Fractures of the tibial shaft treated in a patellar-tendon-bearing cast. A retrospective review of fractures of the tibial shaft treated in patellar-tendon bearing (PTB) casts shows that a high rate of union, in respect of both time required and numbers, and a low morbidity can be expected. The method is easy to apply. In those patients who had the casts applied early, once swelling had settled down, the fractures united more quickly.


Recent trends in traffic injury.

Recent trends in traffic injury. Data in the Registrar-General's statistical reviews for 1958-75 and in the reports of the Hospital In-Patient Enquiry for 1964-73 have been examined to ascertain the light they shed on the changes in the patterns of injury from road accidents over this period. Causes of death, primary injury for hospital inpatients and average length of hospital stay have been examined. It seems that an increasing proportion of deaths are being ascribed to internal injuries and a decreasing proportion to fracture of the skull.


The operative treatment of sacro-iliac subluxation and disruption of the symphysis pubis. A method of internal fixation of the disrupted symphysis publis is discribed which uses readily available AO plates and tools. Patients can be mobilized at 3 days and discharged within 2 weeks. This method of treatment represents a considerable saving in nursing time and a great improvement for the patient, who is usually free from pain after 1 week.


External fixation of double vertical pelvic fractures with a trapezoid compression frame. Seventeen patients with double vertical fractures of the pelvic girdle were treated by early reduction and subsequent fixation of the pelvic ring with a trapezoid frame. This provided firm fixation of the fractured pelvis. With the frame attached, patients without associated injuries were allowed out of bed within 3 weeks and in every case the frame was removed 6 weeks after its application. External fixation of the pelvic fracture afforded relief from pain and greatly facilitated nursing. At follow-up, all the fractures had united in the position secured initially by the frame and no patient complained of pain in the sacro-iliac joints.


Skateboard injuries: a new epidemic.

Skateboard injuries: a new epidemic. Forty-six injuries caused by skateboards were seen in 3 months; these were predominantly fractures and sprains of the distal part of the limb caused by indirect violence. These injuries are likely to become common. They occur most frequently when the skateboard hits a stone or other irregularity on the surface used.


Head injuries in accident and emergency departments at Scottish hospitals. The features of 3500 patients with head injury who attended accident and emergency departments in Scotland during 1974 are described. These represented 10 per cent of all attenders at these departments. Recent alcohol consumption was noted in 25 per cent of adult males; this was commonest amongst those who were victims of assault or pedestrians involved in traffic accidents. Forty-one per cent of patients had scalp wounds; 58 per cent had radiographs of the skull taken and of these 2.7 per cent had fractures of the skull. Although 20 per cent of patients had altered consciousness at some time, only 5 per cent showed any evidence of impaired consciousness when seen at hospital. Twenty-three per cent of those attending were admitted to hospital. Criteria which are important when assessing whether a head-injured patient should be admitted to hospital are listed.


Thoracoabdominal trauma in ski accidents. Higher speed in ski sports has in recent years increased the number of thoracoabdominal injuries. Our restrospective study concerns 30 patients from the region of Chur, Switzerland, injured between 1965 and 1976. The patients were all male with an average age of 26 years. Details of the injuries, operations and treatment are given and a few typical cases are demonstrated.


The treatment of non-union and pseudarthrosis of the long bones with thick nails. This paper is based on Küntscher's method of operative treatment of the long bones(Küntscher, 1962) and is a review of 197 cases of non-union and pseudarthrosis of long bones fixed internally with thick metal nails after preliminary reaming of the medullary canal. New reamers and a new nail have been designed and the results are satisfactory. The rigid fixation of the fragments allowed early movement of the limb and so avoided the complications of prolonged immobilization. Anabolic steroids were administered as a routine to this group of patients. Weight bearing and full function of the limb were regained within 3-5 months of the operation. Poor results occurred in 6 cases (3.2 per cent) due to exacerbation of chronic osteomyelitis.


Problems and pitfalls of compression fixation of long bone fractures: a review of results and complications. The complications encountered in the compression fixation of 70 cortical long bone fractures are reviewed. The results represent the initial experience with the AO fixation equipment following its introduction to a centre with staff relatively untrained in the technique. Infection was the most serious complication, with a deep sepsis rate of 10.5 per cent, but fixation failure, delayed union and refracture also occurred. The various problems are discussed in detail and suggestions are made as to how they can be avoided.


Purification of lipoteichoic acids by using phosphatidyl choline vesicles. Lipoteichoic acid (LTA) is a component of nearly all gram-positive membranes and recently has been found to be excreted into growth media by certain lactic acid bacteria. Cell-free extracts of LTA are usually contaminated with proteins, polysaccharides, and nucleic acids, thus causing problems to investigators studying the true biological function(s) of LTA. This report describes the preparation of purified extracellular LTA of Streptococcus mutans BHT and intracellular LTA of S. mutans AHT by three techniques: gel filtration, hydrophobic interaction chromatography, and adsorption to phospholipid vesicles. Gel filtration, the most commonly employed method for LTA purification, was found to remove nucleic acids, teichoic acids, and much polysaccharide while greatly concentrating LTA. But gross amounts of antigenic carbohydrate and protein remained associated with the LTA preparation. Hydrophobic interaction chromatography employing octyl Sepharose-4B allowed the separation of protein but not polysaccharide from partially purified BHT LTA preparations. By means of a new technique described in this paper, synthetic membranes (vesicles) were found to effectively separate all contaminants from the intracellular (AHT) and extracellular (BHT) LTA of S. mutans. This rapid method, on a comparative basis, proved to be the most effective approach for the purification of LTA from two widely differing sources.


Experimental infection with Treponema hyodysenteriae in guinea pigs. Outbred and inbred (Hartley strain) guinea pigs (GP) were inoculated intragastrically with pathogenic and nonpathogenic Treponema hyodysenteriae. GP 3 to 16 weeks old received T. hyodysenteriae after a fasting period of 36 to 72 h. Infected GP with pathogenic T. hyodysenteriae developed a diarrheal and/or depressive condition, with mucus but not blood in the feces. Of 88 GP, 40 had gross lesions resembling those of swine dysentery. Lesions were limited mainly to the large intestine. TP used as controls or inoculated with nonpathogenic T. hyodysenteriae did not develop these lesions in the large intestine. These studies suggest that the GP may be used as an animal model for swine dysentery.


