Urinary metabolites of halothane in man. The urinary metabolites of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) were investigated in five individuals given trace doses (25 muCi), and in three individuals given large doses (1 mCi) of radioactively labeled 14C-halothane. The latter were donor subjects for heart transplant operations. Separation of the nonvolatile urinary metabolites of halothane was accomplished by chemical extraction, electrophoresis, ion-exchange and high-pressure liquid chromatography, and gas chromatography. Identification of the individual metabolites was by nuclear magnetic resonance and mass spectrometry. Three major metabolites were identified: trifluoroacetic acid, N-trifluoroacetyl-2-aminoethanol, and N-acetyl-S-(2-bromo-2-chloro-1,1-difluoroethyl)-L-cysteine. Smaller unidentified radioactive peaks were also found. The presence of both ethanolamide and cysteine conjugates of halothane is of concern. These urinary products imply the presence of reactive intermediates. The conjugation of such intermediates to proteins and phospholipids may give rise to the high-molecular-weight covalently bound metabolites demonstrated to be present in the liver following halothane anesthesia. Elucidation of the structures of the urinary metabolites provides information important to an understanding of halothane metabolism and its potential hepatotoxicity.


Comparison of heparin and streptokinase in the treatment of venous thrombosis. Heparin or streptokinase was administered in a prospective randomized fashion to 50 patients with phlebographically confirmed venous thrombosis of the extremities of 14 days or less duration. A total of 49 patients completed the investigative protocol with 26 receiving heparin and 23 receiving streptokinase. All patients were evaluated with sequential phlebograms.  Complete thrombolysis with restoration of venous valve function occurred in one of 26 patients receiving heparin and in six of 23 patients receiving streptokinase. Fifty per cent of the patients treated with streptokinase with a total duration of symptoms of three days or less achieved complete lysis. The total incidence of therapeutic complications was similar in the two groups, but was more severe in the streptokinase treated patients.


Management of amputation-stump breakdown. Seven cases of above-knee amputation stump breakdown following surgery for arteriosclerosis obliterans were successfully treated with Travase ointment. (Bacillus subtilis proteinase). Rehabilitation was facilitated because secondary closure of the previously infected necrotic wounds could be more rapidly undertaken.


Combined propranolol and digoxin therapy in angina pectoris. The effects of oral propranolol and digoxin and digoxin alone and in combination on angina frequency, heart size, systolic time intervals and treadmill exercise tolerance, were assessed in 20 patients with coronary heart disease. Oral propranolol alone reduced the average frequency of angina pectoris from 16 to 7 attacks per week (P less than 0.02). However, the mean duration of exercise was not significantly improved because 8 patients with abnormal left ventricular function exhibited a decrease in exercise tolerance. Combined propranolol and digoxin improved exercise tolerance in these patients, and, consequently, mean exercise duration in all patients increased significantly from the control value of 390 +/- 42 to 458 +/- 46 s (P less than 0.01). Propranolol alone also resulted in a significant increase in left heart size from 46.5 +/- 1.3 to 47.7 +/- 1.5 mm/m2 (P less than 0.001), which was reversed by the addition of digoxin. Therefore, oral propranolol combined with digoxin is advantageous in patients with angina pectoris who have abnormal ventricular function or large hearts.


Naproxen in rheumatoid arthritis. A controlled trial. The efficacy of naproxen in treating rheumatoid arthritis patients was evaluated in a double-blind clinical trial using aspirin as the control drug. The study was conducted at seven centers and involved 80 patients. After an unequivocal increase in disease activity during a drug-free period, patients were randomly assigned to either drug and continued in the trial for 16 weeks. Some patients took low maintenance doses of corticosteroids, or gold salts, or both throughout the trial. Both test drugs significantly decreased disease activity as measured by a number of ways. By objective measurements, naproxen was as effective as aspirin, although patients in the naproxen-treated group entered the trial with more severe disease. By some subjective evaluations, naproxen was considered more effective than aspirin. Although patients taking naproxen had less frequent gastrointestinal side effects and fewer symptoms VIIIth nerve toxicity, the differences were not statistically significant. We conclude that naproxen is a useful addition to the physician's armamentarium for the treatment of rheumatoid arthritis.


Progesterone for outpatient treatment of Pickwickian syndrome. Ten patients with the Pickwickian syndrome, characterized by obesity, hypoxemia, hypercapnia, polycythemia, and cor pulmonale, underwent long-term treatment as outpatients with medroxyprogesterone acetate. Although there was no significant weight change in the group, PaO2 rose 12.6 +/- 2.7 mm Hg (SEM) from 49 +/- 2.6 mm Hg to 62 +/- 2.3 mm Hg (P less than 0.001), while PaCO2 fell 13 +/- 2.6 mm Hg from 51 +/- 1.9 mm Hg to 38 +/- 1.2 mm Hg (P less than 0.001). Hematocrit fell from 56 +/- 2.5% to 50 +/- 1.2%, a mean fall of 6% (P less than 0.01), during medroxyprogesterone acetate therapy. In the 2 patients who had cardiac catheterization before and during medroxyprogesterone acetate therapy, mean pulmonary arterial pressure fell 13 and 19 mm Hg. There were no recurrences of cor pulmonale during treatment. These effects on arterial blood gas values and clinical state were sustained during therapy. On withdrawal of medroxyprogesterone acetate during 1-month period, arterial oxygen and carbon dioxide tensions deteriorated to their previous pretreatment values. Reinstitution of medroxyprogesterone acetate caused improvement in both the oxygen and carbon dioxide tensions. We conclude that sublingual medroxyprogesterone acetate therapy is useful in the management of the Pickwickian syndrome.


Bullous dermatosis of hemodialysis.

Bullous dermatosis of hemodialysis. Five patients with chronic renal failure who were undergoing maintenance hemodialysis developed a self-limited bullous dermatosis restricted to light exposed areas, primarily involving the dorsa of the hands. Porphyrin levels and phototesting were normal, but histologic sections of the bullae showed thickening of venule walls, hypogranulated mast cells, and perivenular deposition of immunoglobulins. This combination of features has not previously been described and may reflect a pathologic process unique to chronic hemodialysis.


Amikacin therapy for severe gram-negative sepsis. Emphasis on infections with gentamicin-resistant organisms. Amikacin (BB-K8) is a semisynthetic derivative of kanamycin which is active in vitro against many gentamicin-resistant Gram-negative bacilli. Twenty-three patients with 25 serious Gram-negative infections were treated with this new aminoglycoside. Twelve infections involved organisms that were resistant to gentamicin. Twenty patients satisfied the criteria for bacteriological and clinical cure. This included 11 of the 12 infections involving gentamicin-resistant Gram-negative bacilli. In 4 urinary tract infections there was a good clinical response, but routine follow-up urine cultures at 30 days were positive. One patient failed on amikacin therapy. Eighth nerve toxicity was detected in two patients. These results indicate that amikacin is effective in the treatment of serious Gram-negative infections and is particularly useful in those involving resistant organisms. Further studies are indicated to evaluate ototoxic potential.


Effect of carbon monoxide on maximal treadmill exercise. A study in normal persons. The effect of breathing 100 ppm of carbon monoxide versus compressed, purified air for 1 h on maximal treadmill exericse was studied (double-blind crossover design) in 10 middle-aged, healthy nonsmokers. The mean venous carboxyhemoglobin level significantly increased from 1.67% to 3.95%  after breathing carbon monoxide (P less than 0.001) and significantly decreased from 1.63% to 1.30% after breathing compressed, purified air (P less than 0.001). The mean exercise time until exhaustion significantly decreased from 697.7 to 662.7 s after breathing carbon monoxide (P less than 0.001) and insignificantly increased from 694.9 s to 703.4 s after breathing compressed, purified air. Ischemic S-T segment depression larger than or equal to 1.0 mm after exercise occurred in 1 of 10 subjects after exercise following carbon monoxide inhalation. Increased carboxyhemoglobin levels of the magnitude encountered after smoking or heavy atmospheric pollution impair exercise performance in normal persons.


Mammalian somatic hybrids and human gene mapping. Somatic cell hybridization, as an aid in the study of human map, has made large strides during the past several years. Rodent-human hybrids are readily obtained, and selective systems are available to select hybrid cells to the exclusion of parenteral cells. Various species-specific genetic markers can be studied in the hybrids, and correlation of the expression of these markers with each other and with specific human chromosomes retained allows synteny analysis and chromosome assignment. Methods to determine the relative order of genes and their regional localization are also available. Using these methods, more than 60 human genes have been assigned to 22 human chromosomes.


How Korotkoff, the surgeon, discovered the auscultatory method of measuring arterial pressure. The Korotkoff sounds that measure systolic and diastolic arterial pressure levels were described in a brief communication by N.C. Korotkoff in 1905. He did not state how it happened that he discovered this auscultatory method of measuring "blood" pressure. The search for information on this matter led to studying the thesis for his doctorate published in 1910 on Experiments for Determining the Efficiency of Arterial Collaterals. It seems that when he wanted to be sure that pressureonan artery (digital, or with an Esmarch ligature or a Riva-Rocci cuff) had completely obliterated its lumen, he listened over the artery below the area of pressure. The absence of any sounds meant complete obliteration; a sound appeared with each beat when some flow did occur during partial obliteration of the lumen and when no pulsation could be detected because of the small volume of flow.


Microfluorometric immunoassays with antigens bound to sepharose beads. Sepharose beads, to which protein had been coupled, were used in the development of two types of microfluorometric immunoassays. The first is an inhibition assay: a fixed amount of antiserum was absorbed with different amounts of antigen. This was accomplished in both direct and indirect incubation schemes. The system has been studied with human IgG and mouse IgM as an example. The second is a competition assay: fluorescein-labeled ovalbumin competea with unlabeled unlabeled ovalbumin for the binding sites of a rabbit antiovalbumin. This antiovalbumin was not bound directly to Sepharose but to Sepharose-coupled ovalbumin. In the indirect fluorescence inhibition and the competition assay, the sensitivity levels were determined. They proved to be the same, namely, 25 ng. This means that these fluorescence immunoassays are 10 times less sensitive than conventional radioimmunoassays and 10 times more sensitive than conventional single radial immunodiffusion.


