Competitive nephelometric immunoassay of theophylline in plasma. We have developed an accurate, simple, and rapid method for the determination of theophylline in plasma. The principle of the method is based on inhibition of immunoprecipitation by hapten. A nephelometer is used to measure the scattered light from the immunoprecipitate. The macromolecule, which possesses numerous theophylline moieties and forms immunoprecipitate with anti-theophylline antibodies, can be easily prepared and used as the reagent for the assay. Theophylline in the assay mixture competitively inhibits the immunoprecipitation of the macromolecule. Therefore, theophylline can be determined by the measurement of the decrease of the scattered light. The assay is rapid (incubation time within 15 min), requires as little as 10 microliter of plasma, and requires neither troublesome pretreatment nor separation of antibody-bound from free antigen. Estimations of theophylline levels in patient plasma specimens correlate well to those obtained by the high performance liquid chromatography (correlation coefficient 0.971).


A modified sandwich technique for the measurement of IgE. The paper radioimmunosorbent test (PRIST) has been described as the method of choice for determining low serum IgE levels; the radioimmunosorbent test (RIST) as the method of choice for determining normal and elevated serum IgE levels. By replacing the 125I-labelled anti-IgE antibody used in the paper radioimmunosorbent test by the 125I-labelled anti-IgE reagent used in radioallergosorbent test (RAST) and by changing the serum dilution and the incubation time, this modified sandwich technique (MST) became comparable to the RIST in the normal and elevated IgE-region and showed results similar to the PRIST in the very low IgE-region. The affinity of the 125I-labelled anti-IgE of the RAST proved to be about 2.6 times higher than the antibody used in the PRIST, which explains the improved results in the normal and the good results in the very low IgE-region. The lowest serum IgE level measurable by this method was as low as 0.05 I.U./ml, as determined in 20 cord sera. The mean IgE level in cord sera was 0.45 I.U./ml (range 0.05--2.63 I.U./ml). The results of this study suggest replacement of the antiserum used in PRIST by the one available for RAST.


A high-pressure liquid chromatography method for serum quinidine and (3S)-3-hydroxyquinidine. A bonded reversed phase, high pressure liquid chromatography (HPLC) method for serum quinidine and its major metabolite in serum, (3S)-3-hydroxyquinidine, is presented. The method employs toluene, rather than benzene for extraction of 100 microliter of serum, can utilize either absorbance or fluorescence detectors, and utilizes a column and equipment which is also suitable for theophylline analyses. Quinidine values in sera by the present method correlated well with fluorometric non-chromatographic methods using ethylene chloride (r = 0.932) or benzene-sulfuric acid (r = 0.950) for extraction of the quinidine. The comparison data suggest a therapeutic range for quinidine of 1.3--5.0 mg/liter when measured by HPLC. In over one year of routine use in a clinical chemistry laboratory, the method has proven to be rapid and precise with interassay coefficients of variation of 2.5--5.5%. No interferences with the HPLC method have yet been identified.


Identification of 4-N-2-acetamido-2-deoxy-beta-D-glucopyranosyl-L-asparagine in biological materials by gas chromatography-mass spectrometry. A specific and sensitive method for the identification of 4-N-2-acetamido-2-deoxy-beta-D-glucopyranosyl-L-asparagine (GlcNAc-Asn) in urine in aspartylglycosaminuria and in hydrolysates of glycoproteins is described. The method involves permethylation of GlcNAc-Asn followed by gas chromatographic-mass spectrometric analysis of the methylated derivative. It can be used to confirm the diagnosis of aspartylglycosaminuria and to assess the excretion of GlcNAc-Asn in urine during various phases of the disease. The presence of an N-acetylglucosaminyl-asparagine type of carbohydrate-peptide linkage in a glycoprotein can be determined by applying the method to the partial acid hydrolysate of a proteolytically digested glycoprotein.


Secretion of beta-N-acetylglucosaminidase isoenzymes by cultured cystic fibrosis fibroblasts. Secretion of the lysosomal enzyme beta-N-acetylglucosaminidase (EC 3.2.1.30) by normal and cystic fibrosis fibroblasts has been compared. In contrast to an earlier report, no differences were found in either the rate of secretion, or in the molecular forms of the enzyme secreted by normal fibroblast cultures and cultures initiated from patients with cystic fibrosis. The B isoenzyme of beta-N-acetylglucosaminidase from cystic fibrosis fibroblasts was converted to a more negatively charged form during preincubation for 3 h at pH 5.0 and 37 degrees C. The enzyme from normal fibroblasts was unaffected by this treatment.


A comprehensive laboratory computer system working round the clock. The special features of a laboratory computer system operated by laboratory staff around the clock are presented. The system provides registration of work, production of worksheets, on-line data acquisition and reporting results. The reasons for the special design features are discussed.


Polyamine conjugates and total polyamine concentrations in human amniotic fluid. A study of the quantitative profile of polyamines in amniotic fluid from the 13th through the 40th week of gestation was undertaken. These experimental observations indicate the absence of free putrescine, spermidine and spermine throughout gestation. Quantities of acid-liberated putrescine, spermidine and spermine are highest in late first and late third trimester. Putrescine is associated with peptide or peptides of molecular weight 1000 to 10 000 throughout gestation. Spermidine is found in amniotic fluid covalently conjugated to peptide or peptides with molecular weight 10 000 to 30 000. Spermine appears to exist in amniotic fluid, both in the higher molecular weight fraction (1000 to 10 000) and as acetylated derivatives. The existance of polyamine conjugates is compatible with an in vivo function in the regulation of embryonic growth and development. Abnormalities in polymines conjugated to peptides or their concentration may be useful in the diagnosis of fetal maldevelopment.


Chemical and biochemical studies in human fetuses affected with Niemann-Pick disease type A. Chemical and biochemical studies were performed on two unrelated fetuses affected with Niemann-Pick disease type A, following abortion at about the 19th week of gestation. Abortion was performed as a consequence of previous findings, in amniotic fluid cell cultures, that sphingomyelinase activity was completely absent. Phospholipid analyses of various organs of the fetuses revealed an excess of sphingomyelin in all viscera as compared to control nonaffected fetuses. Spleen and liver were the organs mostly affected. Interestingly enough considerable accumulation of sphingomyelin was found in the placenta. The brain was the only organ in which sphingomyelin storage could not be proved. In addition to sphingomyelin a slight accumulation of cholesterol was noticed. Deficiency of sphingomyelinase activity measured at pH 5.0 was the general characteristics of the affected tissues. It could be concluded that the accumulation of sphingomyelin in various organs throughout the body of fetuses affected with Niemann-Pick disease, was suggestive of the essential role of the enzyme sphingomyelinase and its biochemical maturation, even during the early stages of gestation.


Ammonium sulphate enhancement of the antigen-antibody reaction. Manual and automated nephelometric studies. The enhancing effect of ammonium sulphate on the antigen-antibody reaction is demonstrated. The effect is compared with that of polyethylene glycol by means of manual and automated nephelometry. The enhancement of both ammonium sulphate and polyethylene glycol is shown to be of the same magnitude in the region of large antibody excess. If however, the antigen-antibody ratio is shifted towards the region of equivalence, the enhancement of polyethylene glycol is more pronounced. The applicability of ammonium sulphate in a continuous flow analyzer for the specific quantitative nephelometric determination of serum proteins is discussed.


Measurement of amylase isoenzymes in human sera and urine using a DEAE-cellulose mini-column method. A DEAE-cellulose mini-column method has been developed which allows for the separation and quantitation in human sera and urine of pancreatic and salivary type isoamylases. Determination of the isoamylases was found to be of value in differentiation of hyperamylasemias due to disorders of the pancreas and parotid gland.


The analysis of alkaline phosphatase isoenzyme using 4-methylumbelliferyl phosphate as substrate on a cellulose acetate membrane. A new procedure is established for the analysis of alkaline phosphatase isoenzymes. The electrophoretic separation on cellulose acetate membrane coupled with the detection of alkaline phosphatase activity with 4-methyl-umbelliferyl phosphate as a substrate is described. The proposed method would be useful for the analysis of sample of micro-scale quantities and low activities.


Determination of quinidine and metabolites in urine by reverse-phase high-pressure liquid chromatography. A new reverse-phase high-pressure liquid chromatography assay allowing simultaneous but separate quantitation of urinary levels of quinidine and its major metabolites, 2'-quinidinone, 3-OH-quinidine and a newly detected N-oxide, is described. The compounds were separated on a alkyl phenyl column using 0.05 M phosphate buffer pH 4.5/acetonitrile/tetrahydrofuran (80 : 15 : 5, v/v) as mobile phase and were detected by UV at lambda = 230 nm. The assay procedure includes extraction of the compounds from urine samples into a mixture of dichloromethane/isopropanol (4 : 1, v/v), evaporation of the organic extracts to dryness and reconstitution of the residue in acetonitrile. The new assay was compared to a modification of the Cramer and Isaksson fluorescence assay which has recently been recommended for analysis of quinidine in urine. The consistently higher quinidine levels observed in the fluorescence assay could be accounted for by the quinidine levels and metabolite carry-over as determined by HPLC.


Serum creatine kinase isoenzyme MB activity: evaluation of a kit employing agarose-gel electrophoresis with overlay paper fluorescence scanning. A commercial kit for determining serum creatine kinase isoenzyme MB activity was evaluated. The kit employed agarose-gel electrophoresis followed by incubation of overlay paper on the agarose and then fluorescnece scanning of the paper. Within-day coefficients of variation ranged from 24.9% for a specimen with no elevation of MB activity of 6.6% for a specimen with moderately elevated MB activity. The kit appeared to demonstrate MB in all sera and showed higher than expected values in recovery studies. The kit performed in a relatively linear fashion from 50 to 500 I.U./l total creatine kinase activity. Hemolysis appeared to lower measured MB. For comparison with another method, specimens were also analyzed by microcolumn chromatography, which was found to incompletely separate isoenzymes. The kit produced lower values than microchromatography for specimens with low MB activities and higher values for specimens with elevated MB activities. Patients without corroborative evidence of myocardial injury showed a somewhat hyperbolic relationship between per cent MB and total creatine kinase activity, but MB activity was generally 4 I.U./l or less. Although the kit had serious laboratory shortcomings, it may be as clinically useful as other methodologies.