Isolation and phenotypic characterization of virulence-deficient mutants of Vibrio cholerae. Mutants of Vibrio cholerae was isolated on the basis of reduced ability to induce diarrhea in orally challenged infant mice. Nitrosoguanidine-treated clones were screened for low fluid accumulation ratios in individual mice, and presumptive mutants were confirmed in additional mouse tests. Mutants were examined for alterations in phage type, motility, toxin production, proteolytic activity, neuraminidase production, amylase production, morphology, growth requirements, carbohydrate fermentations, in vitro growth patterns, and cell surface alterations. The types of mutants found included several with previously recognized virulence-associated markers (rough, nonmotile, toxin deficient, protease deficient); several types with pleiotropic alterations (cell morphology, decreased extracellular products); and several with no previously recognized virulence-deficient phenotype (purine requiring, cell surface altered, rapid death in vitro, no defect found). Dose-response kinetics showed that most mutants could provoke diarrhea if given in 100-fold greater numbers than the dose used for screening. Recovery of viable organisms from the gut late in infection showed reduction of survival and/or multiplication capacity for the mutants, with variation in the degree of reduction for the different classes.


Demonstration of eosinophil degranulation on the surface of opsonized schistosomules by phase-contrast cinemicrography. Phase-contrast cinephotomicrography was used to examine eosinophil-schistosomule interaction. Eosinophil degranulation against the surface of schistosomules was observed in the presence of immune serum.


Effect of specific antibody and complement on the survival of Rochalimaea quintana in vitro. No bactericidal effect was produced when Rochalimaea quintana was exposed for 1 h to a combination of high-titered anti-R. quintana rabbit serum and guinea pig complement.


Effect of immunization on susceptibility to experimental Streptococcus mutans and Streptococcus sanguis endocarditis. It has been asserted that humoral immunity is an important potentiating factor in pathogenesis of infective endocarditis, in that prior immunization to certain bacteria may predispose the host to endocarditis caused by those organisms. If so, possible future vaccination of humans with streptococcal antigens for the prevention of dental caries might increase the susceptibility of the population to streptococcal endocarditis. To examine this hypothesis further, we immunized rabbits with killed Streptococcus sanguis or Streptococcus mutans. After complement-fixing antibody had developed, the rabbits were tested for susceptibility to experimental infective endocarditis. Rabbits with high titers of complement-fixing antibody to the infecting organism developed streptococcal endocarditis less often (13%) than animals with lower titers (69%; P less than 0.0002). These findings do not support the hypothesis that pre-immunization predisposes to infective endocarditis and lend no credence to the concept that vaccination of human subjects against dental caries might increase their susceptibility to streptococcal endocarditis. On the contrary, the results of these experiments indicate that specific antibody can confer relative immunity to infective endocarditis.


Age-dependent variations in polymorphonuclear leukocyte chemiluminescence. Polymorphonuclear leukocytes from 46 adults (age 18 to 35), 19 adults (age 70 to 91), 10 children (age 1 to 3), and 22 neonates (cord blood samples) were tested for their chemiluminescence response to opsonized zymosan. Results indicated that both cord blood leukocytes and those from individuals over 70 were significantly lower (P less than 0.05) in their chemiluminescence response. Furthermore, when the latter group was divided into two subsets, one containing subjects over 80 years of age and the other containing subjects between 70 and 80 years of age, those over 80 showed a chemiluminescence response significantly lower (P less than 0.05) than those between 70 and 80. The kinetics of the chemiluminescence response was similar with all samples except the neonatal cells, where the response appeared to peak and subside more slowly. These data demonstrate that polymorphonuclear leukocyte chemiluminescence is depressed in the very young and the very old.


Biological effects of staphylococcal enterotoxin A on human peripheral lymphocytes. The mitogenicity, ability to induce immune interferon, and relationship between interferon synthesis and cell proliferative response were studied using human peripheral lymphocytes stimulated by staphylococcal enterotoxin A (SEA), phytohemagglutinin-P (PHA-P), and concanavalin A (ConA). Maximum cell proliferative responses ([(3)H]thymidine incorporation) and protein synthesis ((14)C-amino acid incorporation) occurred on days 3 and 4, respectively, after stimulation by each of the three mitogens. Maximal immune interferon levels were found 3 or 4 days after mitogen stimulation. SEA-treated cultures produced approximately three times more interferon than did cultures stimulated with PHA-P or ConA. Furthermore, SEA stimulated maximal cell proliferation over a much broader concentration range than did PHA-P and ConA (SEA, 10(-5) to 10(2) mug/ml; PHA-P, 10(1) to 10(2) mug/ml; ConA, 10(1) to 10(1.5) mug/ml). Interferon was also produced at maximal or near maximal levels over a broad concentration range of SEA (10(-2) to 10(2) mug/ml). Also, we found that inhibition of mitogen-induced DNA and protein synthesis to control levels by mitomycin C or cytosine arabinoside partially reduced interferon production. The DNA inhibitor studies indicate that immune interferon synthesis occurs maximally in association with at least some proliferative response and that submaximal levels of interferon production occur in mitogen-treated cultures in the absence of detectable proliferation. The ability of SEA to stimulate maximal DNA and immune interferon synthesis at concentrations of 3.5 x 10(-13) M and 3.5 x 10(-10) M, respectively, puts it in a potency range similar to that of hormones. Thus, SEA may play an important role in gut immunity and Staphylococcus aureus infections at concentrations well below those required for emetic effects.


Experimental Q fever infection in congenitally athymic nude mice. Congenitally athymic nude (nu/nu) mice and their phenotypically normal (nu/+) euthymic littermates were exposed to Coxiella burnetii administered as small-particle aerosols. After challenge, both strains of mice became infected, as characterized by rickettsemia, viable rickettsiae in the spleen, and serological conversion. The major difference noted was that euthymic animals had cleared rickettsiae from peripheral circulation and the spleen within 14 days. In contrast, rickettsiae were detected and isolated from spleen and blood of athymic mice through 60 days.


