofluorometric determination of the distribution of LPG in human RPE cells revealed a progressive accumulation of LPG with increasing age. LPG first appeared in the basilar portions of RPE cells of young eyes. In older eyes, LPG formed into clumps and were noted to fill the entire RPE cell. The RPE topographic distribution of LPG revealed an increased accumulation in the posterior pole, with a consistent dip at the fovea. The ratio of lipofusion accumulation at the posterior pole, to the total RPE, remained constant throughout life.


Studies on the retina and the pigment epithelium in hereditary canine ceroid lipofuscinosis, I. The distribution of enzymes in the whole retina and pigment epithelium. The massive accumulation of autofluorescent lipopigments, representative of autoxidation, is a key morphological feature in canine ceroid lipofuscinosis (CCL). In the eye peroxidase, catalase, and four acid hydrolases were compared with regard to aged and clinical condition in a series of English setters affected with CCL. In unaffected English setters "soluble" peroxidase increased in the RPE to adult levels at 2 yr of age. Affected dogs had higher RPE peroxidase activity earlier in life, which then decline with age. The soluble retinal peroxidase of both unaffected and CCL dogs increased steadily with age, but the latter group of dogs were much lower in activity. By 2 yr of age, RPE and retinal peroxidase values were only 25% and 47% of unaffected dog levels. Although the soluble enzyme of unaffected dogs exhibited a maturational profile, membrane-bound RPE peroxidase showed a hyperbolic curve reaching a maximum at 10 mo of age. By 2 yr of age, the "bound" enzyme in affected dogs was below unaffected levels in the RPE and retina. Three acid hydrolases were slightly increased in the RPE and retina of affected dogs. Acid lipase activity, however, was similar in both unaffected and CCL dogs. Catalase was not found in the RPE of either group of dogs. The catalase activity in the retina of both affected and unaffected dogs was at similar levels. Since catalase is not present in the RPE, the major defense against peroxidase accumulation and peroxide toxicity probably depends upon peroxidase. The present study indicates that a decrease in this key regulating enzyme may be related to the formation of lipopigments in the retina and RPE of dogs with CCL.


Age-related and light-associated retinal changes in Fischer rats. Morphological changes in retinas of aging Fischer 344 rats were characterized. The numbers of photoreceptor cells gradually decreased as rats aged. The outer nuclear layer was 12 cells thick at 3 months, but was reduced to less than 8 cells by 18 months. The decrease of photoreceptor cells was more pronounced in rats housed under a light intensity of 32-ft-c than in rats housed under a light intensity of 1 ft-c. Inner and outer segments of surviving photoreceptor cells were morphologically normal. A new form of retinal degeneration was discovered in aged Fischer rats characterized by selective degeneration of peripheral retina. Degeneration was characterized by severe loss of photoreceptor cells in the far peripheral retina. Microcystoids were found in about 25% ofthe affected retinas, and the loss of photoreceptor cells was followed by proliferation and vascularization of the retinal pigment epithelium and disorganization of retinal structures. The incidence and severity of peripheral retinal degeneration increased with aged and prolonged exposure to comparatively high-intensity light. All Fischer rats ((5/5) housed under light intensity of 32 ft-c developed severe peripheral retinal degeneration by 24 months. Peripheral retinal degeneration was an age-related change but appeared to be exaggerated by ambient light.


Visual evoked response as a function of grating spatial frequency. Transient visual evoked responses (VER's) to the appearance-disappearance of sinusoidal gratings have been investigated for a range of spatial frequencies. Contrary to the results of previous studies, the results show that the transient VER consists of a relatively simple waveform that is most easily characterized by the initial negative peak (N1) whose latency and amplitude vary with the contrast and spatial frequency of the grating. At spatial frequencies less than 3 cycles/degree (c/d) an additional short latency component appears in the response. This component is maximum at 1 to 2 c/d, saturates at low contrast, and is insensitive to the precise position of the grating on the retina. The results are related to the properties of transient and sustained channels assumed to exist in the human visual system.


Studies on lens proteins. I. Subunit structure of beta crystallins of rabbit lens cortex. A method has been developed to isolate and characterize beta-crystallins of rabbit lens cortex. Chromatographic separation of water-soluble structure proteins of rabbit lens cortex on a Sephacryl S-200 gel column yielded four beta-crystallin peaks (beta1, beta2, beta3 and beta4), all eluting between alpha and gamma-crystallins. Their molecular weights were estimated to be 250,000, 130,000, 60,000, and 37,000 daltons, respectively. SDS-gradient gel electrophoresis of these beta-crystallins gave rise to characteristic polypeptides; beta1, two polypeptides of 30,000 and 23,000 daltons; beta2, one major polypeptide of 33,000; beta3; two polypeptides of 28,000 and 26,000; and beta4, two polypeptides of 22,500 and 11,200 daltons. From a knowledge of the molecular weights and the ratio of the polypeptides in each crystallin, their oligomeric structure was calculated to be 5:5, 4, 1:1, and 1:1. The relative abundance of these four beta-crystallins was found to be 25.6%, 7.2%, 27.2%, and 2.8% of the total water-soluble proteins of the lens cortex.


Laminar separation of light-evoked K+ flux and field potentials in frog retina. Light-evoked changes in [K+] 0 and field potentials were recorded from the retinas of grass frogs. In the proximal retina, light induced an increase in [K+]0. This increase had components at light onset and offset, was maximal with small spot stimulation, and reached greatest amplitude at the same depth as the proximal negative response (PNR). Extracellular dye marking revealed that this depth was within the inner plexiform layer. The off-components of both the K+ increase and PNR occurred distal to the on-components, thus supporting recent proposal that "off" synapases lie distal to "on" synapses. Since a well-developed M-wave, having a time course nearly identical to the K+ increase, was also seen in the proximal retina, this field potential appears to be a normal component of the intraretinal electroretinogram.


Photosensitive cataractogens, chlorpromazine and methoxypsoralen, cause DNA repair synthesis in lens epithelial cells. Autoradiographic techniques showed that photoactivation of methoxypsoralen opr chlorpomazine caused diffuse nuclear labeling of lens epithelial cells by thymidine. Chlorpromazine and light also induced thymidine incorporation into lymphocytes, whereas light or drug alone did not cause unscheduled DNA synthesis.


Ocular penetration of 5-fluorocytosine.

Ocular penetration of 5-fluorocytosine. Ocular penetration of 5-fluorocytosine (5FC) was studied in uninfected rabbits after subconjunctival and oral administration. With oral administration, 5FC achieved therapeutic levels in both the vitreous and aqueous humors. The use of a pharmacokinetic model permitted objective comparison of kinetic events within the eye chambers and the serum. The rates of entry and elimination in the vitreous were found to be slower than those in the aqueous, but the mean concentration over 24 hr was the same. The therapeutic levels achieved in the aqueous after subconjunctival administration were of shorter duration, and no detectable levels occurred in the vitreous. Oral administration is clearly therapeutically superior to subconjunctival administration in this model.