A method for studying plasma transport of vitamin D applicable to hypervitaminosis D. In man, vitamin D is normally transported on a specific binding globulin (DBP) and on lipoproteins. In addition, binding to albumin occurs in the presence of vitamin D excess. Agarose gel electrohoresis was used to study the binding of radioactive vitamin D to plasma proteins in lipoprotein-free plasma (d greater than 1.21 g/ml). This method completely separates DBP from albumin and thus enables the quantification of vitamin D bound to these proteins in various clinical and experimental conditions. The same method can be used to study the transport of other vitamin D metabolites.


Correction for the presence of cross-reactants in saturation assays: application to thyroxine cross-reactivity in 3,3',5'-(reverse)-triiodothyronine radioimmunoassay. Cross-reaction of anti-3,3',5'-triiodothyronine (rT3) antisera with thyroxine has proved problematical in the development of radioimmunoassays for rT3. Results of experimental work with two antisera with differing specificities are presented which illustrate certain aspects of cross-reacting assay systems. The mathematical theory of a single binding-site, two ligand assay is discussed and extended by use of a multiple binding-site computer model to a two binding-site, two ligand system. It is suggested that for the practical evaluation of the nature and extent of cross-reaction, a family of response curves for the hormone should be drawn, each curve representing the addition of a fixed mass of the cross-reactant to a set of standard incubation mixtures. Such curves will reveal whether the antiserum is (a) specific, implying that assay results require no correction, (b) behaves as a single binding site system, in which case measurement of the relative potency of the two ligands at the point on the response curve generated by the serum sample will enable an algebraic correction to be made, given that the T4 concentration is known or (c) behaves as a multiple binding-site system where correction necessitates the use of a nomogram.


Validity of "corrected" calcium values.

Validity of "corrected" calcium values. Individual values for the regression of plasma total calcium on albumin vary by more than can be accounted for by analytical imprecision alone; the range (-x +/- 2 S.D.) being 0.004--0.031 mmol/g. Individual regression coefficients (R) are constant with time. Furthermore, a large proportion of individual R values differ from a general population regression by more than can be accounted for by analytical error. Three adjusted calcium reference ranges were derived from the data. Two employed constant correction factors, the general population R value (0.013 mmol/g) and the mean of the individual R values (0.018 mmol/g). The reference range which utilised each individuals' own R value was smaller and therefore potential more useful than the ranges using constant factors.


Decomposition on freezing of reagents used in the ICSH-recommended method for the determination of total haemoglobin in blood; its nature, cause and prevention. The decomposition on freezing of reagents used for the determination of total haemoglobin in blood was reinvestigated. When these reagents containing hexacyanoferrate(III) (ferricyanide) and cyanide are frozen and then thawed, hexacyanoferrate(III) is reduced to hexacyanoferrate(II) (ferrocyanide), cyanide being oxidized to (CN)2. At higher concentrations of the reactants than those present in the ICSH-recommended reagents, this reaction proceeds also at room temperature. During the process of freezing the reaction proceeds at low overall concentration of the reactants because the reactants become highly concentrated at the moving phase boundary. There is no evidence that the reaction that takes place on freezing can be prevented by the addition of ethanol, methanol, ethylene glycol or glycerol. Addition of these compounds does not affect the suitability of the reagent for use in haemoglobinometry.


Thin-layer chromatography of non-volatile organic acids in clinical chemistry. The separation of biologically occurring non-volatile organic acids has been examined by thin-layer chromatography using a variety of solvent systems and thin-layer materials. The advantages of the two-dimensional method devised include the simultaneous demonstration of some keto acids as their oximes, sharp definition of the acidic spots, improved resolution over other published methods and rapid development. The method is very suitable for the biochemical diagnosis of known inborn errors of organic acid metabolism.


Ultrastructure of skin biopsy specimens in lysosomal storage diseases: common sources of error in diagnosis. Common sources of error in the diagnosis of lysosomal storage diseases by ultrastructural examination of skin specimens have been identified in a series of biopsies from 72 patients. Four principal factors have emerged as leading pitfalls and sources of error in diagnosis. First, the skin biopsy technique itself may lead to alterations of normal skin ultrastructure. Second, artifacts may be produced during fixation and preparation of tissue for electron microscopy. Third, cellular organelles and structures normally present in human skin may be mistakenly interpreted as pathological. Fourth, the use of cultured skin fibroblasts for ultrastructural identification of storage material is often accompanied by artifacts induced in tissue culture and is not recommended. Recognition of these common problems may aid interpretation of the fine structure of skin abnormalities. Furthermore, when skin biopsy specimens are used as the primary source of diagnostic material, correlation of both skin ultrastructure and assay for specific lysosomal enzymes in cultured dermal fibroblasts will facilitate diagnostic accuracy.


Electronic data processing in the Danish cytogenetic central register and EDP problems of registers in general. A brief introduction to the Danish Cytogenetic Central Register (DCCR) is given, and possibilities, principles and problems concerning the establishment and maintenance of a national cytogenetic register are presented. Various data carrier media for registers in general are discussed, of which the magnetic disc is considered most appropriate. General principles for programs capable of performing insertions, deletions and other modifications in the data base are outlined as well as the principles for the programs in the DCCR. The individual records should preferably be identified by aid of a central person registration number (CPR) rather than by name. The data should be stored and sorted by this identification in order to facilitate retrieval of a desired record. The structure of the records is discussed with regard to prevention of the occurrence of certain errors as well as the optimization of processing. Flexibility and economy of space are achieved by using programs able to handle records of unequal length, and problems occurring in connection with this are discussed. The question of how to protect sensitive data is dealt with, and two different methods used in the DCCR are outlined. Programs capable of analyzing karyotypes with the purpose of recognizing various cytogenetic syndromes have been developed for use in the DCCR. Various examples of computing times of typical program runs are presented.


Autosomal recessive onychotrichodysplasia, chronic neutropenia and mild mental retardation. Delineation of the syndrome. This report describes and discusses the occurrence in two sisters of a syndrome consisting of onychotrichodysplasia, chronic neutropenia and mild mental retardation. Family studies revealed parental consanguinity and another possibly affected sister, who died in childhood. Analysis of these cases together with one previously reported case permits the delineation of a distinct syndrome probably caused by an autosomal recessive mutation.


Monoamine oxidase and catechol-o-methyltransferase activity in cultured fibroblasts from patients with maple syrup urine disease, Lesch-Nyhan syndrome and healthy controls. Monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) activities have been measured in fibroblasts from nine healthy controls, three patients with maple syrup urine disease (MSUD) and six patients with Lesch-Nyhan syndrome. Both A and B types of MAO activity are found in these cell lines. In comparison to controls, the MAO activity is significantly reduced in cells from patients with Lesch-Nyhan syndrome. A different situation has been observed in the cell lines from MSUD patients: one showed a high MAO activity, another a significantly reduced activity, and the third was in the range of the normal controls. COMT activity is also present in these cells, but with a wide variation. No specific differences have been noted among the controls and the mutant cells.


Counseling for dominant traits: a correction for the ascertainment bias due to referral for analysis. Genetic heterogeneity complicates genetic counseling because the correct mode of inheritance must be determined independently for each pedigree. When autosomal and X-linked dominants inheritance mechanisms are known, as for example with retinitis pigmentosa, then only families where male-to-male transmission is observed may be readily counseled. The other pedigrees may be autosomal but lack male-to-male transmission due to chance segregation. Since only the pedigrees without male-to-male transmission are analyzed for their mode of inheritance, there is an ascertainment bias which must be corrected when evaluating the likelihood of the two inheritance patterns. A method to correct for this bias using conditional likelihoods is given, along with examples to demonstrate its use.


Partial trisomy 13 plus partial trisomy 4q due to unusual segregation of translocation chromosomes. The cytogenetic analysis of a 7-month-old retarded girl with clinical signs compatible with partial trisomy 13 revealed a translocation t(4;13)(q33;q14) and an additional derivative chromosome 13. This karyotype probably resulted from 3:1 segregation during meiosis of the patient's mother.


Melkersson-Rosenthal's syndrome in four generations. Melkersson-Rosenthal's syndrome is a rare condition, the hereditary nature of which is still in dispute. A family with seven affected members in four generations is described, which provides further evidence for the genetic basis of the syndrome.


C-band polymorphism in human chromosome no. 6. Chromosome analysis of G-banded cells from 92 individuals consecutively referred to the Cytogenetics Laboratory show that the paracentromeric band in the short arm (6p11), which stains negatively with G-banding and darkly with C-banding, shows a marked increase in size in about 9% of chromosome no. 6. The results of this study and those from a family in which two variants of chromosome no. 6 are segregating are compatible with a Mendelian pattern of inheritance.


Orientation of major histocompatibility (MHC) genes relative to the centromere of human chromosome 6. Linkage analysis of the data obtained from a three-generation Dutch family segregating for genetic variants of centromeric heterochromatic region in the band p11 on chromosome 6 (6ph), major histocompatibility (MHC) genes HLA-A, HLA-B and HLA-C, glyoxalase I (GLO) and phosphoglucomutase-3 (PGM3) showed that the genetic distance between the HLA gene cluster and 6ph is about 6 cM (at an estimated peak lod score of 3.466), that GLO is closer than HLA to the centromere and that PGM3 is probably not situated on the same chromosomal arm as HLA.


The hepatic transport of sodium [14C]taurocholate in foetal sheep. 1. The biliary excretion of a tracer pulse of sodium [14C]taurocholate injected into the portal vein was compared in adult and near-term foetal sheep. 2. Biliary excretion was virtually complete in both adult and foetus, although appreciably faster in the adult. 3. These results indicate that at birth the mechanisms for bile salt uptake and excretion in the sheep liver are well established.


The comparative bioavailability of carbamazepine in 100 mg and 200 mg tablets. 1. The bioavailabilities of carbamazepine in 100 mg and 200 mg tablets have been compared in a cross-over study of six subjects after two 600 mg doses of the drug, the different preparations being taken at 3 week intervals. 2. Areas under the plasma level curves, absorption rate constants and times to achieve peak plasma levels showed little difference between the two preparations. These findings suggest similar rates and extents of bioavailability of carbamazepine in the two preparations. 3. Calculated mean absorption and elimination parameters for carbamazepine were as follows: kabs = 0.1081 h-1, (s.d. = 0.0289); Tmax = 23.39 h, (s.d. = 8.66); k = 0.0191 h-1, (s.d. = 0.0033); VD = 0.989 1/kg, (s.d. = 0.159); and clearance = 0.0185 1/kg h, (s.d. = 0.0015).