Increased resistance to streptolysin O in mammalian cells treated with oxygenated derivatives of cholesterol. L-cell fibroblast cultures were treated with certain oxygenated derivatives of cholesterol which are known to inhibit cholesterol biosynthesis in mammalian cells. After incubation in the presence of 20-alpha-hydroxycholesterol or 25-hydroxycholesterol for 18 h, the cells became increasingly resistant to streptolysin O. Maximum resistance to toxin was obtained by incubation for 48 h in 0.5 microgram of 20-alpha-hydroxycholesterol or 0.25 microgram of 25-hydroxycholesterol per ml; under these conditions, the cells were 10 to 50 times more resistant than were untreated controls. The ability of the hydroxycholesterol compounds to render the cells resistant was related to the age of the cultures. Maximum protection was found when more sparsely populated cultures were treated with 25-hydroxycholesterol. Older, heavily populated cultures could not be protected even with the high concentrations of 25-hydroxycholesterol. In contrast to control cultures, most of the toxin activity remained in the medium after being incubated with hydroxycholesterol-treated cultures. The results indicate that less toxin binds to the resistant cells and suggest that a reduction in membrane cholesterol content may account for resistance to streptolysin O.


Comparative study of American cutaneous leishmaniasis and diffuse cutaneous leishmaniasis in two strains of inbred mice. Two Leishmania strains, AZV (isolated from a typical case of American cutaneous leishmaniasis) and AMP (from a case of diffuse cutaneous leishmaniasis), were studied in C57BL/6 and BALB/c mice. After infection with 10(4) amastigotes of either strain, C57BL/6 mice developed self-resolving lesions lasting 20 to 23 weeks and showed both delayed hypersensitivity response to leishmanial antigen and specific agglutinating antibodies. On the other hand, BALB/c mice infected with 10(4) AZV or AMP amastigotes developed chronic, large, ulcerated lesions and showed impaired cellular and humoral responses to the parasite. When BALB/c and C57BL/6 mice received 10(2) AMP amastigotes, patterns of infection were similar to those observed after inoculation of 10(4) amastigotes. In vitro studies revealed that spleen cells from AZV- or AMP-infected C57BL/6 mice showed an increased DNA-synthetic response to leishmanial antigen, concanavalin A, and phytohemagglutinin. Spleen cells from AZV- or AMP-infected BALB/c mice showed an increased response to concanavalin A and diminished responses to leishmanial antigen, phytohemagglutinin, and lipopolysaccharide.


Prophylaxis of Bordetella bronchiseptica infection in guinea pigs by intranasal vaccination with live strain ts-S34. The temperature-sensitive mutant strain, ts-S34, of Bordetella bronchiseptica, which cannot grow at or above the temperature 34 degrees C, has been studied in guinea pigs. The strain grew to moderate numbers in the nasal turbinates but did not grow in the lungs. Guinea pigs given strain ts-S34 developed moderate levels of serum antibody. This strain also induced very high resistance to subsequent intranasal challenge with 4,000X the 50% lethal dose of virulent strain S1 of B. bronchiseptica. In these studies, it appeared that the ts-S34 strain had favorable properties for potential use as a live attenuated vaccine.


Formation of antibody to matrix protein in experimental human influenza A virus infections. Antibodies to type A influenza virus matrix protein (M) were assayed by single radial diffusion in 180 paired sera of volunteers challenged intranasally with live H3N2 viruses of varying degrees of virulence. Of these volunteers 20 had had severe clinical reactions (influenza-like); there had been 19 moderate reactions (lesser degrees of constitutional illness), and the remaining 141 reactions had been graded mild, very mild, or nil. Only 2 volunteers were shown to have antibodies to M in the pre-trial serum samples, and 11 developed anti-M rises after virus inoculation. Nine of the 11 had had severe reactions, and 2 had had moderate reactions. There was, therefore, a clear correlation between severity of clinical illness and anti-M antibody formation. In general, anti-M increases coincided with increases to the hemagglutinins and nucleoprotein, and with virus shedding. However, no anti-M antibody could be demonstrated in paired sera of 18 additional volunteers of whom 12 had developed severe reactions after the inoculation of virulent H0N1 and H1N1 influenza A viruses and of whom 12 had shown laboratory evidence of infection.


Prevalence of enterotoxigenicity in human and nonhuman isolates of Yersinia enterocolitica. A total of 414 cultures of Yersinia enterocolitica isolated from human and nonhuman sources were examined for heat-stable enterotoxin (ST) production to determine whether enterotoxigenicity was related to the source of isolation, serotype, or biochemical characteristics of the organism. A total of 65% of all cultures were found to produce ST. Enterotoxin production was much more prevalent in strains isolated from humans (218/232) than in those isolated from animals (17/34), water (9/49), raw milk (14/44), and food (10/55). Strains belonging to the serotypes O:3; 8; 5,27; 6,30; 9, often isolated from human infections, were almost always enterotoxigenic (191/196), although ST production was also highly prevalent among a few other serotypes. The most significant difference was observed between the groups that differed in the ability to ferment rhamnose; only 13 of 130 rhamnose-positive isolates produced ST (10%) compared to 255 of 284 rhamnose-negative cultures (90%). These results suggest that ST production is ubiquitous in Y. enterocolitica, with the highest prevalence among strains associated with human infections.


Growth of Trypanosoma musculi in cultures of murine spleen cells and analysis of the requirement for supportive spleen cells. Growth of Trypanosoma musculi in vitro has been achieved. The number of parasites increased by more than 1,500-fold in less than 8 days under the most suitable conditions. The rate and magnitude of growth was comparable to that which occurs in inoculated murine hosts. Maximum growth was displayed in cultures composed of RPMI 1640 medium supplemented with fetal calf serum, murine spleen cells, and foreign erythrocytes (sheep). No growth occurred in the absence of spleen cells. The adherent, macrophage-rich population supported parasite growth much better than did the nonadherent population. Parasite growth was excellent in the presence of irradiated spleen cells or of cells from thymectomized, irradiated, bone marrow-reconstituted mice. The important cells appeared to be macrophages. The beneficial effect of sheep erythrocytes probably resulted from preoccupation or stimulation of phagocytes. Soluble substances released by spleen cell cultures promote parasite growth, as was shown by experiments with double-compartment culture vessels. The utility of this culture system for analysis of host immune responses against the trypanosome was demonstrated.