Effects of ultraviolet radiation on corneal epithelial metabolism. Acute exposure to ultraviolet light to 257 nm wavelength produced a photokeratitis associated with characteristic metabolic alterations of corneal epithelial metabolism in rabbits. Significant increases in corneal hydration occurred simultaneously with decreased corneal epithelial glycogen content, but adenosine triphosphate content and enzyme activity of epithelial extracts were not affected despite clinical and histological damage to the corneal epithelium. The pattern and time course of ultraviolet damage to the cornea are distinctly different from those of other forms of trauma.


Increased saccadic latencies in amblyopic eyes. Increased saccadic latencies were measured in the amblyopic eyes of subjects having amblyopia without strabismus, constant strabismus amblyopia, and intermittent strabismus. The subjects tracked a small, bright spot of light moving with random, horizontal step displacements of 0.25 to 8.5 degrees over the central retina. Normal saccadic latencies were generally found during monocular tracking with the nonamblyopic eye as well as during binocular tracking. Studies of eye-hand reaction time in amblyopic eyes have shown delays to occur over the central retina; our new finding establishes this for saccadic initiation. Normal trajectories found for all tracking saccades, normal saccadic latencies measured when the nonamblyopic eye was utilized for tracking, and synchronous movement of the eyes under all test conditions point to a sensory rather than motor basis underlying these delays. Our results are interpreted in terms of a processing delay in the sensory pathways leading from the central region of the amblyopic eye to those centers involved in saccadic initiation.


Television pupillometry via digital time processing. A new modification of the dynamic, infrared recording pupillometer of the closed-circuit television type has been developed, utilizing recent developments in high speed electronic counters. The pupillometer is simple and reliable in operation, has excellent response characteristics, and can be used over a broad range of research and clinical applications.


Accommodation and chromatic aberration in young children. Retinoscopy through colored filters (chromoretinoscopy) was used to determine the portion of the chromatic aberration interval in focus when young children (2 to 6 years of age) fixate at far and near. The results indicate that the children may be divided into three distinct groups. In the youngest group there is haphazard focusing within the chromatic aberration interval at far and near. The middle group shows selective focusing of the red end of the chromatic interval at both far and near. Children in the oldest group focus the red end when fixating at far and the green end when fixating at near, thereby sparing accommodation. These results suggest that the eye's use of the chromatic aberration interval to spare accommodation, as found in previous studies carried out on adults, is learned by about the fourth year of a child's life.


Genetic complementation between natural strains of red clover mottle virus. Three strains of red clover mottle virus were purified and their components separated by density gradient and isopycnic centrifugation. The infectivity of the purified components and of homologous and heterologous mixtures of them was assayed using Phaseolus vulgaris. Infectivity enhancement occurred in all combinations of middle and bottom components. Local lesion isolates from heterologous combinations were propagated and their symptoms on Pisum sativum and Chenopodium quinoa are described. It was concluded that symptoms on both host species are determined by the middle component. Top component formation appeared to be influenced by both bottom and middle components.


Isoelectric focusing of parvoviruses.

Isoelectric focusing of parvoviruses. Adenovirus-associated virus type 4 and X14 migrate during electrophoresis to pH 2.6 in sucrose-stabilized, pH 2.5-6.0 gradients. Naturally occurring empty capsids appear to have the same isoelectric point as complete virus particles.


Diabetes as a coronary risk factor in Malta. In a retrospective survey of 1,118 admissions for acute ischemic heart disease (AIHD) at St. Luke's Hospital in Malta in 1963-72, there were 945 (84.5%) cases of acute myocardial infarction (AMI) and 173 (15.5%) cases of acute coronary insufficiency (ACI). The proportion of patients with diabetes was 30.2% (30.7% in AMI, and 27.7% in ACI; age-corrected rates at greater than or equal to 40 years). This was significantly higher (P less than 0.01) than the corresponding rate of diabetes (20.2%) in the general population of Malta. There was a significantly greater prevalence of diabetes among women than among men with AIHD: the proportion with diabetes was 50.0% among women with AMI and 41.3 among women with ACI. The diabetes was mostly of the maturity-onset type. The high frequency of AIHD among diabetics seemed to be chiefly attributable to the effects of the diabetic state, either directly or indirectly through its association with other risk factors: obesity, physical inactivity, excessive eating and high plasma cholesterol levels. Diastolic hypertension and chronic bronchitis and emphysema associated withe heavy smoking were no more common in diabetics than in nondiabetics with AMI.


Effect of diabetes on the course of acute myocardial infarction in Malta. Among 1,118 admissions for acute ischemic heart disease to St. Luke's Hospital in Malta during 1963-72, there were 945 (84.5%) cases of acute myocardial infarction (AMI) and 173 (15.5%) cases of acute coronary insufficiency (ACI). The ratio of AMI to ACI was higher among diabetic than among nondiabetic patients, especially among women. In comparison with the nondiabetic AMI patients, the diabetics, especially women, had a significantly longer interval between onset of symptoms and hospitalization and more often had painless infarcts, both of which resulted in delay of adequate treatment; the diabetics with AMI han more complications and a significantly higher case fatality rate (20.8vs. 14.3% for nondiabetics; in diabetic women the rate was 24.1%). in fatal cases of AMI the mean age at death was lower among diabetics than among nondiabetics. In fatal cases among diabetics death was more often associated with an anteroseptal AMI site, and was the result of one or more of the following: left heart failure (61.6%), shock (38.3%), sudden death from ventricular fibrillation (13.3%), atrioventricular block (8.3%), or systemic or pulmonary arterial thromboembolism (6.5%); it was very rarely the result of diabetic ketosis.


Urinary calcium excretion in schoolboys. Ethnic group differences. The urinary calcium/creatinine ratio was estimated in two groups of schoolboys--village Arabs and urban Jewish (Ashkenazic) schoolboys, aged 10 to 11 years. Both the mean calcium/creatinine ratio and the frequency of hypercalciuria were higher among the Arab boys, and may be related to the higher incidence of chilidhood urolithiasis in Arab children in Israel.


Left ventricular wall thickness during the isovolumic relaxation period. Left ventricular (LV) wall thickness was measured by echocardiography at the onset and at the end of the isovolumic relaxation period (IRP) in a group of normal young subjects. Measured LV minor diameter was constant during the IRP in these patients and there was no change in interventricular septal thickness. Posterior LV wall thickness increased by 12 +/- 6 (SD)% (P less than 0.001) and mean LV wall thickness by 6 +/- 4% (P less than 0.01). An increase in LV wall thickness during the IRP is consistent with simple fluid dynamic principles.