Distribution of ethanol between saliva and blood in man. 1. Forty-eight male subjects drank ethanol (0.72 g/kg) as neat whisky on a fasting stomach within 20 min and the ethanol concentrations in saliva and capillary blood were determined at 30--60 min intervals for the next 7 h. 2. The concentration of ethanol in saliva was generally slightly higher than in capillary blood, as expected from their relative water contents. The mean saliva/blood ethanol ratio between 60 and 360 min from the start of drinking was 1.082 (s.e.m. = 0.0059), (n = 336). Moreover, the saliva/blood ethanol ratio was remarkably constant throughout the absorption, distribution and elimination phases of ethanol metabolism. 3. The saliva (y) and blood ethanol (x) concentrations (mmol/l) were highly correlated (r = 0.976, standard error = 0.011, P less than 0.001). The regression equation was y = 0.109 + 1.071x. The saliva and blood ethanol concentrations reached zero nearly simultaneously, there being no appreciable time lag in the saliva. 4. The results indicate that saliva is a practical medium for ethanol determinations and that blood ethanol can be reliably estimated from analysis of a saliva specimen. Saliva ethanol analysis could well serve as supporting evidence in clinical and medico-legal diagnosis of ethanol intoxication.


Suppression of tuberculin reactivity during natural rubella. Observations with 54 patients. Fifty-four patients with previously positive tuberculin reactions were followed for tuberculin sensitivity, between the incubation period of natural rubella and the 40th day after the onset of rash. In many instances, tuberculin sensitivity was partially or completely depressed beginning in the incubation period and extending for up to 4 weeks after rash onset. Two of 3 cases of subclinical rubella infection also showed this phenomenon. The highest incidence of negative reactions was 83% in the first 3 days after rash onset. A few subjects had a larger skin reaction to tuberculin than the baseline reading during the 2 to 5 weeks after rash onset.


Physiology of heat loss from an extremity: the tail of the rat. 1. Hooded, conscious, male, laboratory rats were subjected to an ambient dry bulb temperature cycle between 12 degrees C and 35 degrees C over a period of approximately 5.5 h. The same procedure was followed using rats in which the temperature surrounding the tail was held constant, and using dead rats. 2. Temperature of the ambient air, and the rectum, flank skin, tail base and tail tip were measured during each ambient temperature cycle. 3. In both living and dead rats, a hysteresis loop was demonstrated for the relationship between all body temperatures measured and ambient temperature. 4. The hysteresis loops for tail temperature differed between living and dead rats in such a way as to indicate that tail temperature began to increase, as a result of an active process, at approximately 30 degrees C, but this response ceased at a lower temperature. 5. The results on rats in which tail ambient temperature was held constant agreed with the preceeding observations. 6. Clear evidence of a counter-current heat exchange system in the vasculature of the rat's tail was not obtained. 7. It is concluded that the tail of the rat resembles an on/off controller in its mode of operation.


Anorectic and motor activity effects of some 1-benzylcycloalkylamines in the rat. 1. A series of 1-benzylcycloalkylamines with cycloalkyl rings of five, six or seven carbons and with various benzyl ring substituents (3-Cl, 4-Cl, 4-F, 3-CF3) was prepared and tested for anorectic and motor activity effects in rats. 2. Two potent, non-stimulant, anorectics were found: 1-(3-chlorobenzyl)-cycloheptylamine, and its N-methyl analogue. The activity of these compounds resembled that of chlorphentermine.


Enhancement by L-dopa of the renal action of aldosterone in the rat. 1. The administration of aldosterone to adrenalectomized rats produces an increase in K+ and decrease in Na+ excretion in the urine. The relationship of the post-aldosterone to the pre-aldosterone urinary sodium and potassium excretion is termed the renal response to aldosterone. 2. The administration of L-dopa enhances the renal response to aldosterone. This enhanced renal response does not appear to be due to the enhanced urinary creatinine and sodium excretion also seen with L-dopa. 3. The enhanced response to aldosterone seen in the L-dopa loaded rat is inhibited by spironolactone (an aldosterone antagonist), carbidopa (an inhibitor of the enzyme producing dopamine from L-dopa in the periphery), and haloperidol (a putative dopamine receptor blocker). The action of L-dopa in enhancing the renal response to aldosterone would thus appear to be mediated by dopamine within the kidney. 4. Modification of the renal response to aldosterone may be one role of the high levels of dopamine produced within the kidney.


Medication packaging: simple solutions to nonadherence problems? Medication nonadherence represents a well-documented, highly prevalent obstacle to successful long-term management of chronic illnesses. Recent research has focused on predictors of nonadherence, interventions for improving adherence, and measurement of medication adherence. Better medication packaging has received little attention as a partial solution to nonadherence complexities. Packaging has the obvious advantages of being continuous, inexpensive, and patient-oriented, while demanding little physician extra involvement. The ideal packaging solution should include six component functions: storage, education, cueing, monitoring, dispensing, and reinforcement. Practically, all six functions are highly interrelated necessitating tradeoffs. Combining several functions usually results in increased cost and decreased portability. A number of proposed devices for specific adherence-improving function are described, ranging from complex to simple. The need for more and better research to define and validate interventions is more critical, now that we recognize the consequences of nonadherence.


Effect of alpha-methyldopa on cardiac output in hypertension. Hemodynamic and blood volume changes, systolic time intervals, and baroreflex mechanisms were studied in 20 patients with hypertension after methyldopa (12 +/- 0.9 mg/kg/day). The drug was administered orally during 7 days' hospitalization on a normal sodium diet (110 mEq/day). There was a fall in blood pressure and in total peripheral resistance, without significant change in cardiac index, heart rate, and stroke index. There were increases in plasma and blood volume (p less than 0.05) but no change in cardiopulmonary blood volume or systolic time intervals. The unchanged heart rate was associated with an increased sensitivity ( less than 0.05) of the baroreflex mechanisms. The study supports the view that the unchanged cardiac output after methyldopa is related to important changes in control of cardiac output, including redistribution of blood volume and modifications in baroreflex mechanisms.


Guanfacine kinetics in patients with hypertension. Guanfacine kinetics were studied in 19 patients with hypertension after single and repeated oral doses. The single-dose study was performed in two homogeneous groups who received 2 mg (n = 9) and 4 mg (n = 10). The plasma concentrations were fitted in a two-compartment open model with first-order absorption. After a lag time of 0.8 hr, the absorption occurred rapidly (t 1/2 congruent to 0.53 hr). The fast and slow elimination phases occurred with t 1/2s of 2 and 19 hr. At therapeutic levels the percent of drug in red blood cells (55%) was independent of total drug concentration. Peak plasma levels had small interindividual variations. Comparison of kinetic parameters and AUC at the two doses studied demonstrated that their bioavailability was equal and the kinetics were linear. In a multiple-dosing study, performed in the same subjects, the plasma levels at steady state were in good agreement with the predicted values (p less than 0.001) and proportional to daily dosage. A single method based on four blood samples collected after 24, 28, 32, and 36 hr allows a reasonable prediction of the effective steady-state plasma levels during chronic dosing with guanfacine.


Effect of d- and dl-propranolol on glucose-stimulated insulin release. The effect of intravenous d- and dl-propranolol on serum insulin levels has been examined before and after the administration of glucose orally to 10 normal subjects. The increase in serum insulin 45 to 90 min after glucose ingestion was reduced during the infusion of either d- or dl-propranolol. The insulin suppression was not accompanied by any alteration in the glucose curves. The insulin/glucose ratios were reduced by both d- and dl-propranolol during the time of maximum glucose and insulin responses. Neither d- nor dl-propranolol induced any significant change in basal glucose or insulin levels before glucose administration. Since d-propranolol has no appreciable beta adrenoceptor blocking activity, it appears that the suppression of glucose-stimulated insulin release by propranolol may be due primarily to local anesthetic properties which are exerted equally by both isomers.


Smoking and warfarin disposition.

Smoking and warfarin disposition. Nine cigarette smokers ingested an average daily 0.032 mg/kg dose of sodium warfarin for 2 wk while continuing to smoke and for an additional 2 wk after having abstained from cigarette smoking for a month washout phase. Steady-state plasma levels of warfarin, clearances, t 1/2, apparent volumes of distribution, steady-state prothrombin times, and plasma thiocyanate levels were measured during both the smoking and nonsmoking phases. During the nonsmoking phase there was a 13% increase in average steady-state warfarin level and a 13% decrease in warfarin clearance rate. There also was a 23% increase in warfarin t 1/2 and an 11% increase in the apparent volume of distribution. Prothrombin time did not change. Thiocyanate levels were 3 to 4 times as high during the smoking than the nonsmoking phase. It appears that cigarette smoking does affect warfarin clearance, t 1/2, and apparent volume of distribution, though the net effect on warfarin's pharmacodynamic activity is negligible, at least at doses which are ineffective therapeutically.


Binding of imipramine to plasma proteins: effect of hyperlipoproteinemia. The binding of imipramine to plasma proteins was studied by equilibrium gel filtration. Imipramine was highly bound to lipoproteins as well as to other plasma proteins. The binding to the lipoproteins was higher in hyperlipoproteinemic patients than in normal subjects and correlated well with both plasma cholesterol and triglyceride levels. The overall percent binding of imipramine was also higher in hyperlipoproteinemic patients than in normal subjects. It is concluded that the varying degree of binding of imipramine to plasma proteins as a result of varying lipoprotein concentrations, as well as the special nature of the binding to lipoproteins, may be of kinetic and possibly clinical significance in hyperlipoproteinemic individuals.