Immunodepression in Taenia crassiceps infection: restoration of the in vitro response to sheep erythrocytes by activated peritoneal cells. The in vitro response to sheep erythrocytes of mesenteric lymph node cells from mice infected with the larval cestode Taenia crassiceps is significantly depressed and can be restored to control levels by addition of activated peritoneal cells depleted of functional T or B lymphocytes. Adherent mesenteric lymph node cells from infected mice are unable to reconstitute the in vitro response to sheep erythrocytes of normal nonadherent cells. The responses of mesenteric lymph node cells from infected mice to the T-lymphocyte mitogens concanavalin A and phytohemagglutinin and the B-lymphocyte mitogen lipopolysaccharide are normal. Mesenteric lymph node cells from infected mice do not suppress the in vitro response to sheep erythrocytes of normal mesenteric lymph node cells. These results suggest that the immunodepression in T. crassiceps-infected mice is primarily the result of alterations in functional accessory cells.


Influence of cadmium on the phagocytic and microbicidal activity of murine peritoneal macrophages, pulmonary alveolar macrophages, and polymorphonuclear neutrophils. A significant depression in the phagocytic capacity of elicited peritoneal macrophages, pulmonary alveolar macrophages, and elicited peritoneal polymorphonucleated neutrophils was manifested when the cells were incubated in medium containing cadmium chloride. With the exception of the neutrophils, a similar influence was observed when the cells were exposed to cadmium acetate. The impaired phagocytic capacity was related to the concentration of the cadmium in the medium. Peritoneal macrophages and neutrophils did not demonstrate any alteration in their microbicidal activity (percentage of ingested yeast which were killed) in the presence of the cadmium salts. However, a significant suppression in the intracellular microbicidal activity of alveolar macrophages was observed when the cells were incubated in medium containing either cadmium chloride or cadmium acetate. This unique response to Cd2+ may be related to general metabolic characteristics of these cells living at an elevated O2 tension.


Role of motility in experimental cholera in adult rabbits. The role of motility in the pathogenesis of cholera was evaluated in ligated ileal loops of adult rabbits. Four strains of Vibrio cholerae (including both Inaba and Ogawa serotypes of both classical and El Tor biotypes) were compared with their aflagellated, but fully toxigenic and prototrophic, isogenic derivatives as to their ability to produce fluid accumulation in the rabbit gut. The nonmotile mutants required an at least 100-fold-higher dose than their respective wild-type strains to produce comparable fluid accumulation responses. The decreased ability of nonmotile strains to produce a fluid response was not due to their failure to multiply in vivo, since they increased in numbers in the rabbit ileum at the same rate as the wild-type strains, but probably was related to their inability to associate with the intestinal mucosa. After 3 h of incubation, 45 to 53% of motile, [35S]-labeled cells adsorbed to the intestinal wall, whereas only 3 to 15% (depending upon the strain) of the nonmotile bacteria were associated.


Suppression of cellular immune responses in guinea pigs infected with spotted fever group rickettsiae. Using a guinea pig model, we demonstrated that infections with pathogenic species of spotted fever group rickettsiae transiently and nonspecifically suppress established cellular immune responses as measured by in vitro lymphocyte transformation and in vivo delayed cutaneous hypersensitivity responses to unrelated, nonrickettsial antigens. The correlation of the duration of this immunosuppression with the virulence of the infecting rickettsial species suggests that this suppression is a pathological effect of the rickettsial infection. Although we did not specifically study the mechanism of this suppression, it is not associated with either lymphocytopenia or leukocytosis.


Neutralization of Clostridium difficile toxin by Clostridium sordellii antitoxins. Neutralization of Clostridium difficile toxin by Clostridium sordellii antitoxin was studied by cytotoxicity assay in tissue culture. The sources of toxin were stools from two patients with pseudomembranous colitis and a culture filtrate of C. difficile isolated from one of the patients. C. sordellii antitoxin was available either in monovalent form or as gas gangrene polyvalent antitoxin. The potency of antitoxins against C. difficile determined by cytotoxicity assay did not correlate with the established values reported for mouse protection tests against C. sordellii toxin. An equivalent zone of optimal neutralization was demonstrated for stool toxin, and a slightly different one for culture toxin. The rate of neutralization appeared to be instantaneous, either at 24 or at 37 degrees C. The efficacy of antitoxin in preventing cytotoxicity in cultured cells preexposed to toxin decreased rapidly with preexposure time. The union between toxin and antitoxin could be readily dissociated by simple dilution or by ammonium sulfate precipitation followed by dissociated by simple dilution or by ammonium sulfate precipitation followed by dilution. Continued incubation of toxin-antitoxin mixture did not increase the firmness of the union; on the contrary, more dissociation occurred. The unusual looseness of the toxin-antitoxin union is probably relatd to lack of serological specificity or affinity. Based on these observations, a practical diagnostic method for antibiotic-induced colitis is outlined.


Survival and multiplication of Vibrio cholerae in the upper bowel of infant mice. The survival and multiplication of Vibrio cholerae strains of varying virulence in the upper bowel of orally challenged infant mice early in infection has been examined. Analysis of changes in the apparent specific activity (counts per minute per colony-forming unit) of the cell population after 4 h compared with the inoculum indicated that strain CA401 established a viable, multiplying cell population, whereas strains VB12 (a rough variant) and 569B were subject to host bactericidal and bacteriolytic mechanisms. An analysis of parameters which may affect the specific activity is included. We have defined the infective potential of the strains in terms of the changes in specific activity. The relative infective potentials are CA401 greater than 569B greater than VB12.


Chemotactic deactivation of human neutrophils: evidence for nonspecific and specific components. Human polymorphonuclear neutrophils have been preexposed to activated complement as zymosan-activated serum (ZAS) or to the chemotactic oligopeptide N-formyl methionylphenylalanine (F-Met-Phe). Spontaneous migration and chemotactic responses toward the deactivating and other cytotaxins were monitored after washing and resuspension of cells in cytotaxin-free medium. Two patterns of deactivation were observed. Preexposure of the leukocytes to high doses of ZAS or F-Met-Phe decreased all subsequent migratory responses. Preexposure of the leukocytes to lower doses of ZAS or F-Met-Phe decreased only a subsequent chemotactic response to the deactivating cytotaxin. These results suggest two mechanisms, or components, of chemotactic deactivation.