Immunofluorescence studies of a possible prethymic T-cell differentiation in congenitally athymic (nude) mice. A rabbit antimouse brain theta reagent was made specific for cells of the T lineage by absorption in vivo in nude mice. When used in double fluorescence together with an antimouse immunoglobulin reagent, four types of cells were found in spleen and lymph nodes of both normal and nude mice: Ig+thetaBr-, Ig-thetaBr+, Ig-thetaBr-, and Ig+thetaBr+. The data show that about 20% of nude mouse spleen lymphocytes are definitely of T lineage (Ig-thetaBr+). On these cells, the detection of the "thetaBr" determinant, which is identical or very close to the "theta" determinant, depends on the large amplification produced by indirect immunofluorescence, which suggests a low density of theta antigen. Similar experiments suggest the presence of cells that express some TL antigen in the spleen of nudes made congenic to a TL+ strain (BALB/c). It is proposed that the T-cell precursor that will further differentiate in the thymus already expresses a low density of theta and, in TL+ strains, TL antigen.


Application of immunofluorescence and immunoenzyme methods in the serodiagnosis of Trichinella spiralis infection. To detect antibodies to T. Spiralis in sera, the IF methods with the cuticle of T. spiralis larvae (the tube test) was compared to the cryostat method. In the latter method, cryostat sections were prepared from isolated T. spiralis larvae or from tongue or diaphragm musculature in which encysted T. spiralis larvae were present. In this case, both cuticle and internal structures were employed as antigenic sites. The cryostat method proved to be more sensitive than the tube test. With the cryostat method, specific antibodies were detected in sera of experimentally infected mice 14 days after infection, whereas with the tube test, antibodies were detected on Day 24 postinfection and consistently thereafter. The enzyme-linked immunosorbent assay (ELISA) was then studied. Quantitation of specific antibodies was achieved with alkaline phosphatase- or peroxidase-labeled antispecies immunoglobulin in antigen-coated tubes. The enzyme that remained in the tube after washing provided a measure of the amount of specific antibodies in the serum. A saline extract of T. spiralis larvae served as the antigen. In the experimental models studied (T. spiralis-infected rabbits and pigs), ELISA proved to be more sensitive than IF. At Day 3 postinfection and thereafter, specific antibodies could be detected. ELISA was modified to satisfy requirements for routine application.


Antibody-induced movement of protozoan surface membrane antigens. Direct and indirect immunofluorescence techniques were used to study the effects of host antibodies on surface membrane antigens of viable Leishmania parasites in vitro. Antisera to L. enriettii and L. tropica caused surface membrane antigens of these parasites to aggregate, move toward the poles of the parasite, and to eventually disappear. This sequence did not occur at low temperature or in the presence of some metabolic inhibitors. Antigen subsequently reappeared on the parasite membrane. These phenomena appear to be similar to those described in mammalian cells. Antibodies may therefore effect an alteration in the surface membrane structure of living protozoan parasites.


Immunoglobulin responses after rubella infection. The indirect immunofluorescence technique has been used to study specific IgG, IgA, and IgM antibodies in adults with acute rubella, volunteers who receive attentuated rubella vaccine, and infants with suspected congenital infection. In acute rubella, IgA and IgM antibodies reached peak titers during the second week after the rash and then declined, but specific IgG persisted. A similar pattern of response occurred after rubella vaccination, but titers were lower. Occasionally, fluorescent staining failed to detect specific IgM in whole serum but demonstrated it clearly in sucrose density gradient fractions. The improvement in fluorescence obtained by staining serum fractions was particularly striking in samples obtained from congenitally infected infants. In these cases, IgM staining with whole serum was often poor, but when fractions were tested, specific IgM was demonstrated in nearly all samples obtained within 9 months of birth. IgM antibody was seldom detected after the first year of life, but IgG antibody persisted. IgA antibody was not detected in congenital rubella.


A comparison between sorbent and Reiter sonicate in the absorbed fluorescent treponemal antibody test. Some syphilitic sera still fluoresce with Reiter treponemes as the antigen after treatment with the sorbent used in the FTA-ABS test; this finding indicates incomplete removal of group antitreponemal antibody. Levels of this antibody in normal sera have been studied in relation to the titration of sorbent for use in the test. A comparison has been made of the results of FTA-ABS tests with sorbent and Reiter sonicate and the TPI test on 1141 selected problem sera. Results with the sonicate displayed closer agreement (60.9%) with those of the TPI test than did tests with sorbent 40.8%). The use of sonicate as the sorbing agent is thought to improve the performance of the FTA-ABS test without diminishing its sensitivity.


Surface antigens on cultured malignant melanoma cells as detected by a membrane immunofluorescence method with human sera. Lack of tumor-specific reactions on melanoma lines. Surface antigens on melanoma cells were studied with an MIF method applied for monolayers of cultured cells. Human sera were used with indirect immunofluorescence. Preparations were fixed in methanol after staining. Reactions of sera with antibodies against trasplantation antigens displayed a  fine granular fluorescence. This appearance was abolished by absorptions with pooled tonsilar lymphocytes. Melanoma patients' sera free from antibodies against transplantation antigens exhibited a coarse patchy fluorescence reaction. Melanoma patients' sera with antibodies against transplantation antigens yielded the second type of MIF reaction after absorptions with normal lymphocytes whereas further absorptions with melanoma line suspensions effectively removed all antibody reactivity...


Studies on defined immunofluorescence in clinical immunopathology. III. Past progress, some new methods, and prospects for the future. Experience with chessboard titrations over the past 9 years has shown that essentially all indirect IF staining systems that employ anti-IgG conjugates can be defined with the aid of assays for F/P ratios and/or antibody concentrations. Some improvements in the radial diffusion assays for antibody protein have been effected by refinements in methodology. Studies with a form of the Dass system showed that over a 16-fold range of light intensities, relatively little change occurred in "titers" of IgG (comparably to titers of patient sera) or in PEP conjugates as seen in DASS chessborad titrations. An analysis of 233 PEP values included in 12 literature reports on indirect IF tests indicate that 88% fall within one doubling dilution of 1/16 unit/ml or about 12.5 mug labeled Ab/ml. The DASS reactions also are within this range. Factors responsible for variation beyond these limits in indirect IF tests were analyzed. The most important factor appears to be experimental errors. Other factors include low titers of primary antibodies, some aberrant conjugates, and a recent shift toward greater sensitivity of chessboard titrations. The latter appears to be due primarily to modes of reading and should be controlled by the constant use of reference sera. It now seems possibe that future IF studies may be defined with the aid of this DASS system. To achieve this goal, it will be necessary to not only elaborate microanalytic techniques of the type that have been considered at this Conference but also to generate macroanalytic methods that can be used in parallel with them as a basis for interpreting microscopic observations both in the DASS system and in IF studies of sera and tissues.


The specificity of fetal IgM: antibody or anti-antibody? Reference materials were produced to standardize the immunoglobulin class specificity and potency of immunofluorescent anti-IgM conjugates used for diagnostic tests for congenital syphilis. In attempting to mimic essential immunologic characteristics of syphilitic and nonsyphilitic infant sera, we evaluated these sera in comparison with processed adult sera. We were quite surprised to discover that some syphilitic babies do not produce significant quantities to IgM antibody to T. pallidum in response to their infection, as would be expected; instead, they make relatively large amounts of IgM anti-IgG. We found this to be true also for newborns and infants infected with cytomegalovirus, rubella, and toxoplasmosis. To our knowledge, this observation has not been previously reported. However, it could have been predicted from the knowledge that older infants and young children normally produce IgM antibodies to maternal IgG allotypes (Gm factors). We are disturbed that these findings suggest that currently recommended indirect immunofluorescence IgM tests for perinatal infection may not be disease specific. Our observations may be important for a better understanding of basic immunologic mechanisms of fetal-maternal to tolerance and fetal response to life-threatening infection.


Ocular leprosy in Hawaii: the past.

Ocular leprosy in Hawaii: the past. Leprosy in Hawaii dates back to about 1840. The first recorded ocular leprosy is from the 1880s. Robert Louis Stevenson and Jack London both wrote descriptions of the ocular signs of leprosy. Pinkerton in 1927 and Van Poole in 1934 reported large series of patients with ocular leprosy. In 1973 there were about 2,168 cases of leprosy in the 50 states. Most ophthalmologists practice in areas where there are leprosy patients.


[Study of anti-macrophage serum and of its effect on antibody formation]. A specific anti-macrophage serum (AMS) has been obtained by immunizing rabbits with mouse peritoneal exudate cells and after repeated absorption with mouse erythrocytes, thymocytes and splenic lymphocytes. A comparative study of the cytotoxic activities of this serum on macrophages, thymocytes and lymph node cells, before and after absorption, showed that macrophage posses antigens which are common to both thymic and lymph node lymphocytes, and other antigens which are in common with lymph node lymphocytes but absent on thymocytes, as well as antigens being particular to macrophages. The absorbed sera had a definite cytotoxic effect on macrophages in vitro. This effect was observed when complement was added immediately or 4 hours after incubation with serum. It was lost after 24 hours. An inhibitory effects of AMS on phagocytosis in vivo has also been observed, which disappeared after one day. Antibody production in vivo was only moderately affected by a pretreatment with AMS. However, addition of AMS to spleen cell cultures stimulated with sheep red blood cells inhibited the appearance of hemolytic plaque forming cells.


The influence of cyclophosphamide on antibody formation in the mouse. A single injection of cyclophosphamide (CY) (300 mg/kg) 8 h prior to immunization results in a complete suppression of the antibody formation in mice. The effect of CY on the number and activity of the surviving cells in the lymphoid organs was studied. For all organs tested there was a decrease in cell numbers to 10% or less till day 3, followed by an increase in cell numbers in bone marrow, spleen and lymph nodes. The increase in cell numbers in the thymus was delayed till after day 11. The bone marrow reached normal levels on day 7. The spleen surpassed the normal levels on day 11, reaching cell numbers which were 50% over the normal ones. For the thymus cells this was found only on day 21. The numbers of lymph node cells remained low and reached normal levels or higher only when the mice were stimulated after CY treatment. This effect of stimulation was further seen in the spleen cell numbers, where after stimulation with antigen in Freund's complete adjuvant (FCA) or only FCA cell numbers of 200% of normal values were obtained. The suppression of antibody formation by CY could be restored by cells from spleen, lymph nodes, Peyer's patches or thymus and bone marrow, indicating a defect in both B and T cells caused by CY treatment. The target cell of CY treatment was studied by reconstitution of anergic mice with spleen or lymph node cells of CY treated mice with or without addition of normal bone marrow and thymus cells. This revealed that although the B cells is the main target cell of CY action, the impact on the T cell population is also considerable. When however CY treatment is followed by antigenic stimulation, there is a steep increase in the activity of the lymph node cells when bone marrow cells are added. This phenomenon resembles the education of thymus cells in the spleen of lethally irradiated mice in the presence of antigen.