Urinary excretion of D-glucaric acid by severely burned patients. The 24-hr excretion of urinary D-glucaric acid (UGA) has been measured in 5 seriously burned adults and compared with 6 healthy adults. In the burn patients mean UGA was 14.4 +/- 5.4 (+/- SD) mumoles/day and 28.7 +/- 6.5 mumoles/day in controls (p less than 0.002). In a 6-year-old female, UGA was also found to be very low. In a seventh burn patient, an adult male taking 20 mg of fluphenazine until his injury, his UGA was still in the normal range (29 mumoles/day) on the day of admission but descended to 21 mumoles/day at 2 days, to 16 at 4 days, and to 13 at 6 days. Treatment with fluphenazine was then reinstituted and on the tenth day UGA was 28 mumoles/day, indicating that after thermal injury UGA can respond to drugs. Although the inference has not been proved that decreased UGA corresponds to a decreased activity of drug metabolism, there is evidence of a strong correlation between increased UGA and increased drug metabolism. A decrease of UGA in disorders that generally lower metabolic activity supports a possible correlation in severe burns. If drug metabolism activity is lowered in the seriously burned patient, drug overdose may well result from the usual clinical doses.


Kinetics of cis-dichlorodiammineplatinum. The cancer chemotherapeutic cis-dichlorodiammineplatinum (cis-DDP) was administered to 8 patients (1-hr intravenous infusion) at a dose of 70 mg/m2. Plasma and urine concentrations of platinum were determined by flameless atomic absorption spectrometry. Measured plasma platinum concentrations revealed a biphasic clearance of platinum with half-life values of 23 min and 67 hr. Platinum values obtained 3 wk after the infusion indicated that a third excretory phase might be present. Urinary measurements showed 17 +/- 2.7% of the administered dose excreted in the first 4 hr and 23 +/- 3.9% excreted in the first 24 hr. Renal excretion appears to be predominantly by glomerular filtration. Non-protein-bound plasma platinum values were calculated and the non-protein-bound platinum was found to be rapidly and biphasically cleared from the plasma with half-life values of 8 to 10 min and 40 to 45 min.


Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.


The biologic half-life of heparin.

The biologic half-life of heparin. Half-lives (t1/2s) varying from 23 min to 2.48 hr have been reported for heparin. It is shown that much of the discrepancy between authors can be attributed to methods used to analyze data. It is suggested that three terms should be carefully used, the t1/2 of bioassayed heparin concentration, the t1/2 of the extension of the clotting time, and the t 1/2 of the clotting time to differentiate among the various methods of analyzing the raw data.


SR-52 program for the solution of two first order differential equations. This paper presents a program written for the Texas Instruments SR-52 programmable calculator to numerically solve a pair of first order ordinary differential equations. The program uses a fourth order Runga-Kutta method and a typical sample run is presented.


A computer program for life table regression analysis with time dependent covariates. This paper presents a computer program for analyzing time-dependent covariables in survival studies by the life table regression model described by Holford [3]. Basically, life table regression incorporates the elements of regression and the life table into a single model. Regression parameters are estimated by the method of maximum likelihood using the Newton-Raphson iterative procedure. The program provides two methods for testing hypotheses concerning regression coefficients, namely the standard normal deviate test and a Wald statistic based on the first and second derivatives of the log likelihood. Residual plots are provided to assess the fit of the model to the data.


A program package for simulation and parameter estimation in pharmacokinetic systems. A set of programs is presented which has been developed for parameter estimation and simulation of models arising from pharmacokinetic applications. The programs can accommodate linear and nonlinear models with multiple inputs and multiple outputs. When the model is defined by differential equations, non-uniform repetitive dosage regimens can be handled. The model may also be entered in integrated form when single dose studies or uniform multiple dose studies are being considered. The programs employ a variable-step, variable-order integration routine to solve the model differential equations, and the Nelder-Mead simplex procedure to determine the parameter values which minimize a weighted least squares criterion. The programs have been written for an interactive time-sharing environment with the experimental data and model equations stored in files for future use.


Evaluation of Cartesian coordinates and radiation doses in points determined with stereo x-ray techniques. A Fortran computer program STEV (stereo evaluation) is described. The principles of the stereo techniques together with the calculation method of the stereo coordinates are given briefly. The determination of the rectangular coordinates from mean stereo coordinates is described. Radiation doses in anatomical points, during intracavitary and interstitial radiation therapy, are calculated, taking into account a statistical evaluation of the measurement errors.


A computer model for hydrodynamic shearing of DNA. A computer simulation model for the hydrodynamic shearing of DNA is presented. In this model the event space consists of a number of positions at which the DNA strand may break. The results of the model compared with the real world result are reported in this paper. Future endeavors to generalize the model would add significantly to the model's value.


Computer design synthesis of a below knee-Syme prosthesis. A detailed design synthesis analysis of the BK Syme prosthesis is provided, to determine the socket's cutout orientation size and shape, cutout fillet shape, socket wall thickness distribution and the reinforced fiber distribution in the socket wall, for a minimally stressed structurally safe lightweight prosthesis. For analysis purpose, the most adverse socket loading is obtained at the push-off stage of gait; this loading is idealised as an axial in-plane loading on the bottom edge of the circular cylindrical socket shell whose top edge is considered fixed. Finite element stress analysis of the socket shell (with uniform and graded wall thickness) are performed for various orientations of the cutout and for various types of corner fillets. A lateral cutout with a streamline fillet is recommended. The wall material (i.e., thickness) distribution is determined so as to minimise the stresses, while ensuring that the wall material's stress limits are not exceeded. For such a maximally-stressed lightweight socket shell, the panels in the neighbourhood of the cutout are checked to ensure that they do not buckle under their acquired stresses. A fiber-reinforced laminated composite socket shell is also analysed, to recommend optimum variables in orientations and densities of reinforcing fibers.


Nephrotoxic antibiotics in patients with renal failures: guidelines for debilitated patients. Fifty-seven cancer patients, who had had an 8--15% loss of body weight in the previous 6 months, were studied to establish the reliabity in wasted individuals of presently available nomograms correlating serum creatinine with creatinine clearance. Other predictors of renal function, such as osmolar clearance, free water clearance, and excreted fraction of filtered sodium, were also considered. In all patients, and especially in those with a measured creatinine clearance 10--50 ml/min, the use of standard nomograms based on serum creatinine resulted in gross overestimation of renal function. None of the other tests of renal function proved reliable for clinical purposes. It is concluded that in wasted patients administration of nephrotoxic drugs that are renally excreted should be adjusted to measured creatine clearance. Using other common predictors of renal function may result in overdosage.


Hydromediastinum after aberrant central venous catheter placement. After central venous catheter placement via the right subclavian route, a hydromediastinum was produced. Aberrant placement of the catheter was undiscovered for 13-1/2 hours despite clinical and radiographic signs. Careful interview of the patient and analysis of postcatheterization chest radiographs are imperative in order to avoid catastrophic consequences of aberrant catheter placement.


Multipurpose central venous access using the cordis sheath introducer system. A nonpyrogenic polyethylene sheath system with a hemostatic valve assembly and side port extension developed by the Cordis Corporation is now routinely used for central venous access in critically ill patients. It is inserted percutaneously via the subclavian or internal jugular vein and allows rapid and efficient catheterization for hemodynamic monitoring, infusion of multiple solutions simultaneously, and uniflow hemodialysis. This system represents a significant advance in catheter technology.


Multiple determination of cardiac output using a two-bottle technique. A technique is described to perform multiple determinations of cardiac output; two 150 ml bottles of 5% dextrose in water, stored in identical conditions, are immersed in an ice slush, contained in a styrofoam cooler. Comparison of cardiac output determinations obtained with this technique and with multiple syringes indicates very close duplication of results. The technique is very inexpensive and allows one to follow patients for up to four hours with as many as 30 consecutive determinations of cardiac output.


Do homologous chromosomes differ? A preliminary investigation based on DNA measurements. This paper is concerned with the problem of deciding whether measurements from homologous chromosomes differ. First, a general mathematical model is proposed for studying the distribution of chromosome measurements. Next, log-likelihood ratios are used to test for correlation between homolog pairs and for differences between homolog means and variances. The tests are applied to measurments on 1946 pairs of chromosomes from 10 normal individuals. Test results are interpreted taking into account the large number (2025 total tests) required by the study. Our results demonstrate that, at the current level of resolution, most homologs do not show differences in DNA content. However, there is some evidence that several homologs pairs differ by small amounts of DNA (less than 0.2% of the autosomal genome). Power studies indicate that sample sizes of 20 to 30 measurements are required to detect differences of this size.


Ellobius lutescens Th. (Rhodentia, Microtinae): Q-, R-, and replication banding patterns. Chromosome 1 polymorphism in the male and presumptive heterogamety in the female. Five specimens of Ellobius lutescens, four males and one female, were studied by several banding methods. Structural polymorphism occurred in the longest chromosome pair of the karyotype of two males: a pericentric inversion in one animal and a paracentric inversion in the other. In the female studied, one chromosome 1 differs from those of the males by a marked elongation of a proximal euchromatic band in the long arm. Thus, the female seems to represent the heterogametic sex. Chromosome 9 showed the same banding pattern in both sexes. The possible meaning of this chromosome constitution for the sex-determining mechanism of E. lutescens is discussed.


Gametic products transmitted by chickens heterozygous for chromosomal rearrangements. Chromosomal analysis was made from 3744 chick embryos derived from reciprocal matings between parents, one of which was heterozygous for a pericentric inversion, a centric fission, or one of three translocations. The objectives were to determine the types and frequencies of genetically balanced and unbalanced gametes transmitted to early embryos by rearrangement heterozygotes and to ascertain if some gametic types were preferentially produced or utilized. The array of embryos obtained from the heterozygous sires did not deviate significantly from the expected, except in the case of the centric fission group. Among embryos derived from heterozygous dams, however, significant deviations from the expected 1:1 ratio for complementary gametic products, resulting from specific balanced and unbalanced segregation types, were found consistently in all three translocation groups and the centric fission group (P less than 0.025). It was concluded that differences exist between heterozygous sires and dams in the frequencies at which some gametic types are produced. The deviations from the expected ratios among progeny of heterozygous dams may be the result of anaphase lagging during the meiotic division of oogenesis.