Cellular and humoral immune responses to herpes simplex virus during and after primary gingivostomatitis. A total of 17 children, aged 1 to 15 years, with gingivostomatitis were investigated to follow the development of immune parameters in those who suffered from herpes simplex virus stomatitis. Mouth swabs were obtained during the acute attack. Blood samples were collected on this occasion and again about 3 weeks later. Humoral immunity to herpes simplex virus was investigated by a complement fixation test and by an antibody-dependent cell-mediated cytotoxicity test. Cell-mediated immunity was investigated in a blast transformation assay with herpes simplex virus type 1 antigen and phytohemagglutinin. Interferon production in herpes-stimulated cultures was measured. Thirteen patients had a herpes simplex stomatitis. Twelve of these children were negative in the complement fixation test on the first serum specimen, but only five were negative in the antibody-dependent cell-mediated cytotoxicity test. These five were still febrile at the time of investigation. Blast transformation was negative at the first investigation in most children, whereas interferon was produced both in leukocyte cultures obtained during the infection and also in cultures made 3 to 4 weeks after the infection. An increase in immune parameters was seen in all patients with herpes stomatitis. From results in blast transformation and antibody-dependent cell-mediated cytotoxicity, it is seen that cell-mediated and humoral immunity can be found at the same time during recovery from this type of infection.


Characterization of the immunosuppression accompanying virus-induced avian osteopetrosis. Infection of chickens with a myeloblastosis-associated virus which induced a high incidence of osteopetrosis was accompanied by immunosuppression. The immunosuppression was manifested in the following ways. The weight of the bursa, spleen, and thymus was depressed in infected chickens. Infected animals had a diminished capacity to form hemolytic plaques in a direct assay. Spleen cells from osteopetrotic animals did not respond to phytohemagglutinin, and the spleen and bursa had a decreased proportion of cells possessing surface immunoglobulin. Osteopetrotic animals failed to show an age-dependent increase in the proportion of cells demonstrating surface immunoglobulin that was observed in normal animals. However, several individual chickens with heavy osteopetrosis responded to antigenic stimulation in a normal fashion, indicating that although immunosuppression usually accompanies avian osteopetrosis, it may not contribute directly to abnormal bone proliferation.


Virulence and immunity of Staphylococcus aureus BB and certain deficient mutants. Coagulase-negative and deoxyribonuclease-negative mutants were isolated from Staphylococcus aureus BB by treatment with N-methyl-N'-nitro-N-nitrosoguanidine. Comparison of virulence (50% lethal dose) to mice of these six mutant strains and S. aureus BB was determined by both intravenous and intraperitoneal routes. The ratios of the 50% lethal dose of coagulase-negative mutants to that of the parental strain S. aureus BB ranged from 201 to 403 for intravenous infection and 30.7 to 52.7 for intraperitoneal infection. The virulence of deoxyribonuclease-negative mutants was essentially the same as that of S. aureus BB. When mice were immunized subcutaneously with live S. aureus BB or its deoxyribonuclease-negative mutants, the resulting protection against the intravenous challenge of S. aureus BB was remarkable. The ratios of the 50% lethal dose for the mice that were immunized by these strains to that for the untreated mice extended from 40.1 to 60.6 for intravenous infection and 6.61 to 11.5 for the intraperitoneal route. However, no effect against S. aureus BB challenge was shown in the mice that were immunized with coagulase-negative mutants.


Stimulation of polymorphonuclear leukocyte bactericidal activity by supernatants of activated human mononuclear cells. Supernatants of phytohemagglutinin-activated human mononuclear cells stimulated polymorphonuclear leukocyte (PMN) activity against the gram-negative organism Serratia marcescens. In the absence of serum opsonins, when control PMN could not impede bacterial growth, stimulated PMN averaged more than 0.6-log kill of the original bacterial inoculum. In the presence of optimal amounts of serum opsonins, when control PMN were significantly bactericidal, stimulated PMN killed, on the average, at least 0.6 log more of bacteria. Stimulation was not found when PMN were preincubated with supernatants for 1 h or less. The data strongly suggested that the action of the PMN stimulating factor was independent of and different from classically described serum opsonins. PMN stimulating activity may be an additional lymphokine-mediated immune defense mechanism enabling hosts to kill invading microorganisms.


Plasmid-dependent attachment of Agrobacterium tumefaciens to plant tissue culture cells. Kinetic, microscopic, and biochemical studies show that virulent Ti (tumor inducing)-plasmid-containing strains of Agrobacterium attach to normal tobacco and carrot tissue culture cells. Kinetic studies showed that virulent strains of A. tumefaciens attach to the plant tissue culture cells in increasing numbers during the first 1 to 2 h of incubation of the bacteria with the plant cells. Five Ti-plasmid-containing virulent Agrobacterium strains showed greater attachment to tobacco cells than did five avirulent strains. Light and scanning electron microscopic observations confirmed that virulent strains showed little attachment. Bacterial attachment was blocked by prior incubation of the plant cells with lipopolysaccharide extracted from A. tumefaciens, but not from A. radiobacter, suggesting that bacterial lipopolysaccharide is one of the components involved in the attachment process. At least one other bacterial product may be required for attachment in tissue culture because the virulent A. tumefaciens NT1, which lacks the Ti plasmid, does not itself attach to tobacco cells, but its lipopolysaccharide does inhibit the attachment of virulent strains.


Immunological relatedness of ribosomes from mycobacteria, nocardiae and corynebacteria, and microorganisms in leprosy lesions. Serological relatedness of ribosomes from microorganisms of the Mycobacterium, Nocardia, and Corynebacterium genera has been analyzed by the microplate immunodiffusion technique. Mycobacterium and Nocardia proved homogeneous and closely related taxa, whereas Corynebacterium was found to be a heterogeneous phylum connected by remote links to the others. The taxonomic position of "diphtheroid microorganisms" (non-acid-fast, gram-positive bacteria morphologically similar to corynebactria), which were found together with Mycobacterium leprae in human leprosy lesions, was also investigated. Ribosomes of diphtheroid bacteria strongly cross-reacted with antisera against several mycobacteria and nocardiae but not against corynebacteria. Moreover, ribosomes from independently isolated diphtheroid strains proved serologically related and yielded strong cross-reactions with antisera against M. leprae as well as with sera from leprosy patients. Hence, diphtheroid microorganisms represent a homogeneous group immunologically related to mycobacteria in general and more specifically to M. leprae.


Complement activation by cell wall fractions of Micropolyspora faeni. The ability of several cell wall fractions of Micropolyspora faeni, a thermophilic actinomycete associated with farmer's lung disease, to activate complement is reported. Cell walls, obtained by mechanical disruption, were purified by enzyme treatment and chemical extractions. Fractions containing the most purified cell walls were most active in consuming complement, as measured by reduction of hemolytic complement levels of normal human serum. Cell wall fractions activated the alternative complement pathway, as shown by monitoring the conversion of C3 proactivator (factor B) to C3 activator (activated factor B) in the presence of specific cation chelators. Selective degradation of cell walls by lysozyme resulted in a decreased ability to consume complement and implicated peptidoglycan as the major complement-reactive component. The role of this nonspecific complement activation in relation to farmer's lung disease is discussed.