[Immunological activities of rat lymphocytes. III. --Isolation of differing subpopulations of lymphocytes by two techniques of T cell separation]. In previous studies we have isolated by density gradient separation a population of relatively dense T lymphocytes capable of inhibiting the mitogenic response to concanavalin A (ConA) and phytohaemagglutinin. In this study we compared two current methods of cell separation for their relative yield in T lymphocytes able or not to respond to Con A. The present results show that cells passed through nylon wool columns--in contrast to those obtained by removal of lymphocytes which bind erythrocyte-antibody-complement complex-partially lose their ability to respond to ConA. The response lost by passage through nylon wool columns can be restored by centrifugation of the T cell suspension on a gradient of "Ficoll-Hypaque". This suggests that methods of T cells purification using density gradient separation may remove the more dense suppressor cells.


[Protective effects of bacterial immunostimulants in mice infected by "Klebsiella pneumoniae" resistant to antibiotics after mutation or by plasmid transfer]. A streptomycin-resistant strain of K. pneumoniae obtained after mutation in vitro was found to be less virulent than the sensitive strain in mice. However, a single injection of lipopolysaccharides (LPS) administered 24 hours before challenge increased the host's resistance to both strains. In contrast, the virulence was not changed in K. pneumoniae accepting R-factors for ampicillin, streptomycin, chloramphenicol, tetracycline and sulphonamide. The plasmids were transferred to K. pneumoniae from two strains of Escherichia coli possessing different R-factors with the same resistance pattern. As in the first case, mice pretreated by endotoxin were protected against a challenge by microorganisms carrying R-factors. The capacity of the stimulated host to destory resistant or sensitive organisms was of the same order. Klebsiella recovered 5 or 24 hours after infection from the blood, liver and spleen did not lost their antibiotic-resistance. In this study, BCG and Corynebacterium granulosum were also used. Like LPS, these two immunostimulants protected very effectively mice infected with K. pneumoniae rendered resistant to antibiotics by R-factor transfer.


Origin of the osseous bioelectric potentials: a review. Recently, an electrophysical approach has been applied to the study of the long bone in order that a more complete understanding of its growth and structural integrity become available. Experimental studies have indicated that weak electric fields may be detected in living bone, in vivo, as the result of externally applied loads, normal weight bearing and pulsatile blood flow. In addition, physiological information may be derived from these electropotentials as functions of their magnitude and polarity. Several sources of these natural osseous bioelectric potentials have been proposed including piezoelectricity, electrokinetic phenomena, p-n semi-conductor junctions, pyroelectricity and photoelectricity. In this paper, these sourcesof bioelectricity are examined, their origins elucidated and their importance ranked in accordance with the maintenance of the structural integrity of the bone.


[Sensitivity of bacterial flora to antibiotics according to data from a clinical hospital]. Antibiotic sensitivity of E. coli O-124, Salmonella and Shigella sonnei isolated from patients during 1968-1972 was studied with the disc method. Increase in the resistance levels to monomycin and neomycin in E. coli O-124 was observed. Sensitivity of Salmonella and Shigella sonnei to some antibiotics did not practically change.


[Transmissivity of drug resistance in Salmonella]. The experiments showed that among 110 Salmonella strains resistant to 1 or more antibiotics 54.5 per cent of the cultures transfered their resistance to E. coli when grown in vitro. The frequency of the transmissive drug resistance in Salmonella was directly proportional to the number of r-determinants in R-factor. The cultures resistant to ampicillin and kanamycin proved to be the most competent donors.


[Study of the mechanisms of levomycetin inactivation by the palgue causative agent and Escherichia coli with episomal and chromosomal resistance. The enzymatic acetylation of levomycetin]. One of the mechanisms of levomycetin inactivation, i.e. enzymatic acetylation of the plague causative agent and Coli bacteria with chromosomic and episomic type of resistance was studied. It was shown that resistance to levomycetin in the recombinants of the plague microbe and Coli bacteria stipulated by one and the same R-factor was associated with their capacity for the antibiotic inactivation mainly with the help of levomycetinacetyltransferase. At the same time the enzyme activity in the mutants was very low and in the cells of Y. pestis and E. coli sensitive to the antibiotic it was absent. Levomycetinacetyltransferase is to somee extent soluble, still a singificant amount of it is connected with the structures of the bacterial cells and in particular with the cytoplasmic membranes. Comparison of the activity of levomycetinacetyltransferase as dependent on the incubation time, substrate concentration, pH and thermal treatment provided determination of quantitative differences in the properties of the enzyme of Y. petis and E. coli with episomic multiple drug resistance. However, under the experimental conditions transfer of R-factor from one host to the other induced no qualitative changes in the mechanism of levomycetin inactivation.


[First phase in the clinical study of the antineoplastic antibiotic, carminomycin]. During the 1st stage of the clinical trials of karminomycin 92 patients with leukemia, solid tumors and lymphoma were treated with karminomycin. Two schemes for the antibiotic use were developed. The 1st scheme was a prolonged one with single doses of 10-15 mg (7.5 mg/m2) administered intravenously twice a week for 3 weeks, the course dose being 60-75 mg (34-45 mg/m2) with 4-week intervals between the courses. The course dose for the patients previously subjected to intensive chemotherapy did not exceed 50 mg (30 mg/m2). The 2nd scheme was a short one with single doses of 8-10 mg (5.5 mg/m2) administered intravenously every day for 5 days, the course dose being 40-50 mg (23-30 mg/m2) with 3-week intervals between the courses. Karminomycin induced in a number of patients a direct side effect, such as nausea, vomiting, asthenia, tachycardia, pain in the heart. In some patients leucopenia, thrombocitopenia, rare stomatitis, alopecia, lowered T peak in the chest curves of the cardiograms were observed after using the course dose.


Potential for in vivo acquisition of R plasmids by one strain of Vibrio cholerae biotype El tor. The feces of five patients admitted to a hospital during an outbreak of cholera in Melbourne, Australia, in November 1972, were examined for the presence of tetracycline-resistant coliforms and tetracycline-resistant strains of Vibrio cholerae. Despite the abundance of tetracycline-resistant coliforms able to transfer this resistance to other strains of Escherichia coli, no tetracycline-resistant strains of V. cholerae were detected. In vitro transfer experiments using the V. cholerae strain responsible for the outbreak as recipient revealed that it was a particularly poor host for most R plasmids.


In vitro studies with combinations of 5-fluorocytosine and amphotericin B. Synergistic antifungal activity of 5-fluorocytosine (5-FC) and amphotericin B was studied using an abbreviated checkerboard titration scheme. 5-FC was titrated in twofold increments (100 to 0.05 mug/ml) in the absence and presence of graded increments of amphotericin B (1.0. 0.5, 0.1, 0.05, and 0.01 mug/ml) in buffered yeast nitrogen base. A limited number of experiments were performed using expanded dual titration checkerboard schemes and growth curve studies. Forty-eight isolates of yeastlike organisms were tested; two were inhibited by the buffer system. Evidence of synergy, as indicated by a fourfold or greater reduction of the minimal inhibitory concentration of 5-FC in the presence of subinhibitory concentrations of amphotericin B, was seen with 11 of 46 isolates, or 24%, at the fungistatic level and with three isolates, or 7% at the fungicidal level. Indifferent results were obtained for 44 and 74% of the isolates, respectively, at the fungistatic and fungicidal levels. Antagonism was observed with three isolates.


Distribution of R plasmids among the O-antigen types of Escherichia coli isolated from human and animal sources. The O-antigen types of 600 independently isolated Escherichia coli strains from human feces have been determined, and the types have been related to the antibiotic resistance patterns of the strains. The relative abundance of each O-antigen type differed in the susceptible and resistant series of strains. The majority (86%) of the resistant strains carried R plasmids. Resistant E. coli (20.3%) were found associated with O-antigen types 8, 9 and 101, whereas the susceptible strains covered a wide range of O-antigen types. Examination of 174 resistant strains isolated from calf feces also showed a prevalence of O-antigen types 8, 9, 101 (24.1%), and it seems probable that strains expressing these three O-antigen types commonly carry R plasmids in the alimentary tracts of man and calves. The number of strains not typeable with the O sera available were similar in the human (12.5%) and the calf (11.5%) series. There are no grounds for distinguishing "human" from "calf" E. coli on the basis of their O-antigen reactions.


Properties of the gentamicin acetyltransferase enzyme and application to the assay of aminoglycoside antibiotics. The acetyltransferase technique of serum gentamicin assay was demonstrated to be specific for aminoglycoside antibiotics. The enzyme involved was isolated and stabilized by lyophilization.


Plasmid-determined epistatic susceptibility to kasugamycin. The effect of two representative plasmids, R100 and F8-gal, on the susceptibility of Escherichia coli to kasugamycin was studied. R(+) and F(+) cells were found to be more susceptible to this antibiotic than R(-) and F(-) cells, respectively. Retransfer and curing experiments of these plasmids show that this increased susceptibility of host cells to kasugamycin was conferred by either of the plasmids. At the early stage of growth of R100(+) cells in the presence of kasugamycin, R(-) segregants overgrew the population and then they were replaced by kasugamycin-resistant mutants of the R(+) cells which became the majority cell line of the population. The former phenomenon is assumed to be due to the increased susceptibility of R100(+) cells to kasugamycin, and the latter is probably related to the finding that R100 enhances the spontaneous mutation of host cells to resistance to kasugamycin. The practical and experimental significance of these findings are discussed.


Nalidixic acid: an antibacterial paradox. Nalidixic acid was found to be most bactericidal against various species of gram-negative bacteria at 50 to 200 mug/ml. With all species tested, increases in the concentration of nalidixic acid above this range reduced, rather than increased, its bactericidal effect so that, at levels in the region of 400 mug/ml, the drug was relatively bacteriostatic. Therefore, the mode of action of nalidixic acid at various concentrations was investigated. It was found that at the most bactericidal concentration deoxyribonucleic acid synthesis, but no ribonucleic acid (RNA) or protein synthesis, was inhibited. However at higher concentrations, where the drug is least bactericidal, both RNA and protein synthesis were found to be inhibited. Results are presented which suggest that the protein synthesis inhibition is a secondary manifestation of the ability of the drug to inhibit RNA synthesis, and that of RNA synthesis is most likely the second target site for the action of the drug when bacteria are exposed to it in high concentrations. The clinical implications of these findings are discussed.