Nonhomologous associations of C-heterochromatin at human male meitoic prophase. In human male meiotic prophase, nonhomologous pairings and connections between C-heterochromatic regions were demonstrated by C-banding and G-11 staining. Approximately 40% of the pachytene stages exhibited bivalent associations at regions of C-heterochromatin. Nonhomologous associations were seen between all possible morphological types of bivalents. Evidence is submitted suggesting that nonhomologous associations between regions of C-heterochromatin are a fairly common event in many organisms, including man, and the possible roles of this phenomenon in meiosis are discussed.


Karyological confirmation of conspicuous ZW sex chromosomes in two species of Pacific anguilloid fishes (Anguilliformes: Teleostomi). Leukocyte and kidney cell cultures were used to examine the sex chromosomes of Japanese freshwater eels (Anguilla japonica) and conger eels (Astroconger myriaster). The conspicuous presence of ZW sex chromosomes, due to a drastic reduction in size of the W, was confirmed in both species, where the Z was the largest metacentric and the W was the smallest metacentric in a diploid karyotype of 38 chromosomes in both species. These species are the first examples of the ZW type of heteromorphism in eels.


Ataxia telangiectasia: chromosomal stability in continuous lymphoblastoid cell lines. Chromosomal breakage in peripheral lymphocytes, cultured fibroblasts and long-term lymphoblastoid cell lines was investigated in five hitherto undescribed patients with ataxia telangiectasia (AT). Increased chromosomal instability was observed in lymphocytes and fibroblasts, and clones possessing a Dq+ marker were observed. Breakage rates were significantly higher in the fibroblasts than in the lymphocytes of AT patients or in similar tissues from patients with Bloom syndrome or Fanconi anemia. However, chromosome breakage in lymphoblastoid lines established from these five AT patients and six others did not differ from controls. These observations suggests that selection pressures, in vivo or in vitro, or both, act differently on the expression of chromosomal instability in these various cell types.


Analyses of diplotene chiasma frequencies in mouse oocytes and spermatocytes in relation to ageing and sexual dimorphism. Diplotene chiasma frequencies from "early" (day 16) fetal oocytes are significantly greater than the average from "late" (day 18) oocytes. A decrease in chiasma frequencies from both ages was found at diakinesis/MI in oocytes of young or old adults females, indicating a loss of chiasmata and/or terminalization. A greater number of type I univalents was found in "late" oocytes than "early" oocytes entering diplotene. No difference were found in chiasma frequencies of male diplotene spermatocytes studied at 23 days, 2 months, or 24 months of age. A greater chiasma frequency was generally found in the female than the male at all ages studied.


A selective medium (GAMA) for the isolation of somatic cell hybrids from HPRT- and APRT- mutant cells. A medium is described which can be used for the selection of somatic cell hybrids between HPRT- and APRT- mutant cells. This medium, called GAMA, contains as its relevant constituents the following: the purines guanine and adenine and the purine biosynthetic pathway inhibitors mycophenolic adic, which blocks conversion of adenine ribonucleotides to guanine ribonucleotides, and azaserine, which blocks de novo purine synthesis.


Chromosomal imbalance in ovulated oocytes from Syrian hamsters (Mesocricetus auratus) and Chinese hamsters (Cricetulus griseus). Chromosomes were studied in ovulated oocytes from Syrian hamsters (Mesocricetus auratus) and Chinese hamster (Cricetulus griseus) to assess the degree of chromosomal imbalance after first meiotic division of oogenesis. Only one hyperploid oocyte among 307 studied was detected in the former, and none in oocytes from the latter species. Structural chromosome alterations, single chromatids due to presegregation, and diploid chromosome sets resulting from meiotic blockage were not observed. The hormones which were used to stimulate ovulation apparently did not enhance first meiotic cleavage errors in these hamster oocytes. The low figures of chromosomal anomalies in hamster oocytes are compared to those from a large sample of mouse oocytes obtained from three different strains and prepared under identical conditions. The relevance of these findings to the obviously higher impact of chromosomal aneuploidy in man is discussed.


Evidence for an association between univalent Y chromosomes and spermatoycte loss in XYY mice and men. It has been observed previously that there is an association between sex chromosome pairing failure during meiosis and spermatocyte death. An hypothesis is advanced suggesting a similar association between a disruption of sex chromosome pairing (specifically, a failure of Y chromosome pairing) and spermatocyte loss in XYY mice and men.


Distribution of spontaneous chromosome breaks in man. The distribution of break points in human chromosomes was analyzed in 15,754 metaphases from 1084 patients. A total of 1099 breaks were specifically localized to a chromosome band or region depicted in the PARIS CONFERENCE (1971) report. The sites of the breaks were very different from the expected random distribution and showed distinct clustering of breaks in some regions. These observations underline the heterogeneity of chromosomal material and furnish comparative data for the study of cytotoxic agents and constitutional chromosomal fragility.


[The small-intestine-stasis syndrome following side-to-side anastomosis]. This review describes the small intestine stasis syndrome after side-to-side anastomosis. Symptoms of intermittent abdominal pains with steatorrhea and loss of weight are caused by disturbance of passage with a rise in bacterial concentrations. Of 27 patients observed 15 had no disorders, while 12 had gastrointestinal symptoms which had been misinterpreted and given conservative treatment for a long time (3--22 years). Treatment is either by antibiotics or by excision of the lateral anastomosis followed by end-to-end anastomosis of the normal intestine. Special attention must be paid to the consequences of side-to-side anastomosis in childhood.


[Surgery of endotheracic struma].

[Surgery of endotheracic struma]. Most cases of endothoracic struma should be considered as systemic illnesses that require thoracic surgery. Concerning cervicoendothoracic borderline cases, the same point of view is advocated, e.g., struma endothoracica falsa and vera alliata. With reference to 38 cases of true and 34 cases of false endothoracic struma, the authors summarize and discuss: 1) their experiences in diagnosis, 2) various routes of access, 3) special thoracic closure techniques, and 4) specific surgical methods on the tumor itself.


[What is certain in the pathogenesis and incidence of primary carcinoma involving the operated stomach?]. It has been postulated that resection therapy for peptic ulcer disease will result in an increased frequency of gastric stump cancer depending on the ulcer type and type of operation (Billroth I, Billroth II, gastroenterostomy). However, an extensive review of the literature shows that after Billroth II resection for gastric ulcer without enteroanastomosis the frequency of primary gastric stump cancer is not greater than in the case of medically treated benign gastric ulcers. The frequency of cancer of the gastric stump seems lower after resection for duodenal ulcer disease. It is possible that the combination of the Billroth II resection with an enteroanastomosis decreases the frequency of cancer of the gastric remnant. Clinical and experimental studies do not allow final statements on cancer frequency after Billroth I resection or simple gastroenterostomy.


[Computed axial tomography (cat) in the diagnosis of diseases of the heart and aorta (author's transl)]. Computed axial tomography (CAT) was used in 70 patients with diagnostic problems centering on the heart (47 patients) or the aorta (23). The method proved suitable for the diagnosis, differential diagnosis and serial control of pericardial effusions and also well demonstrated intracardiac tumours. Aortic aneurysms are also easily demonstrated and their extent can be exactly defined. But aortic wall dissection and stenosis of arteries arising from the aorta are not visualized and therefore require angiography.


[Comparison of bicycle ergometry and step-ladder exercise (author's transl)]. Repeat exercises (three hours apart) on a bicycle ergometer and a vertical step-ladder were performed in a randomised series on 79 subjects: 13 doctors, 44 patients and 22 sportsmen. Duration of exercise was on average 250% longer in the three groups on the step-ladder than the bicycle. Correspondingly, exercise-pulse sums, recovery-pulse sums and exercise indices were two-and-a-half to three times higher than on bicycle ergometry. As a sign of comparability of the exercise by the two methods there was, on average, no significant difference with regard to the final heart rate, although duration of exercise was longer on the step-ladder. 67% of subjects discontinued the exercise because of peripheral muscle fatigue on the bicycle ergometer, compared with only 8% on the step-ladder. During bicycle ergometry lactate concentration rose by 6.7 mmol/l compared with only 0.78 mmol/l during step-ladder exercise. These results indicate that the value of bicycle ergometry exercise is limited by muscle fatigue in the legs: step-ladder exercise can be extended much longer. The practical significance is that patients with coronary heart disease especially have symptoms and/or ECG changes of ischaemia only at higher levels of physical exercise.


[Sensitivity of the haemoccult test in colorectal tumours (author's transl)]. 157 patients with histologically investigated colorectal tumours from 5 hospitals of the University of Munich were tested with the Haemoccult test. In 30 (35.7%) of 84 patients with malignancy of the colon and in 31 (58.5%) of 53 patients with adenomas or polyps the correctly performed test was negative. The test result showed no dependency on age or sex of the patient, nor on size, stage or localisation of the tumour. A problem-orientated history lowered the rate of false negative tests to 2.4%. The high rate of false negative results was not attributable to organisational or technical errors.


[Creatine kinase: reference values and clinical aspects of the revised standard method (author's transl)]. Reference values for the revised standard method for determining N-acetylcysteine (NAC) activated creatine kinase (CK) activity in serum are presented, based on samples from 432 out-patients and 423 in-patients of either sex. CK activity was not age-related. The suggested range of normal values for serum CK activity, measured by the revised standard method at + 25 degree C, is 10--70U/l for females and 10--80U/l for males. Where an elevation of serum CK activity is of uncertain cause, the CK/GOT ratio had been recommended, additional to the CK-MB isoenzyme, for distinguishing between damage to heart and skeletal muscle. The significance of this ratio was checked with the revised standard CK method and the optimized GOT determination. The point of separation between myocardial and skeletal muscle damage is 10 by this methods. In order to use this ratio, total CK activity must be over 150 U/l and liver disease or secondary liver involvement must have been excluded. The CK/GOT ratio gains in importance through findings which limit the specificity of CK-MB as a purely myocardial (infarct)-specific isoenzyme.


[Infections caused by Yersinia enterocolitica: bacteriological, serological, epidemiological and immunological findings in 51 cases (author's transl)]. Within two years 51 infections caused by Yersinia enterocolitica were diagnosed by bacteriological and (or) serological tests (Yersinia enterocolitica Serovar 03 in 48, Serovar 09 in two and Serovar 04 in one). The latter was isolated from the discharge of a badly healing superinfected wound. In the other 50 there was feverish enteritis, in 12 with arthritic complaints. Of the latter 12 nine had the antigen HLA-B27. This investigation demonstrated a slight increase in cases during the cold months. Men were more frequently affected than women and 38 were older than 16 years. In-vitro sensitivity of the isolated Yersinia strains against various chemotherapeutic agents was also tested.