Synthesis, transport, and secretion of plasma proteins by the livers of control and Streptococcus pneumoniae-infected rats. The synthesis, intracellular transport, and secretion of plasma proteins by the liver was studied in both control and Streptococcus pneumoniae-infected rats. Rats were injected with [3H]leucine; at various time intervals, the components of the intracellular secretory system were isolated. The isolation and partial characterization of rough microsomes, smooth microsomes, and Golgi from both control and infected animals are described. After infection, the specific activity of the label in the homogenate and in all isolated cell fractions was significantly increased. In both control and infected animals, the kinetics of labeling suggested that the secretory pathway of the newly synthesized protein was from the rough endoplasmic reticulum to the smooth endoplasmic reticulum to the Golgi and finally to the circulation. Even though infected animals synthesized, transported, and secreted significantly more plasma protein, infection did not significantly alter the secretion time (time between injection of isotope and appearance of labeled protein in the circulation). It is concluded that, after S. pneumoniae infection, the liver still maintains its capability to perform the basic functions of protein synthesis, intracellular transport, and secretion and that newly synthesized plasma protein follows the same intracellular pathway in both control and S. pneumoniae-infected rats.


Synthesis of DNA and protein by Anaplasma marginale in bovine erythrocytes during short-term culture. Bovine erythrocytes infected with Anaplasma marginale were cultured for 1 to 5 days in a CO2 incubation chamber, pulse-labeled with [3H]thymidine and [14C]methionine, lysed, and fractionated by differential centrifugation and continuous density gradient centrifugation in Renografin. Anaplasma and associated fragments of stroma formed two distinct bands in the dense region of the gradient. Electron microscopic examination of pelleted material from the bands from cells cultured for 1 day revealed the presence of organisms that were morphologically intact or in various states of degeneration. Examination of fractions from the gradient for incorporation of label revealed that analplasma present in erythrocytes can incorporate both [3H]thymidine and [14C]methionine. Subsequent experiments demonstrated that organisms cultured for 3 and 5 days incorporated the radiolabeled compounds also, but to a lesser extent. The experiments demonstrate that it is possible to culture analplasma in vitro for short periods of time and monitor their growth characteristics.


Role of colonization in the virulence of Actinomyces viscosus strains T14-Vi and T14-Av. Germfree rats fed a high-sucrose diet were inoculated with Actinomyces viscosus strain T14-Vi (virulent) or T14-Av (avirulent). The mean recovery of strain T14-Vi from six extracted finely ground molars of rats sacrificed after 90 days was 1.1 x 10(8) colony-forming units (CFU). The mean recovery of strain T14-Av was 5.7 x 10(7) CFU, which was significantly less. Strain T14-Vi caused severe alveolar bone loss, but only minimal bone loss occurred in rats infected with strain T14-Av. Scanning electron microscopy of teeth of germfree rats revealed that strain T14-Vi colonized in the fissures as well as on tooth surface areas near the gingiva; strain T14-Av also colonized in fissures but was unable to colonize the teeth near the gingiva. In studies with conventional rats fed a high-sucrose diet, streptomycin-resistant strain T14-Vi colonized on the teeth of all rats inoculated with in the order of 10(8) or 10(7) CFU and on the teeth of about half of the rats inoculated with 10(6) or 10(5) CFU. In contrast, streptomycin-resistant strain T14-Av could not be detected on the teeth of any of the rats in groups similarly inoculated. In vitro "resting" cells of both strains suspended in conventional or germfree rat saliva survived to comparable degrees. [(3)H]thymidine-labeled T14-Vi cells adhered well to hydroxyapatite (HA) beads and to HA beads pretreated with saliva obtained from germfree or conventional rats. In contrast, T14-Av cells adhered less well than did T14-Vi cells to HA, whereas their adherence to saliva-coated HA was negligible. Transmission electron microscopy of negatively stained T14-Vi and T14-Av cells repeatedly passed in 1% phosphotungstic acid revealed fibrils on cells of both strains. T14-Av cells were covered by large amounts of extracellular material which was presumably heteropolysaccharide; little extracellular material was present on the surface of T14-Vi cells. T14-Vi cells had a relatively low affinity for the heteropolysaccharide synthesized by strain T14-Av. Other evidence also suggested that this polysaccharide had a relatively low affinity for saliva-coated HA. Collectively, the evidence indicates that the difference in periodontopathic potential between strains T14-Vi and T14-Av results from their different abilities to colonize teeth. This difference is probably due to the lower adherence of T14-Av cells to teeth rather than to their ability to grow in the mouth. The low affinity of T14-Av cells for tooth surfaces may be due, in part, to the presence of large amounts of cell-surface-associated polysaccharide.


New cellular and extracellular amphipathic antigen from Actinomyces viscosus NY1. A new type of amphipathic antigen was isolated from culture supernatants and cells of Actinomyces viscosus NY1 and partially characterized as a fatty acid-substituted heteropolysaccharide. Similar components have been detected serologically in other strains of Actinomyces.


Response of C3H/HeJ and C3H/HeN mice and their peritoneal macrophages to the toxicity of Chlamydia psittaci elementary bodies. Intravenous injection of toxic doses of Chlamydia psittaci elementary bodies into endotoxin-responsive C3H/HeN mice or endotoxin-nonresponsive C3H/HeJ mice resulted in essentially identical time intervals to death. Inoculation of monolayer cultures of thioglycolate-stimulated peritoneal macrophages from the two strains of mice with 250 elementary bodies per macrophage resulted in immediate host cell toxicity, although the C3H/HeJ macrophages were somewhat less sensitive to elementary body toxicity than were the C3H/HeN macrophages.


Enhancement of the immunogenicity of phase I antigen of Coxiella burnetii. The immunogenicity of the soluble phase I antigen of Coxiella burnetii for guinea pigs was enhanced by a nuclease-resistant complex of polyriboinosinic-polyribocytidylic acid, poly-L-lysine, and carboxymethyl cellulose.