Circulation parameters in the human uteroplacental region studied by a radioactive method. Maternal placental circulation is of great importance, especially in pathological pregnancies, but methods of functional assessment have not been effective. The method used is based on a follow-up of the dynamic behavior of 113mIntracer labeling the mothers's blood at the uteroplacental region. After localization of the placenta two exponential curves of the dynamic behavior of the tracer, one placental and the other myometrial, were obtained. The measurement was made in the third trimester of pregnancy in 30 women with pathological pregnancies and in 51 pregnant control subjects. The clinically sensitive criteria for distinguishing between pathological and control placentas were found to be the ration between the specific blood flow in the placenta and that in the myometrium (lambda p/lambda m) and the slope (alpha) of the straight line passing through the points of this ratio. The value of lambda p/lambda m for pathological pregnancies was 5.4 +/- 1.0 (SD) vs 1.7 +/- 0.6 in control pregnancies, and the value of alpha for pathological cases was 6.3 compared with 1.5 for control subjects. These tests may be useful in the diagnosis of pathological pregnancies with interference in uteroplacental circulation.


Comparison of the metabolic effects of salbutamol administered in a one-minute bolus and a continuous infusion in patients with bronchial asthma. A 1-min i.v. bolus injection of 300 microgram salbutamol produced transient hypokalemia in asthmatic patients, whereas continuous i.v. infusion of 10 microgram/min salbutamol for 30 for 30 min produced significant and sustained hypokalemia. The 1-min bolus infusion of salbutamol has a distinct therapeutic advantage over continuous infusion of this drug, because the hypokalemia produced by the latter may predispose to serious cardiac arrhythmias.


Experimental amyloidosis in mice of different ages. Effects of neonatal thymectomy and amyloidogenic stimulation of pregnant mice. Murine amyloidosis, induced by repeated injections of sodium caseinate, was compared in young and adult Swiss albino mice and in young thymectomized and nonthymectomized mice. Thymectomized mice developed amyloidosis earlier and more severely than intact mice. Mothers of young mice were injected with sodium caseinate during pregnancy and after birth sodium caseinate injections were given to the offspring, but this treatment did not seem to induce amyloidosis in the young mice. A much shorter latent period before development of amyloidosis was seen in the adult group than in the young mice. This may be the result of a depletion of cellular and humoral immunity with aging. The shorter latent period and more severe development of amyloidosis in the thymectomized groups supports the view that an impaired immunological state may constitute a basis for the development of amyloidosis.


Treatment with propranolol and hydralazine throughout pregnancy in a hypertensive patient. A case report. A chronic hypertensive patient was treated with alpha-methyldopa and diuretics throughout the 30 weeks of her second unsuccessful pregnancy. Treatment with propranolol and hydralazine was effective in controlling her blood pressure and was continued throughout her next two pregnancies, both of which were successful. No adverse reactions were observed in either the mother or the infants. The possibility that this combined treatment is beneficial to both mother and child in such cases should be further explored.


Regression of malignant thymoma with metastases after treatment with adrenocortical steroids. A patient with a malignant lymphoepithelial thymoma and pleural metastases is described. Incidental treatment with adrenocortical steroids after an allergic reaction resulted in a marked regression of the masses for a period of 18 months. A second course of treatment resulted in complete radiological regession of the tumors, and the patient has remained symptom free with normal chestX-rays for a further period of 18 months.


Intelligence of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, their parents and unaffected siblings. IQ measurements were performed in 33 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (110.6 +/- 13.9), in 29 unaffected siblings (113.8 +/- 11.3) and in 48 parents (104.4 +/- 9.4). The results were significantly higher than normal in the patients and siblings, but not in the parents. They were also significantly higher in the patients and siblings as compared to the parents. It is concluded that neither pre- or postnatal androgen exposure nor a genetic linkage can be made responsible for the increased IQ in congenital adrenal hyperplasia, but that more likely methodological factors (such as outdated standards) account for the higher values in patients and siblings.


[Visual discrimination conditions in infants with increased risk for cerebral damage]. Infants judged at birth to be at risk for cerebral damage show at 2 to 4 months of age significant differences compared to normal controls with respect to visual behavior at presentation of geometric patterns: Children of the risk group discriminated less consistently between a striped pattern and a homogenous gray surface. Their average time of fixation is significantly longer, and they show increased variance within the test parameters. It was therefore concluded that parameters of visual fixation and discrimination could probably allow for more reliable prognoses for future cognitive development in an infant. A longitudinal study to test this hypothesis is already in execution.


Progression of renal insufficiency in pediatric patients: estimation from serum creatinine. Progression of renal insufficiency was estimated from serial serum creatinine (SCr) determinations in 45 pediatric patients with SCr greater than 2 mg/dl. This was done by plotting the logarithm of SCr (log SCr) versus time or the reciprocal (l/SCr) versus time. Calculation of data by linear regression analysis was restricted to 38 of these patients where at least 4 sequential SCr determinations were available. In 24 patients, a similar straight line relationship was observed on both plots. The semilog plot appeared more suitable in 2, and the reciprocal plot in 7 instances. In 5 patients progression of renal insufficiency was clearly non-linear. In the majority (33 of 38) of pediatric patients, loss of renal function occurred thus at an exponential rate (log SCr) or at a constant rate (l/SCr). The mean rate of progression of chronic renal insufficiency, expressed as SCr doubling time on the semilog plot, was 2.4 months in 10 patients with acquired glomerular diseases, 17 months in 3 patients with cystinosis, 27.7 months in 5 patients with renal hypoplasia or dysplasia, and 21.8 months in 13 patients with urinary tract abnormalities.


Renal transport of amino acids in children with oculocerebrorenal syndrome. Inulin and amino acid clearance studies were made in 6 boys with oculocerebrorenal syndrome (Lowe) aged 11 months to 5 years. Glomerular filtration rate ranged between 50 and 112 ml/min/1.73 m2. Clearance values of all amino acids were increased. Tubular reabsorption of cystine, ornithine, lysine and arginine was relatively more reduced than that of the other amino acids. In Lowe's syndrome the transport system of the basic amino acids and cystine appears to be more impaired than that of other amino acids.


[The milk curd syndrome].

[The milk curd syndrome]. The milk curd syndrome is an as yet little known cause of intestinal obstruction in neonates. Two personal cases are reported, and 37 others are collected from the world literature. Infants with milk curd syndrome have a normal discharge of meconium. The intestinal obstruction appears usually between the 2nd and 16th day after birth. In most of the cases, the milk curd was found in the distal part of the ileum. The aetiology of the milk curd obstruction syndrome remains still unclear. The composition of artificial milk feeding formula in connexion with transitory absorption deficiency of amino acids, and the possibility of a temporarily insufficient excretion of bile acids are discussed.


Pulmonary hypoplasia, multiple ankyloses, and camptodactyly: one syndrome or some related forms? Four perinatally dying infants with multiple congenital malformations, including pulmonary hypoplasia, multiple ankyloses, abnormalities of the face and camptodactyly are presented. The differences both for severity of pulmonary hypoplasia and for the type of associated malformations suggest that this complex of abnormalities is not a single syndrome but a complex of related entities. These entities and some other genetical syndromes may form a "community of malformations" involving facial, skeletal (arthrogryposis, camptodactyly) and placental abnormalities.