[Hyperparathyroidism and metabolic acidosis (author's transl)]. Severe secondary hyperparathyroidism and marked metabolic acidosis occurred in five patients in advanced renal failure due to chronic interstitial nephritis. In all instances there was an immediate and lasting rise in plasma standard bicarbonate concentration after subtotal parathyroidectomy. These observations suggest that the metabolic acidosis in some patients with advanced renal failure is, at least in part, due to hyperparathyroidism and, therefore, responsive to its appropriate treatment.


[Effective out-patient treatment of gastric ulcer with proglumide: preliminary results (author's transl)]. In a double-blind trial 16 persons with gastric ulcer and 35 with duodenal ulcer were treated as out-patients with 1200 mg proglumide daily or 1320 mg magnesium tricilicate daily (as an "active placebo") for four weeks. The ulcers were assessed by endoscopy before and after treatment. The gastric ulcers disappeared in 75% of patients receiving proglumide (six of eight subjects) but in only 25% of those on the placebo (two of eight). There was no significant effect of proglumide on duodenal ulcers (17 in the proglumide and 18 in the placebo groups). Proglumide failed to affect either basal or maximally stimulated acid secretion, nor was there any change in the serum gastrin level. There were no side effects during proglumide administration. This underlines its therapeutic value in the treatment of gastric ulcer, in comparison with cimetidine or carbenoxolone.


[Necrosis of the pancreas (author's transl)]. In a retrospective study, based on 35 392 necropsies, 270 cases of severe acute pancreatitis (stage II or III) were compared with respect to diagnosis, survival time and cause of death. The proportion of correct clinical diagnoses made during life was 29.5% in cases of acute pancreatitis stage II, and 64.1% in severe acute pancreatitis stage III. The average survival time was 13 days. The most common cause of death was shock and intoxication. Most of the deaths in the first phase of the disease were due to pancreatogenic shock and enzyme intoxication. The considerable absorption of toxins from the necrotic tissue becomes a threat to life only after the first week of illness. There was a significant  reduction in death rate on the sixth and seventh day of illness: the period from the fifth to seventh day of illness is, therefore, suggested as a most favourable time for any resection of necrotic pancreas tissue.


[Adrenal and extra-adrenal phaeochromocytoma: diagnostic features and localisation by determining plasma catecholamines (author's transl)]. Urinary catecholamines and urinary excretion of vanillylmandelic acid confirmed the diagnosis of phaeochromocytoma in ten patients. In two of seven a modified glucagon test significantly aided confirmation of the diagnosis. In all patients the tumour was localised both by catecholamine determination in blood from the vein draining into the inferior vena cava (IVC) and by adrenal phlebography. Site of the adrenal tumour was definitively determined by the high catecholamine level in the adrenal veins and by phlebography. Three extra-adrenal tumours, a thoracic and two abdominal ones, were localised by high catecholamine levels in blood from other veins draining into the IVC. Vanillylmandelic acid determinaion was unreliable in the diagnosis of small phaeochromocytomas.


[Uric-acid reduction with high allopurinol dosages (author's transl)]. At the high dosage of 600 mg daily, the uric-acid reducing effect of allopurinol depends on the initial level of uric-acid concentration in the same manner as at the usual dosage of 300 mg daily, but is more marked at the entire hyperuricaemic concentration range of 65--71 mumol/l (11--12 mg/l). After eight days at the same dosage of 600 mg daily allopurinol there is a highly significant correlation between the two variables, corresponding to the equation of uric acid effect of allopurinol = 0.893 x serum uric-acid concentration--29.27. At an uric-acid concentration of 476 mumol/l (80 mg/l); at a uric-acid level of about 595 mumol/l (100 mg/l) the average concentration reduction will be around 357 mumol/l (60 mg/l).


Cell shape as an indicator of volume reabsorption in proximal nephron. If the complex shape of cells and intercellular channels in the renal proximal tubule is determined in part by the forces of large transepithelial water flow, the cell and channel shapes might serve as indicators of the type and magnitude of the forces required for water flow and the routes of that flow. We review here the known morphologic and functional data from the convoluted and straight portions of the rabbit proximal tubule and test the hypothesis of structure-function correlation in that tissue by means of a mass balance equation. If the lateral cell walls are sufficiently deformable to communicate small transmembrane differences in hydrostatic pressure, the resulting phenomenological model suggests an important new role for peritubular serum proteins and can be used to compute reasonable values for cell wall hydraulic conductivity, intercellular protein diffusion constant, and a channel fluid osmolality not more than 1% greater than that of luminal fluid. We conclude that quantitative morphologic studies may serve as a powerful means for evaluating and understanding transport phenomenons in the nephron.


Dimensions of cells and lateral intercellular spaces in living Necturus gallbladder. The size and shape of the cells and lateral intercellular spaces were measured in living Necturus gallbladder epithelium. Interspace volume was determined as a function of the transepithelial hydrostatic pressure difference. The compliance of the lateral membranes of the gallbladder cells was calculated from the interspace pressure-volume curves in both the presence and absence of fluid transport. Cell and interspace volume were studied when the NaCl in the mucosal bath was substituted by equiosmolar quantities of sucrose. The cells decreased in volume after the removal of mucosal NaCl and increased to control volume when the mucosal perfusate was 100 NaCl Ringer. The interspaces collapsed when fluid transport was inhibited by the removal of mucosal NaCl and reopened when NaCl was reintroduced to the mucosal bath. The rate of change of cell volume was used to calculate the active transport rate and the flux of NaCl across the apical membrane. The magnitude of the cell volume change during NaCl replacement indicated that all intracellular NaCl was readily accessible to be transported out of the cell.


Quantitative electron probe X-ray microanalysis of electrolyte elements within epithelial tissue compartments. The electron probe X-ray microanalysis of 1-micron thick frozen-hydrated sections provides a method to measure local concentrations of electrolyte elements (and H2O) in and around the cells in situ with an analytical spatial resolution of better than 0.2 micron and a sensitivity limit better than 10 mM with a standard error of less than 10%. Our microprobe studies on several epithelia transporting isotonic fluids have provided strong evidence that the electrolyte concentration in the interspaces suspected to be the sites of solute-solvent coupling may, on average, be as much as 35% more than in the bathing fluid. There also appear to be distinct concentration gradients in interspaces, the profiles of which differ according to the tissue geometry but particularly according to the location of the leaky cell junctions, suggesting that the osmotic equilibration of the transported fluid may require substantial mass flow through the junctions. In addition, there is evidence a) that the major electrolytes in the cytoplasm of the epithelial cells are not uniformly distributed but may have distinct axial and radial concentration gradients that depend on active solute transport (e.g., that abolished by ouabain); b) that in some epithelia (e.g., rabbit ileum) there is a peripheral cytoplasmic zone that may support fast convective flow for transcellular fluxes; c) that the extracellular structures like the glycocalyx and basement membrane preferentially sequester potassium (and calcium) and could have a non-zero reflection coefficient; and d) that in normal cells, nuclei have ionic composition similar to that of the circumnuclear cytoplasm.


External solution driving forces for isotonic fluid absorption in proximal tubules. We have explored evidence that suggests that lateral intercellular spaces is the mammalian proximal nephron do not serve as a hypertonic "central compartment" driving volume absorption. A primary consideration is the very low transepithelial resistance of this tissue as demonstrated by several laboratories. By making the reasonable assumption that passive ion permeation occurs via a paracellular route, we have concluded that the diffusion resistance of the spaces in insufficient to allow the development of a significant compositional difference between the spaces and the peritubular medium. This conclusion led us to look for potential osmotic gradients existing between the luminal and peritubular solutions. From the perfusion rate dependence of osmotic volume flow in the absence of active transport in isolated convoluted and straight proximal tubules, we calculated that both segments have very high hydraulic conductances, on the order of 3,000-5,000 micron/sec. Consequently, slight differences in the effective osmolality of the external solutions are sufficient to explain net volume absorption both in vivo and in vitro. We have provided evidence for two such driving forces. First, the development of asymmetrical anion concentration differences along the length of the proximal nephron due to preferential reabsorption of HCO-3 provides a driving force if the reflection coefficient for HCO-3 exceeds that for Cl-. Second, slight luminal hypotonicity may develop as a consequence of active solute absorption. Although both mechanisms probably occur simultaneously in vivo, we consider the former to be quantitatively the most important.


Effect of age on pulmonary structure and function of immature and adult animals and man. Literature on the comparative effects of aging on lungs of immature and adult animals and man was reviewed and additional data for dogs were presented. The dog is the only animal for which comprehensive data have been reported. Human lungs grow primarily by addition of alveoli to 8 yr, then by increasing the size of respiratory airspaces. Alveolar sizes of most mammals are similar at birth but vary in proportion to body size in adults. Lung volumes of dogs and man increase in proportion to body growth until young adulthood, and then total lung volume remains constant. Maximal functional efficiencies are reached at approximately 20 yr in man and 1 yr in dogs. Lungs of dogs and man also undergo similar progressive age-related changes during adulthood. Alveoli enlarge and coalesce, resulting in losses of elasticity and surface area and an increase in the fixed lung volume at the expense of mobile volume. Gas mixing and alveolar--capillary gas exchange become less efficient. Static pressure--volume relationships of all adult mammals are shifted toward reduced elastic recoil with age. In contrast to findings in man and dogs, both excised and intact lung volumes of rodents continue to increase after young adulthood. The gas exchange capacity of rats increases in parallel to the volume increase. These species differences demonstrate the need for careful selection of animal models for the study of aging of the human lung.