Leukocytic endogenous mediator in Crohn's disease. Reduced concentrations of plasma zinc associated with elevated levels of serum leukocytic endogenous mediator activity were found in 17 patients hospitalized with acute exacerbation of Crohn's disease. Neither the decrease in plasma zinc nor the increase in leukocytic endogenous activator activity in nine outpatients with quiescent disease was significant. Leukocytic endogenous mediator activity may be increased in inflammatory conditions as well as in microbial infections. Although zinc deficiency may be common in patients with Crohn's disease, exclusive reliance on circulating zinc levels to assess zinc nutriture in active Crohn's disease may be misleading.


Enzymatic degradation of H2O2 by Leptospira. The enzymes responsible for reducing H2O2 were surveyed in 49 strains of Leptospira by using semiquantitative assays for catalase and peroxidase. The survey revealed a differential distribution of catalase and peroxidase activities between the two leptospiral complexes. The pathogenic Leptospira interrogans strains gave strong catalase and weak or negative peroxidase reactions. Conversely, the nonpathogenic Leptospira biflexa strains gave strong peroxidase and negative or weak catalase reactions. An intermediate group of four L. biflexa strains, which were isolated from mammals, fell into the high peroxidase, low or negative catalase group. One water isolate, H-23, gave strong reactions for both enzymes and was examined for virulence and in vitro growth parameters. Results indicate metabolic differences between pathogens and water forms in their abilities to reduce H2O2.


Impaired colonization of gnotobiotic and conventional rats by streptomycin-resistant strains of Streptococcus mutans. Colonization of streptomycin-resistant mutants derived from Streptococcus mutans strain LB1, a human isolate, and strain FA-1, a rodent isolate, was studied in gnotobiotic and conventional rats. Mutants resistent to 2.0 mg of streptomycin per ml were isolated by using both stepwise (suffix "R"M) and one-step (suffix "R"1) selections. Rats were infected with mixtures of parental and streptomycin-resistant strains, and the proportions of each strain present in samples from the intestinal canal, tongue dorsum, teeth, and fissure plaque were determined. Combinations of strains investigated were LB1 and FA-1"R"M; FA-1 and LB1"R"M; LB1 and LB1"R"1; FA-1 and FA-1"R"1. In gnotobiotic rats, nonresistant strains predominated in every oral sample studied at 7 and 21 days after infection. Similarly, when conventional exgermfree rats were infected with FA-1 and FA-1"R"1, FA-1 dominated in all samples. Streptomycin-sensitive revertants were not detected in rats monoinfected with strains LB1"R"1 and FA-1"R"1 for 21 days. No antagonistic interactions were observed between the strains in in vitro experiments. Streptomycin-resistent mutants attached to hydroxyapatite treated with rat or human saliva in equal or higher numbers than did parental strains. However, parental strains appeared to grow faster in Trypticase soy broth then streptomycin-resistant mutants. These observations indicate that induction of streptomycin resistance frequently impairs the colonization properties of S. mutans strains, possibly by altering their rate of growth.


Listeria pneumonitis: induction of immunity after airborne infection with Listeria monocytogenes. After implantation of approximately 10(3) Listeria monocytogenes organisms into the lungs, mice develop an acute pneumonitis with dissemination of infection to a mediastinal lymph node (MedLN), liver, and spleen. The infections in a MedLN and spleen resolve in approximately 7 days, but the lung infection persists for a few days longer. Pneumonitis is accompanied by a lymphoproliferative response in a MedLN and spleen, and immunity to Listeria is conferred adoptively with MedLN and spleen cells but not with mesenteric lymph node cells. Although the spleen appears to be the major repository of sensitized lymphocytes, splenectomized mice combat Listeria pneumonitis as effectively as normal mice. It is concluded that the induction of immunity to lung infection with L. monocytogenes is efficient and that the cause for the rather protracted pneumonitis is due to a defect in the expression of the cell-mediated immunity effector mechanism.


Interferon production in glia and glioma cell lines. Interferon (IF) was produced in glia and glioma cell lines in titers comparable to those produced by human fibroblasts. It was inducible by both Sendai virus and polyriboinosinic:polyribocytidylic acid. "Superinduction" resulted in up to 500-fold-higher titers of IF. The IF appeared to be of the fibroblast type, as revealed by experiments using heat treatment, assay of antiviral activity in heterologous cell lines, and neutralization with specific antisera. Since large amounts of IF may easily be produced with glioma cell lines, such cells may be suitable for mass production of IF.


Heightened resistance of athymic, nude (nu/nu) mice to experimental Pseudomonas aeruginosa ocular infection. BALB/c-derived athymic, nude (nu/nu) mice exhibited a heightened natural resistance to experimental corneal infection with Pseudomonas aeruginosa when compared with their heterozygote (nu/+) littermates. Stereomicroscopic examination of the eyes of nu/nu mice 24 h after corneal trauma and topical bacterial application revealed slightly cloudy corneas (iris visible), whereas nu/+ littermate corneas were opaque (iris not visible). Nu/+ mice failed to resolve the infection, and endophthalmitis and shrinkage of the infected eye occurred in these mice within 2 weeks after experimental Pseudomonas infection, as in the parent BALB/c strain. However, nu/nu mice, similarly infected, resolved the infection within 24 h and never exhibited full corneal opacity or eye shrinkage. Histological examination of the corneas of nu/nu mice 24 h after experimental wounding and bacterial application demonstrated subepithelial capillaries and a few polymorphonuclear neutrophils (with numerous intracellular bacteria) in the central cornea. In contrast, the equivalent corneal areas of infected nu/+ littermates, examined similarly, showed a more striking neutrophilic response (but with few intracellular bacteria) to similar bacterial infection, as well as a lack of blood vessels within the central cornea. The central corneas of uninfected and saline control nu/nu mice also were observed. This area in nu/nu mice exhibited an infrequent polymorphonuclear neutrophil (with no intracellular bacteria) and capillaries similar in size and location to those described for experimentally infected nu/nu mouse corneas. Untreated and saline control nu/+ mice, on the other hand, lacked both vessels and polymorphonuclear neutrophils in the central cornea.