Effects of ionizing radiations on human costal cartilage and exploration of the procedures to protect the tissue from radiation damage. The chemical changes produced following 60Co-gamma-irradiation of human costal cartilage have been monitored using "critical electrolyte concentration" (CEC) measurements utilizing Alcian Blue--magnesium chloride and Toluidine Blue--sodium chloride systems. The decrease in the CEC with radiation can be related to the decrease in hexose and hexosamine contents of the cartilage. Such changes arise as a result of degradation of the glycosaminoglycan component of the tissue. The state of the collagen fibres after irradiation has been examined using the Van Giesson stain and by biochemical assay of the hydroxyproline moeity. Energy transfer methods have been utilized to protect the glycosaminoglycan component of the cartilage from radiation damage.


Enzyme histochemical studies on the Purkinje fibers of the atrioventricular system of the bovine and porcine hearts. In this communication the results of applying various histochemical semipermeable membrane techniques to the localization of several enzymes in bovine and porcine heart are presented. The Purkinje fibers of the atrioventricular conducting system of the bovine heart differ from the myocardium proper in containing a greater activity of the glycolytic and gluconeogenetic enzymes--lactate  dehydrogenase, glyceraldehyde-phosphate dehydrogenase, hexokinase, glucosephosphate isomerase and phosphoglucomutase, and less activity of the aerobic enzymes--NADH: nitroBT oxidoreductase and isocitrate dehydrogenase (NADP+). The metabolic reactions obtained with Purkinje fibers of the porcine heart are less pronounced. These histochemical findings are in accordance with the impression that Purkinje fibers, compared with the common myocardial fibers, have a higher rate of anaerobic metabolism and a lower rate of aerobic metabolism. The activity of the NADPH regenerating enzymes glucose-6-phosphate dehydrogenase and phosphogluconate dehydrogenase (decarboxylating), and the activity of acid hydrolases such as non-specific esterase and acid phosphatase is higher in the Purkinje fibers of both the bovine and porcine heart.


Quantitation of mitochondrial injury in cultured rat heart endothelioid cells with nitroblue tetrazolium. A sensitive method is presented for measurement of changes in the permeability of mitchondria in cultured cells. Rat heart endothelioid cells were used to determine the penetration rate of nitroblue tetrazolium (NitroBT) or other reactants into mitochondria in situ. Nitroblue formazan, produced as a consequence of succinate dehydrogenase activity in the mitochondria, was eluted and measured with a spectrophotometer. Prior injury of cells with hypo-osmolar solutions increased the rate of formazan production. Several methods are described or suggested for the statistical analysis of the data.


Endogenous peroxidase in mast cells localized with a semipermeable membrane technique. Hamster mast cells have been found to give strong peroxidatic reactions at pH 5, 7.5 and 10 when sections of skeletal muscle are incubated for 2.5 h in the dark at room temperature on semipermeable membranes covering a gelled incubation medium consisting of 0.01% hydrogen peroxide, 5.5mM diaminobenzidine and 1.36% agar dissolved in Universal buffer. The technique is very efficient: with it, all mast cells react in marked contrast to the negative reaction they usually give with conventional techniques. The peroxidatic reactions are abolished if tissues are perfused beforehand with either aminotriazole or KCN but not if these inhibitors are incorporated in the gelled incubation medium. This and other evidence suggests that the mast cell reactions are not due to either catalase or haemoglobin adsorbed onto mast cell granules from lysed red blood cells. Skeletal muscle fibres do not exhibit any visible peroxidase activity with the membrane technique.


A quantitative study of the effects of different grades of polyvinyl alcohol on the activities of certain enzymes in unfixed tissue sections. Different grades of the colloid stabilizer, polyvinyl alcohol, used for protecting unfixed cryostat sections during cytochemical reactions, may have different effects on enzymatic activity. The influence of three grades of polyvinyl alcohol on the activities of "soluble", membrane-bound and membrane-enclosed enzymes has been investigated in unfixed sections; the activities were measured microdensitometrically. The largest molecular weight polyvinyl alcohol (G18/140, mol. wt. about 90 000) did not retain glucose-6-phosphate dehydrogenase activity in sections of rat liver even when used at the maximum convenient concentration (12%); G04/140 and M05/140 (molecular weights of 15 000 and 25 000 respectively) retained this soluble enzyme if used at concentrations of 30 and 20% respectively. At these concentrations, lactate dehydrogenase activity was apparently decreased when G04/140 and M05/140 were used; this diminished activity has been shown to be due to the need to establish optimal concentrations of reactants for each grade of polyvinyl alcohol and for each reaction. When optimal concentrations of reactants were used, the activities of this enzyme in the presence of each grade of polyvinyl alcohol were identical. The presence of any type of polyvinyl alcohol did not influence the activities of mitochondrial succinate dehydrogenase or of the smooth endoplasmic reticulum enzyme, delta5,3beta-hydroxysteroid dehydrogenase. However, the presence of polyvinyl alcohol improved the state of the section.


The peroxisome (microbody) membrane: effects of detergents and lipid solvents on its ultrastructure and permeability to catalase. The effects of detergents, organic lipid solvents, and several adjuvants used in cell fractionation on the ultrastructure of the peroxisomal (microbody) membrane and its permeability to catalase have been investigated. Chopper sections of glutaraldehyde-fixed liver were incubated in the presence of various agents, followed by cytochemical staining for catalase and processed for electron microscopy. Catalase activity was also determined biochemically in the incubation medium. Marked catalase diffusion was found after treatment with 1% or 0.5% Triton X-100 or deoxycholate, as well as with 50% ethanol or acetone or 20% propanol or t-butanol. In contrast, 1% digitonin and lower concentrations of the above agents, as well as sucrose or glycerine caused selective diffusion of catalase from a limited population of peroxisomes. Treatment with 10% polyvinylpyrrolidone (PVP), which has been used as a protective agent in the isolation of microbodies, did not produce any alteration in the fine structure and cytochemical appearance of peroxisomes. These findings concur with earlier biochemical studies on freshly isolated peroxisomes and demonstrate the susceptibility of microbodies, even in glutaraldehyde-fixed rat liver to the effects of various agents which affect the microbody membrane. A close correlation between the ultrastructural integrity of the microbody membrane and its permeability to catalase has been found. The significance of these observations for the assessment of the permeability characteristics of the microbody membrane is discussed.