Genetic relation of life span to metabolic rate for inbred mouse strains and their hybrids. Average life spans were estimated for the male progeny from 21 of the 25 possible matings of 5 inbred mouse strains. Oxygen consumption was measured in an open system over a 48-hour interval. Resting metabolism, Mre, and average metabolism, Mav, were determined at 6-8 months of age, and at 24-34 months. Body weight, W, was determined at the time metabolism was measured. Life span, L, is negatively correlated with Mre and Mav, and positively correlated with W at both ages of measurement. This is in accord with the metabolic wear factor that had previously been established among 85 different species of mammals. A new metabolism variable, the energy partition coefficient, defined as the ratio of average to resting metabolic rate, Mav/Mre, has a parabolic relation to body weight, i.e., is maximal at an intermediate body size. The squared body weight deviation in turn has a negative correlation with life span. The correlation of L with Mav/Mre is positive, as expected, but not significant. These data suggest the existence of a longevity factor dependent on the partition of energy between the phasic metabolism of activity and the continuous maintenance metabolism.


Bronchial mucosal cells.

Bronchial mucosal cells. The eight epithelial cell types and their features are described--the basal, Kultschitzsky, intermediate, brush, ciliated, serous, Clara, and mucous cell. In the irritated airway the separate secretory cell types are able to change, through transitional cell types, from the Clara and the serous to the mucous cell. Each type of epithelial cell may be associated with intraepithelial nerves, including sensory and motor, some adrenergic, some cholinergic. The epithelial surface is covered with a periciliary fluid layer in which the cilia beat. Turnover time of the epithelial cell population is faster in the young animal than old, in male than female, and in extrapulmonary than intrapulmonary airways. The epithelium responds differently to the first single exposure to tobacco smoke--in extrapulmonary airways a 'discharge' effect causes a fall in the apparent number of secretory cells while in intrapulmonary airways secretory cell number increases. Further exposures increase the secretory cell number to its maximum more rapidly in extrapulmonary than intrapulmonary airways. Differences between the response of the secretory cell population to isoproterenol and salbutamol indicate differences in the beta-adrenergic receptors in different airway regions.


Neuromuscular structure and function in the airways. The smooth muscle and the neural pathways of the airways have many similarities to the muscle and innervation of the gastrointestinal tract, as expected from their common embryological origin. The smooth muscle and its innervation vary in structure and function from species to species and extrapolation from one species to another may not be valid. In the human trachea and main stem bronchi the smooth muscle has numerous cell-to-cell connections of the nexus or gap junction type. The principal nervous pathways in the human airways are excitatory, which is cholinergic, and inhibitory, which is nonadrenergic or purinergic. Adrenergic nerves have not been demonstrated in the smooth muscle, but may be present in the ganglions that are found around the trachea and bronchi. Possible defects in the innervation may lead to alterations in the intrinsic activity, of the smooth muscle and be responsible for certain reactive states of the smooth muscle.


Postnatal formation of alveoli: interstitial events and physiologic consequences. This paper details some of the interstitial events associated with the formation of alveoli during early postnatal life and the physiological consequences of alterations in this process. Formation of alveoli coincides with differentiation of dormant interstitial fibroblasts into myofibroblasts within new alveolar buds and lipid-filled fibroblasts at the base of these buds. The myofibroblasts appear to be involved in synthesis and secretion of elastin and perhaps other connective tissue elements. Glycosaminoglycans identified with ruthenium red or tannic acid appear in the extracellular matrix of the buds. The role of the lipid-filled fibroblast is uncertain. Since lung size increases at a greater rate than airway size during the early postnatal period, conditions that stimulate or depress postnatal lung alveolarization influence relative airflow rates. Highland natives have larger than normal lungs and low relative maximal expiratory airflow. Hamsters whose growth has been blunted by protein malnutrition have small lungs but large relative maximal expiratory airflow. These results illustrate the physiological importance of dysanaptic lung growth.


Conservative surgery for endometriosis in the infertile female: a study of 206 patients with implications for both medical and surgical therapy. Two hundred and six women with endometriosis classified as mild (88), moderate (50), or severe (68) were evaluated after conservtive surgery. The duration of infertility was not related to the severity of the condition. In 137 patients, endometriosis was the only known cause of the infertility. Pregnancy rates in this group were 73.2%, 55.9%, and 40.4%, respectively, for patients with mild, moderate, and severe endometriosis. Of 56 patients with mild endometriosis (peritoneal involvement only), 78.0% had been infertile for 2 or more years; 73.2% became pregnant. These facts suggest that endometriosis, even in its mild form, does interfere with the conception process and that, in some way, surgery is efficacious. The surgery was most beneficial in the early postoperative period. Of patients who conceived, 30.5% did so within 3 months, 48.8% within 6 months, and 86.0% within 15 months after surgery. The data suggest that if medical suppressive therapy is to be used in conjunction with conservative surgery to enhance fertility, it should be used preoperatively rather than postoperatively.


The relationship between long-distance running, plasma progesterone, and luteal phase length. The chronic effects of long-distance running upon the menstrual cycle were studied in a healthy, ovulatory 30-year-old woman. Luteal phase plasma concentrations of follicle-stimulating hormone, luteinizing hormone, 17beta-estradiol, and progesterone were compared during a control and a training cycle. The luteal phase was shorter in cycles of greater mileage. Mid-luteal phase plasma progesterone concentrations were significantly lower during training.


Measurement of plasma human chorionic gonadotropin (hCG) and beta-hCG activities in the late luteal phase: evidence of the occurrence of spontaneous menstrual abortions in infertile women. Plasma luteinizing hormone (LH-human chorionic gonadotropin (hCG) and beta-hCG activities were measured during the late luteal phase in 321 cycles of 147 infertile women. In 71 cycles the hCG measurement permitted the diagnosis of pregnancy between the 10th and 14th days after the thermal nadir. The slope of the regression line derived from hCG levels during the first 22 days of pregnancy was significantly lower in pregnancies which aborted before the 60th day than in normal pregnancies (P less than 0.01). Among 72 cycles ended by apparently normal menses which exhibited an LH-hCG activity at least equal to 7 mIU of hCG/ml during the late luteal phase, the beta-hCG activity was measured in 49 cycles during which hCG had not been given. Significant beta-hCG activity (greater than or equal to 4 mIU of hCG/ml) was detected in 19 cases. This finding supports the assumption that secretory trophoblastic tissue had been present and that spontaneous menstrual abortions had occurred in these women.


Experience with two different medicated intrauterine devices: a comparative study of the Progestasert and Nova-T. A comparative study of the Progestasert (UPS) and the Nova-T in 326 randomly selected women was carried out. The observation period was 1 year. The over-all continuation rates for the two types of intrauterine devices (IUDs) were similar. The expulsion rate for the Nova-T (9.2%) was considerably higher (P = 0.001) than that for the UPS (1.2%). Medical removals for bleeding/pain were more frequent (P = 0.028) for the UPS (15.4%) as compared with the Nova-T (6.1%). The pregnancy rate for the UPS (Pearl index = 4.8) was insignificantly higher than that for the Nova-T (Pearl index = 2.8). Two of the pregnancies in the UPS group were ectopic. No significant changes in the reactive immunoglobulins (IgA, IgG, or IgM) were observed in either of the groups. Our results indicate that neither of these two IUDs is preferable to the already existing medicated IUDs, such as the Copper T or the Copper 7.


Diethylstilbestrol-induced upper genital tract abnormalities. In utero diethylstilbestrol (DES) exposure has recently been associated with apparently unique abnormalities of the upper genital tract. Utilizing a standardized technique of hysterosalpingography (HSG) and a linear planimeter, the following measurements were made in a group of 13 DES-exposed women and compared with a control group of 22 women undergoing HSG during infertility investigations (mean +/- standard error: endometrial cavity area, 323.23 +/- 32.13 sq mm versus 626.56 +/- 52.75 sq mm; endometrial cavity circumference, 128.65 +/- 5.08 mm versus 140.52 +/- 5.56 mm; upper uterine segment length, 28.80 +/- 1.11 mm versus 38.03 +/- 1.81 mm; lower uterine sugment length, 36.03 +/- 4.77 mm versus 42.24 +/- 2.39 mm; intercornual distance, 36.40 +/- 2.56 mm versus 38.25 +/- 1.58 mm; internal os diameter, 3.90 +/- 0.44 mm versus 4.43 +/- 0.23 mm; widest diameter of the endocervical canal, 3.78 +/- 0.40 mm versus 9.39 +/- 0.60 mm; isthmic tubal diameter, 1.25 +/- 0.08 mm versus 1.20 +/- 0.01 mm; ampullary tubal diameter, 4.79 +/- 0.43 mm versus 4.65 +/- 0.22 mm. The endometrial cavity area, upper uterine segment, and endocervical canal measurements were significantly smaller in the DES-exposed group (P less than 0.01). The upper genital tract abnormalities observed appeared to be unlike spontaneously occurring Müllerian malformations and correlated with DES-induced cervicovaginal changes. Primary dysmenorrhea and menstrual irregularity occurred in 40% and 47%, respectively, of the DES-exposed patients.


Factors affecting sperm motility. I. In vitro change in motility with time after ejaculation. Semen specimens from 33 donors were analyzed intermittently between 1 and 24 hours after ejaculation. Motility was determined objectively by analyzing still-camera photomicrographs taken with the aid of the new multiple exposure photography (MEP) technique, from which the following information was obtained: the percentage of motile spermatozoa, the average velocity and frequency distribution of spermatozoal velocities, and index of motility as well as sperm concentration. From curves drawn for each of the 33 analyzed specimens, these conclusions were drawn: 1. The percentage of motile spermatozoa decreases progressively, beginning 1 hour after ejaculation, at a rate of about 5% to 10%/hour. 2. In the majority of cases, sperm velocity increases for the first 4 hours and then decreases gradually. 3. There is no unique pattern of sperm motility and velocity with time for all specimens, especially during the first 4 hours. However, three typical curves of motility change were found during the first 4 hours: increase in motility, moderate decline in motility, and rapid loss of motility. 4. The frequency distribution of velocities of motile spermatozoa revealed typical normal curves at all times, but these curves became flatter as time elapsed. An explanation for these divergent patterns and the possible role of these findings in some physiologic and clinical problems are discussed.


Gonadal function in males treated with cyclophosphamide for nephrotic syndrome. Analysis of semen from 16 patients treated with cyclophosphamide for nephrotic syndrome showed azoospermia in three and oligospermia in seven. Analysis was normal in the other six. Prolonged treatment, particularly with larger total dosage, was associated with a higher incidence of gonadal dysfunction. Recovery was not evident at follow-up, 2 years and 9 months to 9 years and 1 month after cessation of the therapy. Limitation of treatment with cyclophosphamide to 8 weeks/course (2.5 mg/kg/day) minimizes this side effect without greatly increasing the rate of relapse of the nephrotic syndrome in the first 2 years after therapy.