Relation of beta-lactamase activity to antimicrobial susceptibility in Serratia marcescens. One-hundred clinical isolates of Serratia marcescens were tested for susceptibility to cephalothin, carbenicillin, ticarcillin, ampicillin, and cefoxitin. The majority of the 100 isolates (>/=70%) were susceptible to carbenicillin, ticarcillin, and cefoxitin; less than one-half were susceptible to ampicillin; none were susceptible to cephalothin. Ten isolates from the 100 organisms tested were selectively assayed for their beta-lactamase activity. Enzyme activity was measured using either iodometric or spectrophotometric methods, and the microbiological assay technique. It was concluded that beta-lactamase production was not the sole determinant in beta-lactam antibiotic resistance. Resistance without demonstrable beta-lactamase was evident in strains for cephalothin, ampicillin, and cefoxitin. In addition, one strain which was susceptible to all antibiotics except cephalothin, elaborated considerable beta-lactamase activity.


Evaluation of topical polyinosinic acid-polycytidylic acid in treatment of localized herpes zoster in children with cancer: a randomized, double-blind controlled study. Twenty-four children with cancer and localized herpes zoster were randomized to receive either topical polyinosinic acid-polycytidylic acid [poly(I:C)] or a saline placebo. Solutions containing 1.0 or 2.5 mg of drug per ml were applied to the lesions every 3 h, seven times a day for 7 consecutive days. Serial, standardized color photographs were used to evaluate the progression of lesions and maximum percentage of dermatome involvement. In patients receiving poly(I:C), the median days of new lesions after therapy was 2.0 days as opposed to 3.5 days in placebo-treated patients. This difference was not statistically significant. Moreover, the total median days of lesions and percentage of dermatome involvement were similar in both groups, as were complications. Neither the concentration nor the total dose of drug was related to the outcome of infection. We conclude that topical poly(I:C), as used in this study, was of no benefit in treatment of localized herpes zoster.


Sequence effect on ampicillin blood levels noted in an amoxicillin, ampicillin, and epicillin triple crossover study. Amoxicillin, ampicillin, and epicillin (500 mg of each) were given orally to fasting men and women in a triple crossover study. Peak serum concentrations were significantly higher for amoxicillin than for ampicillin and significantly lowest for epicillin. The concentrations of antibiotics in serum were comparable in men and women. Total urine recovery was highest for amoxicillin (56.7%) and lowest for epicillin (27.5%), and higher in men than in women for each of the three antibiotics. Saliva, sweat, and tears contained only very small amounts of amoxicillin and, rarely, ampicillin or epicillin. A significant (P < 0.02) sequence effect was noted in that peak serum concentrations of ampicillin were higher (6.4 mug/ml) if epicillin had been taken the previous week than when ampicillin was taken first (2.7 mug/ml).


Feasibility of administering aminoglycoside antibiotics by continuous intravenous infusion. Eleven patients each received gentamicin sulfate, tobramycin, and sisomicin by continuous intravenous infusion after an initial loading dose. Subsequent doses of antibiotic were adjusted in an attempt to maintain constant serum concentrations. There was considerable variation in the serum concentration from patient to patient and in the same patient from day to day with each drug. Although the dosages of gentamicin sulfate and tobramycin were similar, the serum concentrations of the latter drug were consistently lower. Despite the daily administration of doses of at least 300 mg of gentamicin and tobramycin per m(2) and 160 mg of sisomicin per m(2), nephrotoxicity occurred in only three patients. This is a low frequency of nephrotoxicity, considering the dosages of drug administered. Although therapeutic efficacy was not an objective of this study, 8 of 11 documented infections were cured. This approach to the administration of aminoglycoside antibiotics deserves therapeutic trials.


Effect of surfactants on antibiotic resistance. The effectiveness of surfactants as potentiators of antibiotic activity on several resistant strains of bacteria, selected from clinical sources and laboratory collections, was studied using a tube dilution assay. Bacterial strains included members of the Enterobacteriaceae and staphylococci. Cetyltrimethylammonium bromide (CTAB), Tween 80 (Tw80), a mixture of n-alkyldimethyl betaines (L14), and alpha-(2,4,5-trichlorophenoxy) propionic acid (TCP) were tested in combination with pencillin G (PenG), methicillin (Met), streptomycin (Sm), polymyxin B (PmB), and chlortetracycline (CTC). Growth response to the drug combinations was compared with the response to each drug alone. CTAB and L14 but not Tw80 or TCP were found to potentiate the activity of CTC on strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Studies on the inhibition of protein synthesis by CTC in cells of a strain of E. coli suggested that the surfactants increased the uptake of antibiotic into the cells. CTAB and L14 almost completely sensitized strains of P. mirabilis, Serratia marcescens, K. pneumoniae, and E. coli to PmB. With the exception of K. pneumoniae, TCP was also effective in potentiating the activity of PmB on the above strains whereas Tw80 showed potentiation only with a strain of E. coli. CTAB and L14 but not TCP or Tw80 potentiated the activity of PenG but not Met on strains of staphylococci. Studies of penicillinase in the cells suggested that the surfactants inhibited the formation of this enzyme possibly at the level of induction. None of the surfactants were found to potentiate the activity of Sm.


Binding of bacteriocin Clo DF13 to Clo DF13 plasmid deoxyribonucleic acid in vivo and in vitro. The bacteriocinogenic plasmid Clo DF13 is present in Escherichia coli to the extent of 10 copies per cell. A complex of Clo DF13 plasmid deoxyribonucleic acid (DNA) and protein can be isolated from cells. Treatment of the complex with ionic detergents or proteases dissociates the complex but does not convert any supercoiled Clo DF13 DNA to the open circular form, indicating that this complex is not a relaxation complex. The complex is stable in 0.5 M NaCl and contains one polypeptide species. The protein, present in the complex, appeared to be bacteriocin Clo DF13 for the following reasons: (i) the protein is de novo synthesized in Clo DF13-harboring minicells, indicating that this protein is Clo DF13 specific; (ii) this protein shows bacteriocinogenic activity on a bacteriocin Clo DF13-susceptible indicator strain; (iii) this protein has the same molecular weight (60,000) as bacteriocin Clo DF13. DNA-protein binding experiments, involving QAE-Sephadex column chromatography and nitrocellulose membrane filters, demonstrate that bacteriocin Clo DF13 has also affinity in vitro for Clo DF13 DNA. Membrane filter binding experiments revealed that bacteriocin Clo DF13 does not interact with other DNA species, such as ColE1 DNA, yeast DNA, calf thymus DNA, phiX174 DNA, and also not with denatured Clo DF13 DNA. In addition no binding to Clo DF13 DNA of a related bacteriocin, colicin E3, could be detected. These results indicate that the binding of bacteriocin Clo DF 13 to double-stranded Clo DF13 DNA is very specific.


Enhancement by nalidixic acid of the thermal susceptibility of the Ts-7 mutant of Escherichia coli TAU-bar. Nadilidixic acid at 5 x 10(-6) M produced a substantial increase in thermal susceptibility of Ts-7, suggesting either that the thermal and nalidixic acid targets are identical or closely interdependent.


Stability of Escherichia coli membrane proteins during chloramphenicol treatment. It is shown that there is no degradation of previously formed inner and outer membrane proteins of Escherichia coli during 1 h of chloramphenicol treatment.


Detection of mannitol formation by bacteria. A test is described by means of which formation of mannitol from fructose by lactic acid bacteria can be readily detected. The test is based on removal of interference of residual fructose by dehydration with hydrochloric acid followed by thin-layer chromatography.


Immunocytochemical localization of cathepsin D in rabbit skin. The lysosomal proteinase cathepsin D has been localized in rabbit skin by immunocytochemical techniques. The enzyme was found in the basal layer of the epidermis, hair follicles, sebaceous glands, fibroblasts, and endothelial cells. An autoradiographic technique, using the Fab' fragment of IgG, was also used for more effective identification of cell types that contain cathepsin D.


Congenital myotonic dystrophy in Britain. I. Clinical aspects. A clinical and genetic study of congenital myotonic dystrophy in Britain has been carried out in 70 patients from 54 sibships. The clinical aspects are analysed here, and the existence of a syndrome clinically distinct from myotonic dystrophy of later onset is confirmed. Characteristic features included neonatal hypotonia, motor and mental retardation, and facial diplegia. A high incidence of talipes occurs at birth together with hydramnios and reduced fetal movements during pregnancy, factors suggesting prenatal onset of the disorder in many cases. Prolonged survival is the rule after infancy, but the occurrence of numerous neonatal deaths in the sibships suggests the existence of unrecognized cases dying in the neonatal period.


The pathogenesis of pulmonary edema in acute pancreatitis. Acute pulmonary edema appeared 3 or more days after the onset of acute pancreatitis in 7 patients, an approximate incidence of 8%. The severity of pancreatitis in these patients was characterized by massive requirements for intravenous colloid and by marked hypocalcemia. In addition, at least 5 of the 7 patients had very high serum levels of triglycerides at the time of hospital admission. Hemodynamic studies during pulmonary edema showed normal central venous pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance. Cardiac index was appropriately elevated. Respiratory treatment, consisting of endotracheal intubation and controlled ventilation with PEEP, was successful in allowing reversal of the pulmonary injury and recovery of respiratory function within 1-2 weeks in all cases. Two patients died later from pancreatic abscesses. The findings indicate that a distinct form of pulmonary injury may occur in acute pancreatitis, characterized by loss of integrity of the alveolar-capilllary membrane, leading to pulmonary edema. The mechanism of injury is not known but may be caused by circulating free fatty acids, phospholipase A, or vasoactive substances. The pulmonary membrane lesion appears to heal during the period of intensive respiratory support.


Hypothalamic and nutritional obesities in mice. A comparative study of growth and body composition. Obesities induced in mice by a single injection of gold thioglucose or by a change to a fat-enriched diet(containing 8% fat) were studied in young and adult mice of Charles River strain. These two forms of obesity were compared and contrasted with normal animals maintained on 2.5% fat diet for life. The comparison was based on individual growth, age-realted fat, water and defatted dry weight of carcasses and their distribution of weights within larger populations. Young animals on diets containing 8% fat showed an elevated accumulation of fat but not of water. Individual variations lead to an abnormally distributed population where in some animals the excess in weight was characterized by an excessive fat and lean body mass and in others by an excess fat only. Some animals showed no excessive weight when compared to animals maintained on 2.5% fat. The rapid gain in weight which followed a successful injection with gold thioglucose showed a normal distrubution and was correlated with an accumulation of fat in young and adult animals. A significant retention of water was observed only in adults. The relative merits of these obesities as models for human regulatory obesities are briefly discussed.