Methodological aspects of the histochemical localization and activity of some cerebellar dehydrogenases. In a detailed study focused on the methodological problems in dehydrogenase histochemistry [e.g., fixation, diffusion of enzymes and of reduced inermediates, conversion of NADPH and NADP to NADH and NAD, respectively, penetration of tetrazolium salt and formazan substantivity, 'nothing dehydrogenase' reaction, use of exogenous CoQ10 and of flavoprotein substitute (PMS)], the distribution and activity of succinate dehydrogenase, NAD(P)H-tetrazolium reductase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase (H and M types), and of L-glutamate dehydrogenase (E.C.1.4.1.2 and E.C.1.4.1.3) have been investigated in the rat cerebellum. It was evident from the study that reliable results could only be obtained if all the aforementioned factors had been considered. The image of actual concentration of SDH in the neuropil of the molecular layer could only be recorded by adding CoQ10, while other structures exhibited greater balance between SDH and endogenous mitochondrial CoQ. Contrary to previous studies, a reversed localization of the activity of G-6-PDH and LDH was noticed. The elements of molecular and Purkinje layers were rich in G-6-PDH, while the granular layer was nearly depleted. The actual level of LDH could only be recorded if NADH-tetrazolium reductase was bypassed with PMS. The H and M types of LDH coexisted in the three cortical layers, the H type being prevalent and the M type attaining its highest level in synaptic glomeruli followed by the structures of the molecular layer and the Purkinje cells. High activity of GDH was noticed in Bergmann glia followed by synaptic glomeruli, while most other structures showed weak to moderate activity. The two GDH types coexisted in all structures showing activity, except for Bergmann cells, which only showed presence of the E.C. 1.4.1.3 type. Furthermore, Bergmann glia was exceptional by showing no activity of SDH and LDH, but strong activity of G-6-PDH and NADPH-tetrazolium reductase. The granular cells were exceptional by showing weak or no activity of all enzymes in question.


Isolation and thin-layer chromatographic identification of several peptides with NH2-terminal tryptophan and their histochemical demonstration in the ACTH cells of the rat hypophysis. Methods for the isolation and thin-layer chromatographic identification of amino-terminal tryptophyl-peptides presumably responsible for histochemical tryptophyl-peptide reactions in the ACTH cells of the rat hypophysis are described. In the hypophyseal extract several tryptophylpeptide bands--depending on the homogenization solution--were demonstrated on thin-layer chromatograms. Tryptophyl-peptides were demonstrated from their fluorescence induced 1) with glyoxylic acid (glyoxylic acid introduced into the homogenization solution), 2) by exposure of the chromatographic plates to combined formaldehyde and chloral vapour or 3) by exposure to combined formaldehyde and acetyl chloride vapour. A positive PAS reaction was demonstrated in some tryptophyl-peptide bands. Thus, some tryptophylpeptides seem to contribute to the observed PAS positivity of the ACTH cells.


D-Ephedrinephosphate, DEP: a new substrate with specificity for prostatic acid phosphatase (PAP). This report describes the synthesis and physical (including spectral) properties of a new substrate, D-ephedrinephosphate, DEP1, which is histochemically highly specific for a secreted non-lysosomal prostatic acid phosphatase, PAP. This specificity is in contrast to other substrates which are nonspecific, i.e., which demonstrate acid phosphatases that originate from various cell types and are mainly lysosomal. When this substrate is used for light and electron microscopic histochemistry in a modified Gomori medium, PAP is demonstrated mainly in secretory granules and in the Golgi apparatus (and its related vacuoles) of prostatic epithelial cells of several species of mammals including man. This corroborates our previous suggestion that PAP is not a lysosomal enzyme as are many of the other acid phosphatases. This high degree of specificity of DEP for PAP supports the usefulness of this compound in the histochemical and biochemical characterization of PAP, and in the diagnosis of localized or disseminated prostatic disease.


Mechanism for transport of nitro-blue tetrazolium into viable and non-viable leukocytes. The permeability of the membrane of phagocytic leukocytes (WBC) to the non-complexed nitro-blue tetrazolium (NBT) cation has not been well explored. In this study both complexed and non-complexed (or free) NBT have been incubated with viable cells. The entry of NBT into the WBC was determined by both colorimetric and infrared analyses. Very little free NBT enters the viable WBC compared with NBT complexed with serum factors. NBT entry was also studied in non-viable WBC by use of the infrared system. The entry of NBT into the non-viable cells was independent of serum complexing factors. Much larger quantities of both free and complexed NBT enter non-viable cells than enter viable WBC. It is concluded that the membrane of the viable WBC is quite impermeable to the free NBT cation. Ultrastructural studies suggest that the gaps in the plasma membrane of non-viable cells could allow the passage of relatively large amounts of both free and complexed NBT.


The vegetative network in the guinea pig and rat sacral spinal cords. The intermediate zones in the sacral segments of guinea pig and rat spinal cords are histochemically investigated for the presence of catecholaminergic and cholinergic structures. The presence of a well-developed noradrenergic network is demonstrated. This network connects the preganglionic vegetative nuclei in horizontal and vertical directions. In addition, only some fibers from the bundles composing this network show acetylcholinesterase activity.


Evidence of the presence of extraperoxisomal catalase in chloragogen cells of the earthworm, Lumbricus terrestris L. The DAB reactivity of the midintestine of the earthworm, consisting of epithelial layer, muscle layer, and chloragogen tissue, was examined electron microscopically. Besides the mitochondrial membranes of the examined cell types and the hemoglobin content of the blood vessels and chloragogen cells, a considerable DAB reactivity was found in the whole cytosol of the chloragocytes. The DAB reaction of the cytosol was more intensive when incubation medium for catalase, less intensive when incubation medium for peroxidase, was used and did not occur when H2O2 was omitted. Cytosol of the chloragogen cells was isolated and preliminary assay of catalase and peroxidase activities was made. Cytosol samples showed moderate peroxidase activity, but catalase activity measured by the decomposition of hydrogen peroxide showed a very high rate. Catalase and peroxidase activities of the cytosol were heat-sensitive and might have been inhibited by azide and cyanide, respectively. Results prove the assumption that the intensive DAB reactivity of the chloragocyte cytosol is caused by its extraperoxisomal catalase content.


[The value of stapedius reflex examinations in patients with myasthenia gravis (author's transl)]. The behavior of the stapedius reflex was examined by means of the Z0-70 Madsen electroacoustic bridge in 41 patients (aged 9-73) with myasthenia gravis. A higher stapedius reflex threshold (90-130 db) at normal hearing was found in 66% of the cases. In 46.3% of the cases, an increased fatigue of the stapedius muscle was observed, as characterized by the lowering of the amplitude or the disappearance of the reflex after several successively repeated recordings. The examination of stapedius muscle fatigqu may be helpful indiagnosing early forms of myasthenia, in following the results of therapy for the disease, as well as in assessing the efficiency of antimyasthenic drugs.


[An orbital rhabdomyosarcoma mimicking a mucocele (author's transl)]. Rhabdomyosarcomas are rare tumours of the paranasal sinuses nad orbit. However they represent a broad group of childhood malignant soft tissue tumours. The presentation of these tumours often causes great diagnostic difficulty, especially if they involve the medical orbital wall. Certain diagnostic problems are discussed from our own experiences.


[Restricted motility of the tongue--the reason for or a symptom of childhood speech disorders (author's transl)]. From the assessment of more than 1000 children aged 3 to 6 years is a significant relationship between articulation speech disorder s and defective motiiity of the tongue. In addition to this direct relationship there might be an indirect connection as well. A central nervous disorder could possibly be the common reility of 865 kindergarten children was examined by a test method developed by ourselves. At the same time the degree of language disturbance and of speech defect were measured. Whereas there was again language disturbance and tongue mobility, this latter defect has no influence on the kind of speech disorder observed. There is probably therefore no direct relationship between restricted tongue movement and articulation skills. It is important to consider whether articulation defects and restricted motility of the tongue have a common use in the central nervous system.