Spermatic grauloma: an often painful lesion. Spermatic granulomas are specialized abscesses which frequently occur at the site of vasectomy. Although some are often silent, others can be agonizingly painful. A series of 154 granulomas is presented. Of these, 83 were symptomatic and 63 required surgery for relief of pain.


Danazol binding to rat androgen, glucocorticoid, progesterone, and estrogen receptors: correlation with biologic activity. Danazol was found to possess androgenic and glucocorticoid activity in rat bioassays. In contrast, danazol displayed no significant estrogenic activity. In support of these findings, danazol bound to the 8 S androgen receptor of rat prostate cytosol and to the glucocorticoid receptor of rat liver cytosol, but danazol did not bind well to the estrogen receptor of the rat uterus. Finally, danazol bound to the progesterone receptor of the rat uterus, but controversy continues as the whether danazol possesses progestational, antiprogestational, or no progestational effects.


Early ultrastructural changes in the rat testis after ductuli efferentes ligation. The early effects of ligation of the ductuli efferentes on testicular ultrastructure were studied in adult rats. As soon as 24 hours after the operation a large number of vacuoles appeared in the cytoplasm of Sertoli cells; vacuolization persisted for as long as 9 days, but localized in the apical part of the cells. Giant multinucleated cells containing annular clumps of chromatin were observed 1 day after ligation. The number of giant cells increased steadily as well as the alterations shown by their chromatin and cytoplasm. Isolated young spermatids also suffered morphologic changes that varied from almost normality to absolute necrosis. The thickness of the limiting membrane increased, as well as the number of cell layers. Deep infoldings, apparently caused by shrinkage of the tubules, were also noticed. Spermatogonias, spermatocytes I, mature spermatids, and spermatozoa did not present abnormalities. The interstitial tissue and the Leydig cells also appeared normal. It is concluded that ductuli efferentes ligation affects primarily the Sertoli cells; the formation of giant cells and the alterations shown by early spermatids and basement membrane are probably not specific but consequences of the injury to the Sertoli cells.


Intrafollicular pressure within preovulatory follicles of the pig. Antral pressure was measured within the follicles of unstimulated ovaries in prepubertal pigs and following an ovulatory stimulus with exogenous gonadotropins. No increase in intrafollicular pressure (IFP) was observed as the time of ovulation approached. A wide range of IFP was noted within follicles of the unstimulated ovary. In many follicles IFP was greater than 30 cm H2O, suggesting that the antral fluid was not in hydrostatic equilibrium with the surrounding thecal capillaries. IFP of unstimulated follicles could be increased to more than 400 cm H2O by antral injection of mineral oil without follicular rupture--a demonstration of the need for stigma formation in the release of the ovum from the follicle. Stimulated follicles were found to be more distensible than unstimulated follicles. The follicles also fell into two groups--those in which sustained versus transient elevation in IFP occurred following oil injection. It is postulated that the follicle wall develops the ability to undergo stress relaxation during follicular maturation and that this process plays a role in regulating IFP.


Connective fibers involved in the dermoepidermal anchorage. An electron microscopical study. The human dermoepidermal anchoring fibrils, the oxytalan fibers and the elaunin fibers have been related with dermoepidermal adherence. In the present work their ultrastructure and origin are studied. The similarity between the segment longspacing tropocollagen molecular aggregates and the anchoring fibrils band patterns is evidenced. This fact supports the concept that the anchoring fibrils may be formed by a mechanism of side by side tropocollagen molecular aggregation after its polar binding to the basement lamina. The oxytalan fibers were studied in the superficial dermis, and their direct continuity with the elaunin fibers was demonstrated. The role of these fibers in the dermoepidermal mechanical adhesion is discussed.


Leprosy in the Netherlands. A review of leprosy patients registered at the Department of Dermatology, University of Amsterdam in the years 1972-1976. Recently, there has been a sharp increase in the number of leprosy patients in The Netherlands, due to an increased immigration from Surinam where leprosy is hyperendemic. The patients registered at the Dermatological Department of the University of Amsterdam during the years 1972-1976 were reviewed. It was found that 28% of the untreated patients had recently suffered a relapse. A substantial percentage took the medication irregularly or discontinued treatment prematurely and quite a few patients required other types of treatment besides chemotherapy, such as surgical treatment and physiotherapy.


Dermatotillomania.

Dermatotillomania. A clinical and histopathological description is given of a number of lesions in 4 patients, mainly caused by picking at the skin. The name dermatotillomania is proposed for this group of lesions.


Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application. II. Comparison with some other antimicrobial agents. The antimicrobial activity of 5-chloro-2(2,4-dichlorophenoxy) phenol (triclosan, one of the active ingredients of Logamel, Ciba-Geigy) was compared in vitro with that of other antimicrobials exclusively or occasionally used as topical agents in dermatology: hexachlorophene, clioquinol, chlorquinaldol. gentamicin, neomycin, nystatin, econazole, clotrimazole and salicylic acid. Upon determination of the MICs for 53 strains of aerobic and anaerobic bacteria, yeasts and fungi, triclosan was found to display a high degree of activity against most of the test organisms and to have the broadest spectrum of chemotherapeutically significant antimicrobial activity of the substances tested.


Vitiligo associated with BCG-methanol extraction residue in malignant melanoma. Report of a case. A pronounced vitiliginous reaction developed at the sites of MER/BCG injections given as an adjuvant immunotherapy to a patient with malignant melanoma. To our knowledge, this is the third report on patients exhibiting vitiligo apparently induced by immunotherapy and the first in association with MER. This association may be a sign for an antimelanocytic effect and may offer a further confirmation for the autoimmune nature of vitiligo.


Treatment of mycosis fungoides with heat-killed BCG and cord factor. 6 patients with mycosis fungoides in different stages of the disease were successfully treated with intralesional injections of 1% mineral oil emulsions of killed BCG and cord factor, and/or topical application of an ointment containing killed BCG and cord factor.


High-grade malignant lymphoma arising from Sézary's syndrome. A case report. Skin infiltrates and tumors characteristic of mycosis fungoides, together with other clinical features typical of Sézary's syndrome (such as erythroderma, itching and Sézary cells in the peripheral blood), were found in a 76-year-old female. Histologically, there was a shift from a well-differentiated to a poorly-differentiated lymphoblastic infiltration indicating the transformation from a low-grade to a high-grade malignant (T-cell) lymphoma.


Immunologic response in onchocerciasis: relations to microfilaria density in the skin biopsy and to some frequent symptoms. During physical and immunologic investigations on onchocerciasis in 1,298 persons in the Republic of Liberia, the following results were obtained. There is a significant correlation between immune response and Onchocerca volvulus infection detected by a microfilaria-positive skin biopsy. On the other hand, the immune response is not influenced by the number of parasites in the skin, and there is no correlation of the immune response with Onchocerca nodules and with pruritus. There is a high proportion of serologically false-positive and false-negative results, and thus a diagnosis cannot be made simply by establishing evidence for antibodies in one person.


An approach of ultrasound diagnostic techniques of the skin and subcutaneous tissue. The authors have examined ultrasound echograms and photographs of the skin and subcutaneous tissue changes in some skin diseases, reporting their findings. In spite of the preliminary clinical casuistry, this quick, simple and painless technique without irradiation hazard to the patient shows the advantage relating to the other techniques, routine roentenography especially. In conclusion, it is the authors' opinion that the improved scanning technique and greater experience should offer such valuable results, used as an additional method in dermatological diagnostics.


Association of pemphigus chronicus with pregnancy. The evolution of pemphigus chronicus has been studied in 3 pregnant women. In the first patient, pemphigus vulgaris appeared 2 years prior to pregnancy. In the other 2 patients the disease began during pregnancy. Both women were treated with corticosteroids during their pregnancy which was normal as was delivery. A complete remission was seen in the first case 7 years following cortocosteroid therapy, and 8 months after therapy in the second case. Prolonged corticosteroid administration had no adverse effects on the fetus. The occurrence of pemphigus chronicus in the Republic of Macedonia during the past 15 years was only 0.14% of all patients referred to the Department of Dermatology. Female patients with this disease slightly outnumbered males. All forms of pemphigus seen in this period were diagnosed both clinically and histologically. The total number of cases was 53, of which pemphigus vulgaris was 74.4%, pemphigus vegetans 7%, pemphigus foliaceus 9.3% and pemphigus seborrhoicus 9.3%. We present our cases of pemphigus in pregnant women with regard to the fact that only few such cases have been published.


Influence of insulin and contractile activity on muscle size and protein balance. Although the biochemical mechanism by which insulin and contractile activity affect protein turnover in muscle are still unclear, certain physiologic conclusions can be made; (a) Increased work can induce muscle hypertrophy even in the diabetic or starving animal. Thus, work-induced growth differs from normal growth of muscle in not requiring insulin. (b) Like insulin, repeated contractions stimulate the transport of amino acids into muscle. Contractile activity or passive tension can also reduce the rate of protein degradation in this tissue. These effects can be shown with isolated muscles in vitro, but the mechanisms coupling contractile activity to these anabolic processes are unknown. (c) Insulin also reduces overall protein breakdown in skeletal muscle, heart, and liver, apparently by regulating lysosomal function. (d) Insulin reduces selectively the breakdown of cell proteins with relatively long half-lives. This hormone does not affect the rapid breakdown of abnormal proteins which probably does not occur within the lysosome. (c) Normally, liver and muscle degrade large, acidic cell proteins quite rapidly, but this selectivity is lost in the tissues of diabetic or starved organisms, in which proteolysis is accelerated.


Delayed progression of diabetic retinopathy by divided insulin administration: a further follow-up. We have previously reported a slower rate of progression in the number of microaneurysms in insulin dependent diabetic patients treated by divided insulin injections when compared to patients receiving a single daily insulin injection [Diabetes 25, 463--469 (1976)]. This observation is strengthened by the present analysis which uses complementary data obtained after a further year follow up: the mean yearly increase in the number of microaneurysms was 9 +/- 1 in the single injection group and 3 +/- 1 in the multiple one (p less than 0.001).