Very high dosage vs standard dosage fluphenazine in schizophrenia. A double-blind study of nonchronic treatment-refractory patients. Previous work with chronic schizophrenic patients and a pilot study with nonchronic treatment-refractory schizophrenic patients indicated that very high doses of fluphenazine hydrochloride (1,200 mg/day) have a greater antipsychotic effect than do standard doses. Increased side-effects were not reported. In a double-blind six-week random assignment study, 18 nonchronic treatment-refractory patients received the very high dose and 13 the standard dose. The standard-dose treated patients had greater improvement on a variety of measures. Analysis of Inpatient Multidimensional Psychiatric Scale scores indicate that some patients taking very high doses had akinesia, and extrapyramidal side-effect that in part accounted for their inferior response.


Amitriptyline-perphenazine interaction in ambulatory schizophrenic patients. A controled study of drug interaction. In a double-blind placebo, controlled clinical study, lasting 12 weeks, 48 male and 48 female ambulatory schizophrenic patients were randomly assigned to one of four treatments: placebo; amitriptyline hydrochloride, 125 mg/day; perphenazine, 20 mg/day; or amitriptyline-perphenazine, 20 mg/day. Treatment groups contained an equal number of male and female patients. Perphenazine alone or in combination was substantially more effective in reducing psychopathological disorder than was the placebo, but there was no evidence to indicate the superiority of the amitriptyline-perphenazine combination over perphenazine alone. Amitriptyline alone was not substantially better than placebo and could not be considered an efficacious medication for the maintenance treatment of these patients. Less response to treatment was made by patients with longer-term records of prior hospitalization.


Comparison of efficacy of lithium carbonate and chlorpromazine in mania. Report of collaborative study group on treatment of mania in Japan. A multi-institutional cooperative study comparing lithium carbonate with chlorpromazine was conducted, using a controlled double-blind design in a series of 80 cases of endogenous manic psychosis, to evaluate the drugs' clinical utility and efficacy, characteristics of therapeutic effect, and side-effects. Dosages employed were consistently at an equipotent ratio of 4:1 (lithium carbonate:chlorpromazine). Physicians' overall ratings showed lithium carbonate as significantly superior to chlorpromazine in efficacy for manic psychosis. Improvements of basic mood and of disturbance in speech and voice were prominent with lithium carbonate. Onset of the therapeutic effect of lithium carbonate was within ten days of medication in 65% of the patients, significantly faster than with chlorpromazine. Side-effects encountered with lithium carbonate therapy at dose levels not higher than 1,800 mg/day were milder and less frequent compared with those seen with chlorpromazine.


[Protective effect of glucose-insulin-potassium solutions in myocardial damage caused by emetine]. This study was carried out on 170 dogs. Cardiotoxic effects of doses of 15 mg/kg of emetine hydrochloride were studied in 20 dogs. 20 mg/kg of emetine hydrochloride were administered intravenously over 60 min. to the remaining 150 animals. These dogs were distributed in groups of 25. One group received emetine alone. Phleboclyses with saline serum, glucose-insulin-potassium, glocose-insulin, glucose-potassium and glucose serum alone, respectively, were administered to the other 5 groups during the emetine infusion and cardial contraction and several electrograms were recorded. Mean systolic blood pressure was measured continuously in the femoral artery. Observations covered a 4 hour period. During the infusion of emetine alone, ventricular myocardial contraction and systemic arterial pressure decreased abruptly. Intra-atrial, atrio-ventricular and intraventricular conduction disorders, as weel as primary ventricular repolarization changes, were also observed. At the end of this infusion, the Q-T interval increased 25% and the heart rate decreased 26% of the control values. In the group also receiving glucose-insulin-potassium solution, the fall of the ventricular contraction amplitude was significantly less than in animals given emetine alone. Primary ventricular repolarization changes were less evident. The mortality rate reached only 4 per cent. In conclusion, the doses of emetine hydrochloride employed here have depressive cardiocirculatory effects. Glucose-insulin-potassium solution, administered simultaneously with emetine, seems to have a favorable metabolic effect against the emetine cardiotoxicity. This protective action of the G-I-K solution is superior to that obtained with each component, administered separately, and with saline serum.


[Double-blind therapeutic trial of spironolactone in arterial hypertension]. Spironolactone is a diuretic, selective aldosterone, antagonist with its own antihypertensive action which prevents body loss of potassium. Its clinical use has been documented on the treatment of essential arterial hypertension; however, there does not seem to be enough information to form a solid chemical criterion. This work is a clinical evaluation of the antihypertensive effect of the drug using double-blind technic with 41 patients with essential arterial hypertension, all external patients from the Instituto de Cardiología. They were divided in two groups, selected at random, to be able to observe their tensional range with spironolactone every two weeks, during 16 weeks; and using a placebo for the next 16 weeks. On group following this order; and the other one viceversa. After 32 weeks, the results observed show the effect of placebo, as well as spironolactone on arterial pressure and the statistic comparison, states the real antihypertensive effect of the drug on this group of patients. Every day doses were from 300 to 450 mg., and with it there was a rise in seric potassium of an average of 1 mEq/l. The authors suggest that this drug is useful in cases of essential hypertension although its pathway isn't deeply known. Apparently, the antihypertensive effect of spironolactone is not solely on patients with hypertension due to primary aldosteronism. The intervention on various hipertensinogenous factors in relation to its effect are discussed.


Lithium carbonate response in depression. Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history. The antidepressant efficacy of lithium carbonate was assessed in a double-blind trial in 23 hospitalized depressed patients. Unequivocal response was significantly more frequent in bipolar than in unipolar depressed patients. Lithium carbonate responders had a greater visual average-evoked response amplitude increase in response to increased stimulus intensity, termed "augmenting". No correlation could be demonstrated between lithium carbonate efficacy and either erythrocyte catechol-O-methyl transferase activity, age of symptom onset, number of hospitalizations, or family history of affective disorders.


Total sleep deprivation on endogenous depression. Ten endogenous depressive patients were deprived of sleep for two whole nights according to the following schedule: sleep/sleep deprivation/sleep/sleep deprivation/sleep. No drugs were administered. Experimental conditions were as neutral as possible. Blind and nonblind ratings were taken. The patients were generally rated as improved after sleep deprivation, but a substantial effect, though temporary with rapid relapse, occurred in only two cases. After subsequent sleep, relapse followed as a rule. The net antidepressive effect of the total procedure was slightly more than nil.


A comparison of antidepressant medications in neurotic and psychotic patients. The responses of 225 newly hospitalized depressed women to amitriptyline hydrochloride, imipramine hydrochloride, and thioridazine were compared with particular reference to the psychotic-neurotic distinction. During the first week, more psychotic patients required sedation and more antidepressant medication than did neurotic patients. All treatment groups showed improvement in psychometric criteria after the first week. There was decreasing improvement through the successive weeks, and no statistically significant differences among treatments emerged. Responses of the neurotic group were superior to those of the psychotic group, but there was no psychometric evidence of interaction between diagnostic classification and treatment effect. The results do not support the hypothesis that any one of these treatments is preferable for neurotic patients or for psychotic patients.


[Modern nosology and the pathomorphism of kidney diseases]. In studies of the Bright disease the most promising have proved to be functional-physiological and immunological lines, genetic, morphological and enzymological investigations. Achievements of nephrology in studies of nosological forms have made it possible to describe new disorders, to give different interpretation of the diseases existed earlier, and to fractionate the "monolith" nosological forms, which complicates the development of classificational forms of kidney diseases. Singling out of individual disease is impeded, moreover, by the pathomorphosis of kidney diseases, a phenomenon particularly noticeable during the last decade, which not infrequently is difficult to be distinguished from pathology of therapy. The existing classifications of kidney diseases do not meet any longer theoretical and practical needs of current nephrology. In elaborating rational classificational schemes one should be guided not by one but by several principles, including etiological, pathogenetic, clinical, and structural ones, hereditary pathology being considered quite separately.


[Utilization of luminescent monospecific sera against human immunoglobulins G, A and M for diagnostic purposes]. A method for obtaining luminescent sera, consisting in isolation of pure antigens G, A, M from human gamma-globulin and blood serum from patients with myeloma disease is suggested. A native antiserum was obtained by immunization of rabbits with water-insoluble polycondensate of antigens "sewn" with glutaric aldehyde. Adsorption of antisera as well as specific antigens was carried out with antigen- and antibodyimmunosorbent, the latter being obtained with the help of both glutaric aldehyde and sefarose 4B treated with cyanogen bromide. The sera had a specific titre in the precipitation reaction against their own antigens 1:32 and were highly specific. A globulin fraction was obtained by sedimentation with polyethylene-glycol. Marking of the specific protein with fluoresceine isothiocyanate was carried out using the dialysis method with subsequent purification on sefadex and DEAE-cellulose. The application of the abovementioned sera made it possible to ascertain the character of distribution of deposits of immunoglobulins in glomeruli in systemic lupus erythematodes, glomerulonephritis and in the cells of the synovial fluid sediment in rhematoid arthritis.


[Morphometric study of the thyroid gland]. The article surveys the most important morphometric methods used for investigating the thyroid gland. Applicability of various histophysiological criteria for evaluation of the functional state of the organ and investigation of changes in its individual structural components in physiological and pathological processes is discussed. The connection between various quantitative indices and the most rational morphometric techniques based on the methods of planimetry and stereology are considered.


[Characteristics of the pathomorphological manifestation of salmonella infection in guinea pigs and hamsters]. Observations on the manifestations of salmonellosis infection in various species of laboratory animals made it possible to establish general regularities inherent to this infectious disease, to reveal features depending on metabolic, morphological and microbiological characteristics of a given species of animals. These comparative data are of importance for understanding the factors determining resistance or sensitivity of the macroorganism to infection. Pathomorphological and microbiological investigations of experimental salmonellosis infection in hamsters and guinea-pigs showed that changes characteristic of this infection were manifested considerably weaker in guinea pigs than in hamsters. Of special interest were lesions of the large intestine mucosa wall in guinea pigs and those of the lungs in hamsters. These data may be a subject of a special study. Development and course of the experimental infection were not accompanied by the development of disbacteriosis. Pathogenic bacteria were eliminated on the 2nd--4th day in guinea pigs and on the 5--7th day in hamsters.