[Functional hearing loss in speech audiometry (author's transl)]. In a group of 238 patients assessed for medico-legal reasons, 26 subjects were found to have functional hearing problems. In detecting the presence of functional hearing loss, the reliability of speech audiometric patterns was shown. Each patient demonstrated at least one suspicious response. The evaluation revealed an irregular configuration of curves ("step-like", 56%) and a better understanding for monosyllabic testwords than for digits (28.8%) as the most important criteria. In the control group of 40 hard-of-hearing patients without functional hearing losses, testing-irregularities were found in only 2.5-3.7% of the patients. Furthermore, discrepancies between speech reception thresholds and pure tone averages (84.6%) as well as poor test-retest reliability in tone audiometry contributed to an identification of functional hearing loss. Békésy-audiometry Type V was obtained in 73% of those patients studied.


Notes on loneliness.

Notes on loneliness. Loneliness in this article is discussed in order to make it more discernable. Psychoanalytic literature has been surveyed relevant to loneliness and related issues. Noted is the importance of individualism in America, citing Thoreau as a model for individualism. Edgar Allan Poe's story "The Man of the Crowd" is discussed to illustrate desperate loneliness. The topic of loneliness connects to issues of empathy, loneliness in treatment, the countertransference response to loneliness, the study of self experience, and the problems created by the use of the term identity. The historical perspective indicates how we are time bound to the vocabulary, theories, ideas and myths of our era, to which, in our loneliness, we cling.


Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism. The time course of ventilatory adaptation to medroxyprogesterone acetate (MPA) and potential mediators of this response in plasma and lumbar CSF were determined in five healthy adult males. A significant decrease in arterial PCO2 (PACO2) at rest and exercise was noted within 48 h of drug administration with the maximum effect reached within 7 days and amounting to a 5-Torr decrement in PACO2. Blood and lumbar cerebrospinal fluid pH because significantly alkaline to control as soon as the ventilatory resporse was noted and remained alkaline during the treatment period. The ventilatory and dP/dt max response to exogenous CO2 was unchanged but their response to moderate exercise was increased after MPA. MPA-rlated materials were detected in both the plasma and CSF as soon as the ventilatory response was noted. The increase in CSF MPA-related materials approximated the unbound fraction determined in plasma. We conclude that [H+] in plasma and CSF is a function rather than a cause of ventilator acclimatization to MPA. MPA-related materials are capable of crossing the blood-brain barrier and could potentially exert their ventilatory stimulant effect by some central mechanism.


Mechanics of the human diaphragm during voluntary contraction: dynamics. We determined the static, isometric relationship between diaphragmatic EMG (Edi) and transdiaphragmatic pressure (Pdi) in man at specified abdominothoracic configurations, assessed with magnetometers. During inspiratory airflow, measurements of Edi and Pdi were taken as the respiratory system passed through the same configuration as obtained during the static isometric contractions, allowing a comparison of static and dynamic contractions of the diaphragm at a given length and curvature. When voluntary inspiratory maneuvers are performed with no associated outward displacement of the abdominal wall, or with slight inward displacement, the Pdi developed dynamically is the same as that developed statically at a given Edi. When outward movement of the abdominal wall occurs during inspiratory airflow, the Pdi developed dynamically depends on the rate of abdominal displacement, not on overall inspiratory airflow rate. We conclude that the velocity of shortening of the diaphragm increases directly as the rate of abdominal displacement. We construct a pressure-flow analogue of the force-velocity relationship for the diaphragm and discuss the functional implications of these observations in relation to spontaneous breathing.


Elastic constants of trapped lung parenchyma. Isolated dog lobes were maximally trapped with air, and their parenchymal elastic properties were measured at the trapped volume. Indentation tests were performed on the surface of the lobes, followed by uniaxial and torsion tests on excised pieces of parenchyma. Similar values for Young's modulus were obtained from the indentation and uniaxial tests. The values for the shear modulus from the torison tests also were consistent with Young's modulus measured by the other procedures. The indentation test provided an accurate estimate of Young's modulus or the shear modulus for trapped lobes, and the results suggest that it is a valid method for estimating these constants in nontrapped lobes.


Effect of parenchymal shear modulus and lung volume on bronchial pressure-diameter behavior. A method that interrelates lung pressure-volume behavior, bronchial pressure-diameter behavior, and parenchymal shear modulus is presented. The method was used to predict changes in intraparenchymal bronchial diameter that occurred when lobe pressure-volume behavior and parenchymal shear modulus were markedly changed by inducing air trapping in isolated dog lobes. Predictions agreed with measurements, thereby supporting the general method. Measured values for the shear modulus were approximately 0.7 times the transpulmonary pressure for the control state. Estimated values for the peribronchial pressure difference from pleural pressure during a deflation pressure-volume maneuver for transpulmonary pressures below 12 cmH2O were small, approximately +/- 1 cmH2O, its sign being positive or negative, depending on whether the bronchus was dilated or contricted.


Faster adjustment of O2 uptake to the energy requirement of exercise in the trained state. The purpose of this study was to determine the effect of endurance exercise training on the time course of the increase in VO2 toward steady state in response to submaximal constant load work. Seven men participated in a strenuous program of endurance exercise for 40 min/day, 6 days/wk for 10 wk. Their average VO2max increased from 3.29 liters before training to 4.53 liters at the end of the training program. VO2 was measured continuously on a breath-by-breath basis at work rates requiring 40%, 50%, 60%, or 70% of VO2max before training. After training the subjects were retested both at the same absolute and the same relative work rates. The increases in VO2 toward steady state occurred more rapidly in the trained than in the untrained state both at the same absolute and at the same relative work rates. The finding that O2 uptake rises to meet O2 demand more rapidly in the trained than in the untrained state provides evidence that the working muscles become less hypoxic at the onset of exercise of the same intensity after training.


Indices of thermoregulatory strain for moderate exercise in the heat. The effect of varying humidity and dry bulb temperatures was studied on five normal male unclothed subjects while exercising (40-45 min) at 28% VO2max. Air movement was 0.75 m.s-1. The initial test and the 16th test on each subject both done at 50 degrees C and 30 Torr (32% rh). Each subject did the intervening 14 experiments twice per day at varying ambient temperature (Ta) and water vapor pressure (Pa) levels, so selected to progressively increase skin wettedness levels. Mean skin temperature (Tsk) and esophageal temperature (Tes), heart rate (HR), skin evaporative heat loss (Esk), and warm discomfort were continuously observed. Skin wettedness (w) was evaluated as the ratio of the observed Esk to the maximum evaporative capacity of the environment. A rational effective temperature (ET) is defined as the dry bulb temperature at 50% rh in which the total heat exchange from skin surface would be the same as in the test environment, described by the observed Ta and Pa. The results showed that 1) during steady state both HR and Tes were unaffected by Ta from 26 to 41 degrees C responding to the level of exercise intensity, when Pa less than or equal to 20 Torr; 2) both mean body temperature, found by weighting Tsk:Tes by 1:9, and ET were each significant indicators of physiological strain when Pa greater than 20 Torr; 3) a level of strain, caused by skin wettedness values greater than 0.5, is suggested as a primary condition necessary for inducing heat acclimation.