[Listeriosis in agricultural animals (problems of the epizootiology, pathological anatomy and pathogenesis)]. Data are presented on the main problems of epizootology, pathological anatomy and pathogenesis of listeriosis of agricultural animals. It was shown that under natural conditions all species of agricultural animals are susceptible to the condition but ship are affected most often. Various clinico-anatomic forms of the disease are considered: nervous, septicemic, metrogenic, mixed, subclinical and latent. Domestic animals were observed to suffer predominantly from the nervous form of the disease. Basing on literature reports and his own findings, the author elucidates with greater detail problems of pathomorphology and pathogenesis of the nervous form of listeriosis and shows the importance of the neurogenic pathway in the development of listerious encephalomyelitis.


Scleral perforation. A complication of the soft contact lens. A large area of conjunctiva and a smaller area of full thickness sclera eroded immediately adjacent to the edge of a soft contact lens. The soft lens was worn to protect the epithelium of a corneal graft in an alkali-burned eye. The conjunctiva-sclera necrosis appears to be a complication of a distorted and tightly fitting lens.


Fat embolism: physiopathology, diagnosis with management. This paper describes the components of the post-traumatic syndrome. The pathological state of fat macroglobulinemia by occlusion of arteriolar terminal branches of vital organs causes the fat embolic syndrome. The main physiopathological problem is pulmonary insufficiency in an acute or subacute form. The cerebral embolus is second. The symptomatology varies and is not characteristic. According to their importance they were described as minor or major in the diagnosis of fat emboli. Only recently, treatment for the fat emboli syndrome has been initiated, consisting mainly in supportive measures, respiratory care and anti-inflammatory drugs, mainly cortisone.


[Longitudinal growth of the tibia using the model of a congenital pseudarthrosis of the tibia (author's transl)]. Authors could not confirm a growth disturbance--suggested by other workers--at the distal end of the tibia in a modell experiment of congenital pseudarthrosis of the leg.


[Elongation of the anterior cruciate ligament--reefing or displacing (author's transl)]. Among old injuries involving the cruciate ligaments elongation of the anterior cruciate ligament is found in 20%. Follow-up examinations revealed that the purse-string suture technique does not guarantee permanent tightness of the anterior cruciate ligament. In consideration of the unsatisfactory results obtained by the purse-string suture technique it is suggested to effect tightness of the anterior cruciate ligament by the transfer of its distal insertion. The technique is described.


A radiographic evaluation of microporosity in a nickel base casting allow. Three series of tensile test pieces were produced using a nickel base partial denture casting alloy. For the first series induction heating was employed, for the second a resistance crucible, and for the third an oxy-acetylene torch. All specimens were radiographed and a classification developed to indicate the radiographic soundness of each specimen. Radiographic soundness was subsequently related to the results obtained from mechanical testing.


The value of associating pentazocine with drugs used in accepted intravenous techniques. Pentazocine, a systemic analgesic, can be utilized in local analgesic and intravenous techniques to provide better operating conditions in difficult cases, a reduction in the dosage of other agents employed, and a smoother recovery period.


Hepatitis B antigen, auto-antibodies and liver disease in a haemodialysis and transplantation unit. This study concerns hepatitis B antigen and antibody, (HBAg and HBAb) auto-antibodies and liver disease in a renal haemodialysis and transplantation unit between February, 1970 and December, 1972. Fourteen per cent of patients on maintenance haemodialysis, 25% of renal transplant recipients, and 5% of the staff were HBAg positive during this period. Three family members of antigen positive patients developed hepatitis; all were either antigen or antibody positive. Both immuno-electro-osmo-phoresis and radio-immuno-assay were used to detect HBAg. No additional carriers were identified among the dialysis or transplant patients by applying the more sensitive technique, although two persons with hepatitis were positive only by RIA. None of the staff members who developed antigen positive hepatitis died, and no one became a carrier. Dialysis patients who had icteric hepatis also cleared the antigen from the serum. Clinical hepatitis did not occur in immunosuppressed graft recipients who were carriers of the ay subtype of the antigen, nor was there histological evidence of liver disease in 18 of 19 of such carriers studied. Moreover, there was no association between long term carriage of the antigen and the presence of the auto-antibodies characteristic of chronic active hepatitis. Rapid reduction of immunosuppression was followed by acute hepatitis in one carrier, while another, whose antigen was of the ad subtype, developed micro-nodular cirrhosis.


The surgical management of subphrenic abscess: a historical study. This paper is a study of the evolution of the management of subphrenic abscess from the earliest reports to the present day. Its purpose is to compare and contrast the attitudes and practices established during the earlier years with those of the present, in particular in relation to changes consequent on the introduction of antibiotics.


Experimental gut anastomoses and their revascularization. A study was made of the healing and revascularization of intestinal anastomoses in the small and large intestines of rabbits. Single-layer and double-layer suture, techniques were used and compared, and revascularization of the anastomoses was particularly examined after devascularization of their distal segments. The anastomotic segments were removed at intervals after construction varying from one to six weeks and studied histologically after haemotoxylin and eosin staining, by xylol-clear thick sections and by angiography, a gelatin Micropaque emulsion being used to fill the vascular network. Forty-four rabbit intestinal anastomoses were studied. Inverted intestinal anastomoses took about two weeks to develop continuous mucosa on the luminal side, and were completely healed after six weeks. Revascularization began after eight days with both single-layer and double-layer anastomoses, proceeding from the submucosal and the surrounding muscular layers. The vascular pattern mirrored the healing stage of the anastomosis. Irregular fine vessels crossing the anastomoses were seen in specimens examined at the second week. After three or four weeks, the vascular patterns of the anastomoses showed an irregularity of calibre and direction because of the presence of residual scar tissue, and the mucosal surfaces were covered with regenerating epithelium. Healing and revascularization were complete after six weeks.


Circadian changes in the temperature of human beings. Temperature in man measured or recorded by different means, is not constant but varies in a predictable and rhythmic fashion. Circadian (about 24-hour) rhythms have been demonstrated and studied in healthy men and women as well as in patients under a wide variety of experimental conditions and diseases. With the help of special computer programs (Halberg's cosinor) inferential statistical analyses can be performed. There validate and characterize a biological rhythm (i.e., core temperature) by several parameters: the period (tau) the acrophase (phi) (timing of the peak), the amplitude (A) and the rhythm-adjusted mean (M). Each one of these parameters is given with its confidence limits when the studied rhythm is detectable (p less than 0.05). The human temperature (oral, rectal and skin) circadian rhythm has been validated and quantified in healthy newborns, in healthy adults on various diets (including near-fasting conditions: 220 cal/24h, casein) and various type of activities. Food intake does not appear to influence the temperature circadian rhythm. The rhythm persists with a change of period and/or acrophase during isolation underground, without time dues or clues. Its acrophase can be shifted by manipulating synchronizing factors (i.e., shift-working, transmeridian flight). Alteration of circadian temperature rhythm may result from the timed administration of certain drugs (i.e. reserpine) and from certain chronic diseases (without overt fever). A first attempt to use both thermography and chronobiological method has been made independantly by Gautherie et al [40] and Smolensky [41] in the prediction of therapeutic value of a given modality during the course of breast cancer treatment.


Comparative studies on subacute sclerosing panencephalitis virus and a usual measles virus with special reference to their capacities to produce viral hemagglutinin in Vero cells. Various comparative studies were made on the capacities of a cell-associated subacute sclerosing panencephalitis agent (SSPE agent, Niigata/1 strain) and a usual measles virus (Toyoshima strain) to produce measles virus hemagglutinin (MV-HAnim) in Vero cells. The results obtained by various methods, such as the hemagglutination test (HA), hemadsorption test (HAd), antibody blocking test, antibody inducing test and fluorescent antibody technique (FAT) using monospecific antibody to MV-HAnin, consistently suggested that the SSPE agent was an incomplete measles-like virus having little if any MV-HAnin, but sharing immunologically closely related viral components other than MV-HAnin with those of the usual measles virus. The significance of these findings is discussed with respects to the latency of the SSPE agent.


[The influence on pedicle flap blood supply and necrosis rate of plastic displacement with pentoxifylline and dextran 40]. Using a standardized procedure we have experimented on rats in order to examine the rate of necrosis in pedicle flaps in conjunction with 3,7-dimethyl-1-(5-oxo-hexyl)-xanthine (pentoxifyline, Trental) and dextran 40. Compared with the control group and that treated with dextran 40 the group treated with Trental showed significant decrease in necroses. The influence of drugs on blood supply demonstrated in this srudy as being significant is discussed.


[The effect of oxyfedrine on cardiac performance in coronary patients. Tests using electrocardiographic and metabolic parameters in atrial stimulation]. In 17 patients with coronary heart disease the effects of the beta-active agent L-3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone (oxyfedrine, Ildamen) were proved at rest and during atrial pacing by measurements of coronary venous O2-saturation, myocardial lactate extraction, angina threshold and ST-segment depression. In 88% oxyfedrine had antianginal effectivity with rise in angina threshold (+11%), reduction of ST-segment depression (--48%) and reduction of lactate production(--63%). The rise in coronary venous O2-saturation ("35%) and the electrocardiographic and metabolic reduction of hypoxic reaction indicate the improvement of nutritional coronary flow. Therefore improvement of myocardial O2-balance is derived from the reduced energy requirement by decrease of heart size and ventricular wall tension and the rise of myocardial O2-supply by coronary dilation in spite of the increased energy requirement by ascending contractility. Conclusively the application of oxyfedrine is preferred in coronary heart disease with simultaneous congestive heart failure.


Toxicological and clinical aspects of cyanide metabolism. This contribution deals with the occurrence of cyanide and its biological pathways in the body. Especially possibilities of detoxification are pointed out. Intoxications are caused by acute and chronical cyanide uptake. Tobacco amblyopia, retrobulbar neuritis in pernicious anaemia, Leber's optic atrophy, Nigerian nutritional neuropathy, and sterility in female heavy smokers are attributed to cyanide intoxication. Various methods for treating acute and chronic cyanide intoxication are discussed.


A new isoniazid preparation designed for moderately fast and "fast" metabolizers of the drug. The bioavailability of a new isoniazid preparation consisting of 37% ordinary isoniazid (INH) and 63% matrix component was investigated in 11 slow, 8 moderately fast, and 9 "fast" acetylators of the drug. Initially, a 15 mg/kg dose of normal INH was administered to all the participants. In addition, the two groups of fast metabolizers received 30 and 45 mg INH-matrix/kg, respectively, with a one-week interval between the test doses. These high dosages of the INH-matrix could be given without encountering toxic reactions because of the delayed absorption of the matrix formulation. In moderately fast acetylators, with a triple dose of matrix isoniazid, it was possible to mimic the blood levels produced by 15 mg ordinary INH/kg in slow inactivators. However, in "fast" acetylators the blood concentrations achieved with the 45 mg/kg dose of INH-matrix were somewhat lower. This study also showed that a large input rate is essential to procure the required, high blood levels in fast metabolizers. The therapeutic implications of the results of this bioavailability trial are discussed.


An X-ray study on the acute action of diphenoxylate on the intestinal motility in volunteers. The intestinal inhibitory activity of 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidine-carboxylic acid ethyl ester (diphenoxylate) after a single oral dose of 5 mg was studied in 10 volunteers with X-ray diagnostic methods. The diphenoxylate treatment lengthened the transit time of the barium sulphate to caecum from 3.2 to 4.3 h. The X-ray cinematography showed the slower duodenal emptying in 5/10 of the subjects, but only in 1 of these the velocity of the peristaltic wave was clearly decreased. The results demonstrate directly the acute inhibitory action of diphenoxylate on intestinal motility with the dose used generally 3--4 times daily for the symptomatic treatment of diarrhoea.


A double-blind clinical study on long-term use of oxyphenbutazone and tolfenamic acid in connection with telecobalt therapy. Thirty-one patients who suffered from various cancers in the pelvic region were treated in a double-blind clinical long-term study either with placebo, N-(2-methyl-3-chlorophenyl)-anthranilic acid (tolfenamic acid, Clotam) or oxyphenbutazone in order to diminish the local reactions after telecobalt therapy. The results were difficult to judge and no clear differences were seen between the groups. The side-effects were slight and unspecific, except gastrointestinal distresses, which occurred with both tolfenamic acid and oxyphenbutazone, but were more severe with the latter. No significant changes were seen in the blood counts, liver or kidney function tests with tolfenamic acid. In the oxyphenbutazone group S-ALAT, S-AFOS and direct bilirubin were slightly elevated. Blood in feces was more frequent in the drug-treated than in the placebo group. In the light of the present and earlier studies tolfenamic acid appears to cause less side-effects than oxyphenbutazone in prolonged treatment.


Effect of two weeks' treatment with chlordiazepoxide or flupenthixole, alone or in combination with alcohol, on psychomotor skills related to driving. The effects of two weeks' treatment with chlordiazepoxide 10 mg t.i.d. or flupenthixole 0.5 mg t.i.d. on human psychomotor performance related to driving was examined on 20 healthy male students aged 20 to 23 years. The tests used were a choice reaction, two co-ordination and an attention test having correlation with traffic behaviour. Neither chlordiazepoxide nor flupenthixole impaired psychomotor performance on the 7th or 14th days of the experiment. The combination of either drug with 0.5 g/kg of alcohol impaired co-ordination and attention to an extent which can be considered dangerous for traffic and occupational life. Their interaction with alcohol was not so strong as that between diazepam and alcohol. The combination of chlordiazepoxide with alcohol tended to increase the anxiety of the normal subjects.


[Biochemical action mechanisms and pharmacokinetics of psychoactive drugs]. A short review is given on the effects of antidepressant drugs (tricyclic thymoleptics and MAO inhibitors), neuroleptics and lithium salts on catecholamine and serotonin metabolisms in brain. The second part deals with some pharmacokinetic investigations with these psychotropic drugs. In connection with tricyclic thymoleptics some factors influencing steady-state plasma concentration and their relation to the therapeutic effect are discussed. Furthermore, recent investigations into the pharmacokinetics of lithium salts are dealt with.


[Data acquisition in clinical trials].

[Data acquisition in clinical trials]. Methods of data acquisition in clinical trials are reviewed and their advantages and disadvantages are discussed. To avoid the effort of multiple data acquisition and to eliminate possible transcription errors the data of the patients should be collected and stored in a data bank only once also in case of a drug study. From the data bank the results can be used for the different clinical purposes as well as for the statistical evaluation when testing drugs.


[Comparison of the effects of niflumic acid and aloxiprin in patients with progressive chronic rheumatoid arthritis in a double blind trial]. The effects of niflumic acid (trifluoro-methyl-3-phenylamino-2-nicotinic acid) and of aloxiprin (aluminium acetyl-salicylate) in patients with rheumatoid arthritis were compared in a double-blind cross-over trial. Check-up examinations prior to the institution and after the termination of the therapy, as well as after individual treatment periods of two weeks with alternating sequential administration of the two drugs, were carried out with a standardized method. The assessment included subjective (pain intensity) and objective criteria (Lansbury's index), as well as laboratory results (erythrocyte sedimentation rate, uricaemia). With the exception of the articular index disclosing a superior effect of niflumic acid, the other criteria showed no statistically significant differences between the effects of the two drugs.


[Studies on the influence of pentosanepolysulfate and a combination of pentosanepolysulfate, metamizol and paracetamol on inflammatory liability (author's transl)]. The influence of pentosanepolysulfate (SP 54) and a combination of pentosanepolysulfate, metamizol and paracetamol (Probaphen) on the course of an experimentally induced erythema caused by intracutaneous injection of a lipopolysaccharide from Pseudomonas has been studied in man. The intramuscular injection of Probaphen as well as SP 54, separately given, showed a significant antiinflammatory effect. A similar effect was also achieved after administration of Probaphen suppositories. Probaphen shortened the inflammatory reaction more effectively than did SP 54 alone. The oral application of Probaphen, however, did not influence the course of inflammation.


[Comparative studies on wholebody retention of iron(II)-sulfate and a combination of iron(II)-sulfate and DL-serine]. The wholebody retention of an 59iron-sulphate-DL-serin combination (group B) was compared to that of 59iron-sulphate in healthy female volunteers. Mean 59Fe-retention of group B(n = 9) was found to be 40% higher than that of group A(n = 10); however, this difference was mathematically statistically not significant--especially because of the high standard deviation of group B.


Are hormones psychoactive? Evoked potential investigations in man. The somatosensory evoked potential (SEP) of physically and mentally healthy male subjects was recorded before as well as 4 hours after administration of one single dose of placebo, cyproterone acetate (an antiandrogen), and mesterolone (an androgen). Quantitative evaluation of drug-induced changes in SEP latencies and amplitudes, which, when plotted in terms of t-values, result in the so-called "SEP profiles", did not demonstrate any significant alterations after placebo. Contrary to this, cyproterone acetate induced systematic and significant changes characterized by a latency increase in the early peaks and latency decrease in the late peaks of the SEP. Apart from the non-significant amplitude changes, such alterations were previously described by us as typical for drugs of the anxiolytic class. Mesterolone on the other hand, produced a significant latency decrease in the early part and a latency increase in the late part of the evoked response which was found to be typical for the SEP profiles of tricyclic antidepressants. The amplitude did not show any systematic changes. Based on step-wise discriminant analysis of these data we could significantly differentiate both hormones from placebo as well as from each other. A comparative analysis of low and high doses did not yield any significant differences between the two levels. It was concluded that both test substances have psychoactive properties; whereas cyproterone acetate reveals anxiolytic qualities, mesterolone exhibits antidepressant ones. These findings are discussed from the clinical as well as from the neurophysiological point of view.


New approaches to the classification of the lymphomata. Our recently proposed functional approach to and classification of the malignant lymphomata based upon the T and B cell systems, lymphocyte transformation and their development as blocks or a "switch on" in lymphocyte transformation has been reviewed. This functional classification contains 5 major groups: (a) U cell or undefined for those proliferations without specific markers; (b) T cell; (c) B cell; (d) histiocytes as macrophages; (e) unclassifiable for those technically insufficient for specific cytological classification. Retrospective study of several case populations indicates that the majority of non-Hodgkin's lymphomata exhibit features of follicular centre cell (FCC) lymphomata of either cleaved or non-cleaved types. The prognostically favourable status of nodular lymphomata seems to result from the retained capability of follicle formation by FCC types with limited abnormality. Lymphomata of large cell types previously classified as histiocytic lymphoma or reticulum cell sarcoma predominantly resemble transformed lymphocytes and rarely exhibit features of histiocytes as macrophages. They are designated "immunoblastic sarcoma" when they occur as large transformed lymphocytes and may have either T or B cell immunological markers. Immunoblastic sarcoma has been observed to develop in individuals with chronic abnormal immune states, Sjögren's syndrome, alpha chain disease, in patients on immunosuppression therapy for graft rejection and in senescence. There is accumulating evidence of lymphomata of T cells but none are firmly established. These include Sézary's syndrome, mycosis fungoides and the convoluted lymphocyte type, prev-ously included designated as acute lymphocytic leukaemia with mediatinal mass. The results of initial functional studies provide support for the proposed classification and indicate that the modern pathological investigative approach requires the collection of fresh lymphomatous tissue and an integrated immunocytochemical and morphological approach for the precise characterization of human lymphoma cell types.


Antigenic analysis of the lymphomata.

Antigenic analysis of the lymphomata. Soluble protein extracts of non-Hodgkin's lymphomata are fractionated by Sepharose chromatography. Each protein segregate is tested as a target antigen in immunoelectrophoresis using antiserum prepared by immunization with each fraction and an F and S antiserum of Hodgkin's tumour. F and S antigens are prominent in a histiocytic lymphoma with lymphoid infiltrate and Hodgkin's disease. A monospecific F antiserum is used to determine the stromal distribution of the antigen by immunofluorescence in tumour infiltrates and also to demonstrate F antigen activity in the medulla of the adolescent thymus. Implications of these findings are discussed and a general plan for analysis of the lymphomata outlined.


Kinetic studies of circulating lymphocytes in malignant lymphatic disease using the impulse cytophotometer. Measurements of the DNA content of mononuclear cells in the blood of patients with malignant lymphatic disease were made. In one case of acute lymphoblastic leukaemia, a large fraction of large type of blasts were in S phase. In the blood of a patient with leukaemic transformation of lymphosarcoma, a population of aneuploid tumour cells with a high percentage of cells in S phase was recognized. The increase of DNA synthesizing cells in the blood of patients with malignant lymphoma was associated with activity of the disease. The fraction of DNA synthesizing cells was raised sharply during chemotherapy.