Physiological and biophysical limits to work in the heat for clothed men and women. Heat-acclimated, lightly clothed men and women (four of each) walked on a treadmill at 25% and 43% VO2 max, respectively, (M =194 W.m-2), under seven air temperatures (Ta) ranging from 36 to 52 degrees C. Each experiment involved 1 h of fixed and a 2nd h of progressively increasing ambient vapor pressure (Pa). The relative steady state of rectal temperature (Tre), mean skin temperature (Tsk), and heart rate (HR) reached in the 1st h were forced upward during the 2nd h by the rising Pa. The critical air vapor pressure (Pcrit) was identified by the Tre point of inflection for each Ta. One man did not fully reach steady state, but inflection could be determined for his physiological responses. The mean values of all points of inflection were calculated for Tre, Tsk, and HR. Significant sex difference in HR was found only by excluding the results of the one man. Tre and Tsk showed no significant difference between men and women. The coefficient for evaporative heat transfer (he), which could be derived using the Pcrit for the low Ta range, was 14.5 +/- 2.2 W.m-1 Torr-1.


Response of the renin-aldosterone system in the camel to acute dehydration. Plasma renin activity (PRA), renin substrate concentration (PRS), aldosterone concentration (PA), and cortisol levels were determined in five camels during dehydration (8-10 days complete denial of water) and at timed intervals after rapid rehydration in cool spring and hot summer weather. Plasma sodium concentration increased from 138 +/- 3.7 to 147 +/- 2.5 (mean +/- SE) meq/l during spring dehydration, and from 146 +/- 1.3 to 157 +/- 1.14 meq/l during dehydration in the summer. Plasma sodium concentration returned to control levels over the course of several hours following rapid rehydration. Only minor changes in plasma potassium concentration occurred. The hormonal changes were accentuated in the summer dehydration. PRA increased slightly on dehydration, and returned to control levels over the course of several hours following rehydration. PA increased slightly on dehydration but was markedly elevated 24 h after rehydration. PRS showed a slight increase following rehydration in the spring experiment, but no significant change in the summer experiment. Changes in cortisol were insignificant. The results are consistent with a role for angiotensin and aldosterone in enhancing sodium and water reabsorption from kidney and large intestine on dehydration in this species.


Effects of exercise on sleep.

Effects of exercise on sleep. We tested the hypothesis that EEG sleep stages 3 and 4 (slow-wave sleep, SWS) would be increased as a function of either acute of chronic exercise. Ten distance runners were matched with 10 nonrunners, and their sleep was recorded under both habitual (runners running and nonrunners not running, 3 night) and abruptly changed (runners not running and nonrunners running, 1 night) conditions. Analyses of both visually scored SWS and computer measures of delta activity during non-rapid eye-movement (NREM) sleep failed to support the SWS-exercise hypothesis. The runners showed a significantly higher proportion and a greater absolute amount of NREM sleep than the nonrunners. The runners showed less rapid eye-movement activity during sleep than the nonrunners under both experimental conditions, indicating a strong and unexpected effect of physical fitness on this measure. Modest afternoon exercise in nonrunners was associated with a strong trend toward elevated heart rate during sleep. Mood tests and personality profiles revealed few differences, either between groups or within groups, as a function of exercise.


Optimal rate of work for mountaineers.

Optimal rate of work for mountaineers. The physiological responses of seven young male highlanders were recorded at high altitude while they were carrying loads (0, 25, 35, 45, and 55 kg) on snow at different speeds, supporting the loads on their backs by circular straps around the forehead. The rates of work calculated from the gross weight (body weight plus actual load in kg) multiplied by the speed of walking, m.min-1, ranged from 4,460 to 8,440 kg.m.min-1. The relationship between the rate of work and energy expenditure was rectilinear within the present range of values. The oxygen consumption (51.6 and 59.7 ml.min-1.kg-1 BW) for 55-kg load (at 4.09 and 4.64 km.h-1) possibly reached maximal aerobic capacity. At higher energy output at high altitude the subjects were exhausted after a short period of work. The proportion of increase of oxygen consumption per kg gross weight carried or per kg.m was almost constant up to a 55-kg experimental load. It is suggested that for day-to-day operations work should not be undertaken at more than 30-40% of maximal work capacity; a rate of work around 4,000 kg.m.min-1 (25-30 kg actual load at 3.0 to 3.5 km.h-1) may be considered as optimal for highlanders and porters at high altitude.


A roentgenographic method for measuring nasal mucous velocity. Nasal mucous velocity was estimated by following the motion of radiopaque discs of Teflon by means of a fluoroscopic image intensifier. From 5 to 10 discs were deposited on the superior surface of the inferior turbinate with a forceps. No local anesthesia was employed and the subjects experienced no discomfort. The linear velocity of the discs was obtained by playing the videotape onto a television monitor, measuring distance with a ruler, and dividing by elapsed time. Duplicate runs of 1-2 min, 15 min apart were very reproducible but runs at 4-h intervals or daily over a 5-day period had a coefficient of variation of 30%. Average nasal velocity for individual ranged from 0 to 22.5 mm/min and group means ranged from 6. 8 to 10.8 mm/min. There was no statistically significant difference in nasal mucous velocity between young and elderly subjects nor was there a sexual difference. The saccharin test of nasal mucous transport was unsatisfactory because of inability to repeat the test more often than 1-2 h and its propensity to produce mild discomfort in a significant number of subjects. Saccharin times did not correlate significantly with values of nasal mucous velocity.


Current-to-voltage convertor for measurement of oxygen. A highly sensitive, miniature, inexpensive circuit for the measurement of PO2 in vivo has been described. The circuit is constructed from a current-to-voltage convertor, clamping circuit, differential amplifier, and reverse voltage and overvoltage protector. The design of the circuit allows us to apply voltage bias to the measuring electrode while grounding the preparation. The clamping circuit holds the selected bias voltage constant while the differential amplifier subtracts this bias potential from the PO2 signal yielding an output voltage that is proportional to the current sensed by the oxygen electrode. The circuit is protected from reverse voltage and overvoltage.


A gas-stream heater to control local skin temperature under evaporative sweat capsules. A compact 4-W gas-stream heater for use with ventilated sweating capsules is described. The heating element is constructed from two modified 75-omega power resistors connected in parallel and contained in the capsule gas inlet tube. Heater power is controlled with integrated circuits which compare the output of a thermocouple, measuring either capsule skin or air temperature, with a predetermined target temperature. The unit responds fairly slowly to sudden large changes in target temperature, but once a steady state is achieved, maintains target temperature levels despite changes in evaporative heat loss. The device is well suited for studies in which local skin temperature or capsule air temperature must be elevated and clamped while the effects of other local stimuli or central thermoregulatory activity are studied, and in studies where the skin temperature effect on transepidermal water loss must be controlled.