Non-Hodgkin's lymphomata: clinical and immunological data in relation to histology. Two hundred and forty-four previously untreated patients seen since 1964 in the department of haematology at Saint-Louis hospital were analysed. Clinical data included results of initial work-up and prognosis evaluated by survival rate matched with principal variables: age, sex, histopathology, staging, incidence of clinical and biological systemic symptoms. Immunological data included results of systematic studies made in each category of non-Hodgkin's lymphomata. Hyperbasophilic lymphoma, a special group recently characterized, is discussed.


Non-Hodgkin's lymphomata: clinical features in relation to histology. An analysis is given of the clinico-pathological correlations of non-Hodgkin's lymphomata in 332 patients referred to the Netherlands Cancer Institute in Amsterdam and the Rotterdam Radiotherapy Institute. Clinical staging proved to be an important prognostic index. In Stage I the 5 year survival was 55%, in Stage II 25% and in Stages III and IV less than 10%. The presence of follicular structures in non-Hodgkin's lymphomata has similarly an important prognostic significance especially in Stage I and II. In lymphocytic lymphomata a larger cell size is correlated with less favourable prognosis. The presence of macrophages in non-Hodgkin's lymphomata is found in patients with short survival. The histiocytic lymphomata have a different survival pattern from the lymphocytic lymphomata in Stages I and II.


A clinicopathological study of stages I and II non-Hodgkin's lymphomata using the Lukes-Collins classification. A series of 226 patients with Stages I and II non-Hodgkin's lymphomata, treated with intensive irradiation to the involved regions, were studied using the Lukes-Collins classification. A statistically significant difference was found in the length of survival of patients with the follicular and the diffuse types of lymphoma. A difference in survival was also observed among those with the 3 subtypes of follicular lymphomata. The extent to which the follicular pattern could be recognized and whether or not lymphoma cells were confined to the follicular structures likewise had a bearing upon the survival of patients with follicular lymphomata. In this series, no significant difference in survival was found between the histological types of diffuse lymphoma. The relationship of the methods of staging to survival in this series, and the findings at staging laparotomy in other series suggest that the lymphangiogram is less valuable for detecting intra-abdominal disease in the non-Hodgkin's lymphomata than in Hodgkin's disease, probably because of the high incidence of involvement of mesenteric lymph nodes in the non-Hodgkin's lymphomata.


Staging laparotomy in non-Hodgkin's lymphoma. In 57 patients with non-Hodgkin's lymphoma, a clinical, radiographic, scintigraphic and pathological correlative study showed the following results: (1) the inferior venacavagram, lymphangiogram and gallium-67 scan have a low sensitivity in detecting lymphoma: their accuracy is high when the findings are interpreted as abnormal (93%, 83% and 80% respectively), but low when they are interpreted as normal (47%, 67% and 58% respectively); (2) the clinical evaluation of spleen and liver is unreliable; (3) the incidence of lymphocytic lymphoma in the para-aortic-iliac nodes is high; (4) a pattern of involvement by contiguity and a predilection for the spleen were observed in lymphocytic lymphoma; (5) in lymphocytic lymphoma there is no liver involve without concomitant splenic involvement; (6) no definite pattern of spread could be seen in histiocytic lymphoma; (7) surgical staging changed the classification of the lymphoma in 56% of cases, 46% being reclassified to a more advanced stage; (8) surgical staging significantly improves the assessment of the stage of disease and therefore permits accurate treatment planning.


Staging laparotomy in non-Hodgkin's lymphomata. Staging laparotomy was performed in 106 selected untreated adults and in 6 children. In adults the histological pattern at initial biopsy was interpreted as nodular lymphoma in 33% and as diffuse lymphoma in 67%. Diffuse histiocytic was the most frequently observed histological subtype in the present series (54%). Diffuse undifferentiated lymphoma was noted in 2/6 children. Waldeyer's ring involvement was noted in 27% of adult patients. Systemic symptoms were present in 7%. Surgery detected occult lesions in 27% of patients (para-aortic nodes 3%, spleen 12%, liver 12%, coeliac nodes 15%, splenic hilar nodes 26%, mesenteric nodes 15%, gastrointestinal tract 1%, bone marrow 12%). The chance of detecting splenic and hepatic involvement was definitely higher in patients with nodal disease above and below the diaphragm in comparison with those with either supra-diaphragmatic or infra-diaphragmatic adenopathy. Lymphography yielded a 96% accuracy proving once more to be a sufficiently reliable diagnostic method. Staging laparotomy is a useful procedure in non-Hodgkin's lymphomata in order to gain information on the natural history and to plan treatment. It remains to be determined whether findings observed through surgical staging will lead to improved treatment and survival.


Spread according to histology in non-Hodgkin's lymphomata. The spread of non-Hodgkin's lymphomata was investigated in a group of 323 cases. Differences were sought between 4 histological groups: lymphocytic vs histiocytic lymphomata and diffuse vs follicular types. Histiocytic and follicular types were rare in childhood. Histiocytic lymphomata, compared with lymphocytic ones, were more often confined to sites above the diaphragm. They exhibited a higher rate of loco-regional recurrences within the first 3 months and also of late recurrence after 4 years. Lymphocytic lymphomata of the follicular type more commonly presented with nodal involvement below the diaphragm as primary or secondary site than the diffuse form. Follicular types of lymphoma compared with diffuse types, occurred more frequently in women. They were more seldom seen as primary or secondary sites in extranodal localizations. They had a smaller chance of late disease recurrence and were associated with a longer survival time after first recurrence. The mediastinum often remained clinically uninvolved. With regard to this mediastinal "skip" no differences were found between the histological groups.


The natural history of non-Hodgkin's lymphomata stages I and II. Progress in the management of non-Hodgkin's lymphomata has been impeded by lack of information on the natural history of these diseases. Confusion about the significance of histopathology, extranodal presentations and routes of spread renders much of previously published data relatively uninterpretable. To evaluate the relative prognostic significance of presentation, histopathology and lymphography, a retrospective study was undertaken on 226 patients with Stage I and II disease, who were treated with intensive irradiation to the involve regions. The slides on these patients were reviewed and reclassified in terms of the Rappaport system. The results of this study demonstrated that a nodular histopathological pattern was the most important prognostic factor. The significance of this finding and other factors are discussed in terms of possible new approaches to treatment.


Non-Hodgkin's lymphoma in children.

Non-Hodgkin's lymphoma in children. The clinical and pathological features of 64 children with non-Hodgkin's malignant lymphoma seen between April 1962 and June 1973 are described. Forty-one children had diffuse, undifferentiated, non-Burkitt lymphoma (lymphoblastic lymphoma). They tended to be boys under 10 years of age and their median survival was 1 year. Almost one-third are surviving for 1-11 years, most in initial complete remission. Nineteen children had diffuse, poorly differentiated, histiocytic lymphoma. They tended to be boys more than 10 years of age, their median survival was only 6 months, and only the 3 patients with Stage I peripheral node tumour survived. Two children had nodular, lymphocytic, poorly differentiated lymphoma and 2 had lymphoma resembling the Burkitt type. From our clinical and pathological observations, we conclude that non-Hodgkin's malignant lymphomata in children cannot be separated from the acute lymphocytic, histiocytic and unclassified leukaemias by cytological or histological methods. What is called diffuse, undifferentiated, non-Burkitt type, or lymphoblastic lymphoma is actually acute lymphocytic leukaemia without apparent invasion of marrow and peripheral blood by neoplastic lymphocytes at time of diagnosis. What is termed diffuse, histiocytic lymphoma is acute histiocytic leukaemia without apparent infiltration of marrow and peripheral blood at initial presentation. One could say just as well that acute lymphocytic leukaemia is Stage IV lymphoblastic lymphoma and that acute histiocytic leukaemia is Stage IV histiocytic lymphoma. Further classification of lymphocytic and histiocytic cancers by newer functional, chemical and morphological methods should include both what is called lymphocytic or histiocytic leukaemia and what is called non-Hodgkin's lymphoma as one group of diseases, susceptible to subclassification by the new methods. We recommend that Stage I lymphocytic and histiocytic cancers be treated with local irradiation. Patients with Stages II-IV tumours should receive anti-leukaemic forms of therapy including prolonged multiple agent chemotherapy and preventive central nervous system irradiation. Staging laparotomy should be considered in patients with Stage I tumour in low cervical, axillary and inguinal nodes.


A clinico-pathological study of non-Hodgkin's lymphomata in childhood. In a series of 27 children with non-Hodgkin's lymphomata during a 29-year period there were 21 boys and 6 girls. Thirteen had lymphocytic lymphoma, 9 histiocytic and 5 lymphoma with a prominent starry-sky appearance. All but one had diffuse lymphoma and no case of mixed cell type lymphoma was seen. Patients with lymphocytic lymphoma had extralymphatic manifestations more often than patients with the other types, and leukaemic transformation, which was seen in 6 patients, was especially common in lymphocytic lymphoma. Patients with Burkitt-type tumours did not respond well to radiation therapy with conventional fractionation. The survival in the present series was very poor, only 3 out of 27 children still being alive. A more aggressive therapeutic approach, guided by a differentiated microscopic classification and appropriate staging procedures, may be expected to give better results.


Prognostic significance of primary site after radiotherapy in non-Hodgkin's lymphomata. In contrast to Hodgkin's lymphomata, non-Hodgkin's lymphomata originate in approximately a fourth of the cases in extranodal organs and sites. The prognosis of patients with primary extranodal organ involvement of the non-Hodgkin's lymphomata is similar to that of patients with primary lumph node involvement of the Hodgkin's and non-Hodgkin's lymphomata, dependent on the special spreading of the disease corresponding to the 4 stages of the Ann Arbor classification. This applies to the primary involvement of a single lymph node region (Stage I) or a single extralymphatic organ or site (stage IE) as well as to further stages of spreading within the lymphatic system (Stages II and III) including secondary localized involvement of an extralymphatic organ and site (Stages IIE and IIIE). The same qualitative dependence of the prognosis of Hodgkin's and non-Hodgkin's lymphomata on the spatial spreading, corresponding to the Ann Arbor concept, legitimizes, in spite of some quantitative differences, the application of the Ann Arbor classification system to all malignant lymphomata.