Heat-injured rats: pathochemical indices and survival time. Rats were exercised on a treadmill (9.14 m/min) in a hot environment (34.5 degrees C, 30% rh) until a rectal temperature of 42.0--42.5 degrees C was reached. Analysis of plasma constituents in subsequent serial blood samples demonstrated a highly significant inverse correlation between lactate concentration (P less than 0.001) and potassium levels (P less than 0.005) in blood samples taken immediately postexercise when both of these were correlated to survival time. Alternatively, plasma creatine phosphokinase (CPK) activity in these samples, although significantly elevated over control levels (P less than 0.001), was not correlated with either survival time or lactate-potassium concentrations. When fluid was administered prior to the run and immediately thereafter to repress pathological effects, there occurred no changes in plasma lactate and potassium levels between the postrun sample and a second sample taken 60 min later, while CPK levels were significantly reduced (P less than 0.01) in the second sample. However, levels of all three indices were significantly elevated (P less than 0.01) in a third sample taken terminally despite the fact that the animals were restrained and sedentary during this interval. These findings indicate that the hyperthermic injury may have had fundamental pathological effects on metabolism and membrane integrity producing lactacidemia and hyperkalemia of sufficient magnitude to compromise cardiovascular performance.


Extravascular water content of heart and lungs after acute myocardial ischemia. We measured the extravascular water content of hearts and lungs of anesthetized dogs subjected to one of the following protocols: a)sham operation, b) circumflex artery ligation, c) increased left atrial pressure (Pla), or d) increased Pla and circumflex artery ligation. After 4 h, extravascular water of the heart and lungs increased significantly in the three experimental groups when compared with values from sham-operated dogs. After circumflex artery ligation, extravascular heart water increased 29% and lung water 8%, although Pla and calculated pulmonary microvascular pressure (Pmv) did not change. Extravascular heart water also rose 30% after increasing Pla from 23 to 37 cm H2O by inflating a left atrial baloon. In these dogs, extravascular lung water increased as a hyperbolic function of Pmv. Increasing Pla to 20 cm H2O in dogs with coronary artery ligation resulted in a 16% increase in heart water. Also at each Pmv, extravascular lung water was greater in dogs with coronary artery ligation than in dogs without. These data indicate that the increased extravascular lung water after coronary artery ligation cannot be explained solely by hemodynamic mechansims. We suggest that acute myocardial ischemia contributes to an increase in vascular permeability in the heart and lungs.


Respiratory responses to intravenous and intrapulmonary CO2 in awake dogs. Ventilatory responses to CO2 inhalation and CO2 infusion were compared in the awake dog. The CO2 was introduced directly into the systemic venous blood via a membrane gas exchanger in a femoral arteriovenous shunt circuit, and the extracorporeal blood flow, QX, was maintained constant at one of two rates: low, 0.5 l/min; or high, 2.0 l/min. A total of 13 experiments was performed in four dogs comprising 50 control and 25 inhalation and infusion observations at each of the two flow rates. Comparison of CO2-response curve slopes, S = delta V E/delta PaCO2, between CO2 inhalation and infusion showed no significant difference either within or between flow rates. The mean value of S for all conditions was 1.88 l/min per Torr with a 95% confidence interval of 1.66 -2.14. An independent additive ventilatory drive amounting to 28% of low-flow control VE was found at the highflow rate. We conclude that at constant blood flow the responses to both CO2 inhalation and infusion are hypercapnic and not significantly different.


Effect of pulmonary vascular engorgement on respiratory mechanics in the dog. The immediate effects of pulmonary vascular engorgement (PVE) on lung and chest wall mechanics were studied in anesthetized, paralyzed dogs with the chest wall intact. A balloon-tipped catheter advanced retrograde into the left atrium was used to produce partial mitral valve obstruction and increases in pulmonary artery and left atrial preassures equal to 15 and 20 cm H2O, respectively. This increased pulmonary blood volume (PBV) by 50% and reduced dynamic lung ocmplicance 14%. With the airway occluded at different lung volumes, transient PVE produced a 6% decrease in compliance on the deflation limb of the pressure volume curve of the lung and a shift in the chest wall pressure-volume curve, which was consistent with an increase in chest wall volume equal to the increase in PBV. During apnea with the airway open, PVE reduced lung gas volume and increased chest wall recoil. We conclude that the changes in chest wall recoil associated with PVE are the result of an increase in total lung displacement volume.


Carbohydrate, lipid and amino acid metabolism following physical exercise in man. To elucidate early metabolic adaptations of physical training obese and nonobese subjects were studied before and at different intervals after 1 h of bicycle exercise at 70% of maximal working capacity. Four h after exercise intravenous glucose tolerance (IVGT) and plasma level of alanine were decreased. Compared to the diurnal variation plasma concentration of cortisol was increased. Twenty-four hours after exercise plasma concentrations of cortisol and trihlycerides were decreased. Furthermore, plasma insulin during IVGT test was decreased and blood glycerol increased in the obese subjects. There were no changes in basal insulin, IVGT, or plasma levels of amino acids which were elevated in the obese subjects (valine, isoleucine, leucine, tyrosine, phenylalanine). Forty-eight hours after exercise plasma insulin during IVGT test and plasma triglycerides remained decreased in the obese subjects. Low cortisol levels 24 h after exercise might result in increased insulin effect leading to low plasma insulin levels seen in physically trained subjects. Elevated glycerol levels in the obese subjects might be the first sign of diminishing fat stores secondary to increased lipolysis.


Tracer priming the bicarbonate pool.

Tracer priming the bicarbonate pool. We have described a technique whereby the time necessary to reach an equilibrium enrichment of expired CO2 during a primed-constant infusion of [U-13C]glucose was shortened from 7 to 8 h to 1 hour or less. We applied the theory of the primed-constant infusion technique to the bicarbonate pool, with the "constant infusion" of labeled carbon dioxide originating from oxidation of the infused [13C]glucose rather than from a labeled infusion of bicarbonate.


Oxygen electrode design criteria and performance characteristics: recessed cathode. A computer simulation of the steady-state operation of recessed (Whalen-type) polarographic oxygen electrodes has been developed to give the design factors important for performance optimization. The simulation makes use of a specially formulated three-dimensional orthogonal coordinate system with the geometry identical to the actual recessed cathode and gives the oxygen concentration field induced by it in the surrounding medium. Equations are presented which allow one to calculate, for any recessed cathode, the current sensitivity, maximum stirring artifact, measurement error, and time constant. Comparisons with analytically obtained expressions for the corresponding quantities for idealized, spherosymmetric cathodes demonstrate the unique aspects of recessed-cathode performance. For commonly used electrodes, a recess length-to-cathode diameter ratio of greater than 10 is found to give a negligible stirring artifact, a negligible measurement error, and a rapid response.