Modification of surface composition of Actinomyces viscosus T14V and T14AV. The morphology and serology of Actinomyces viscosus T14V and T14AV were compared. When grown in supplemented tryptic soy broth, the virulent strain (T14V) possessed an extensive network of cell surface fibrils. In this medium, the avirulent strain (T14AV) possessed a microcapsule, absent on strain T14V, and a comparatively small number of surface fibrils. Mild acid extraction (Lancefield procedure) solubilized common antigenic components on both strains as well as components detectable only in the virulent strain T14V (virulence-associated antigens 1 and 2). When grown in Socransky chemically defined medium or Carlsson complex medium, the avirulent strain possessed increased amounts of surface fibrils and virulence-associated antigens. Whole cells and extracts of avirulent cells grown in Socransky medium absorbed antibodies to virulence-associated antigens with approximately the same efficiency as did whole cells and extracts of strain T14V, suggesting antigenic similarity between the two cell types. The results strongly support the hypothesis that observable differences between A. viscosus strains T14V and T14AV represent quantitative, rather than qualitative, differences in particular cell surface components. In addition, the magnitude of these differences can be modified by changing growth conditions.


Bactericidal capacity of phorbol myristate acetate-treated human polymorphonuclear leukocytes. Thus far, the functional capacity of phorbol myristate acetate- (PMA)-treated human polymorphonuclear leukocytes has been undefined. PMA induced exocytosis of lactoferrin, the specific granule marker, but not of myeloperoxidase, the azurophil granule marker. This phenomenon was demonstrated both biochemically and with fluorescent antibody conjugates. PMA-treated neutrophils contained virtually no specific granules when viewed by electron microscopy. Separation of the granule classes by linear sucrose density gradient centrifugation revealed the loss, from PMA-treated neutrophils, of lactoferrin and the specific granule (D20(20) = 1.89) band usually resolved from normal neutrophils. Cells treated with PMA appeared to retain those functions normally associated with intraleukocytic microbicidal action. The hexose monophosphate shunt activated by phagocytic challenge was present in PMA-treated neutrophils. As demonstrated by electron microscopy, the azurophil granules of these cells appeared intact, and they retained the capacity for degranulation with translocation of myeloperoxidase to the site of phagocytized Escherichia coli. The PMA-treated neutrophils also remained capable of degrading the ingested microorganisms. PMA-treated neutrophils exhibited a decrease in phagocytic ability at all levels of bacterial challenge. In the presence of a high multiplicity of bacteria they demonstrated an impairment in killing. These same cells were able to kill low multiplicities of E. coli as well as control cells. It thus appeared that the loss of the specific granules, plus other undefined PMA-induced alterations, impaired neither the viability of these neutrophils nor their killing ability in the presence of a modest phagocytic challenge.


Microcapsule of Campylobacter fetus: chemical and physical characterization. The antiphagocytic antigen (antigen [a]) comprising the microcapsule of a strain of Campylobacter fetus subsp. intestinalis has been purified from culture supernatants by ammonium sulfate fractionation and free-flow electrophoresis. Antigen [a] is a glycoprotein containing about 4% carbohydrate consisting of hexose, pentose, and methylpentose. The composition of the protein was typical of bacterial extramural structural proteins in its low content of basic, aromatic, and sulfur-containing amino acids. The protein had a high content of aspartic acid, threonine, glycine, and alanine. Antigen [a] had an Rf of 0.33 on polyacrylamide gel electrophoresis and a molecular weight calculated in sodium dodecyl sulfate-polyacrylamide gel electrophoresis of approximately 98,000. In contrast to its free form in culture supernatants, antigen [a] in vesicles derived from sheared cells appeared to exist in a complex with lipopolysaccharide. This complex could be dissociated by ethylenediaminetetraacetic acid or by ethylenediaminetetraacetic acid plus Triton X-100. A mutant strain that lacked a microcapsule, when incubated with soluble antigen [a] in a calcium medium, became agglutinable by monospecific [a] antiserum and showed an additional structural layer similar in appearance to the microcapsule on its cell wall. Points of similarity are emphasized between antigen [a] of C. fetus and the outer structural protein of the taxonomically related Spirillum serpens.


The epidemiology of hepatitis B infection in housestaff. Ninety-nine medical and surgical house officers were prospectively evaluated during internship and residency for the development of hepatitis B virus (HBV) infection. The overall incidence of hepatitis B was 10.2% per year. Eighty-six percent of episodes were subclinical. The greatest risk factor appeared to be frequent hand-to-mouth activity such as smoking or licking requisition labels. The presence of a hemodialysis or transplantation unit may be an additional institutional risk factor. HBV infection was not associated with a history of needle-sticks or contact with known antigen-positive patients. Educational efforts to minimize HBV infection should concentrate on handwashing techniques and discouragement of hand-to-mouth activity in patient care areas.


The influence of maternally derived antibody on the efficacy of further attenuated measles vaccine. The natural decline of passively acquired maternal antibody titers and the influence of these antibodies on the efficacy of live, further attenuated measles vaccine were studied in 7 to 12 month old infants. Hemagglutination-inhibition (HI) antibody titers were determined in the pre- and postvaccination sera. HI antibodies at low titers were detected in 20 (46%) of the 43 infants investigated, in five of six infants at seven months and two of nine infants at 12 months of age. The serological conversion rate following vaccination of the infants exhibiting transplacental maternal antibody was as low as 38%, in contrast with 100% sero-conversion of the infants without measurable antibodies of maternal origin. HI antibody titers were low in the infants seven to nine months of age, reflecting poor antibody responses to the administered vaccine. For the 12 month old infants the geometrical mean antibody titer was 1 : 52. It is concluded that transplacental maternal antibody, even at low concentration, inhibits induction of HI antibody in the vaccinees and therefore measles vaccination must be initiated after 12 months of age in order to achieve successful immunization of the children. Infants who receive the vaccine before their first birthday have to be revaccinated at or after 15 months of age.


Neurological infections caused by herpes simplex virus in adults. Over a period of 33 months, 281 neuro-infections were tested for herpes simplex virus. In 26 cases herpes simplex virus was identified as the aetiological agent by isolation of the virus from the cerebrospinal fluid and by serological tests. The illness took the form of severe encephalitis in four cases, less severe encephalitis or meningoencephalitis in 12 cases, aseptic meningitis in seven cases, meningo-encephalitis with radiculitis in one case, ascending radiculomyelitis in one case and radiculitis in one case. The diagnostical and therapeutical problems of herpes simplex neuro-infections are discussed.


[Tobramycin Concentration in Human Lung Tissue (author's transl)]. In 27 patients it was experimentally demonstrated that after an i. m. injection of 80 mg tobramycin concentrations are obtained in human lung tissue which for about two hours are higher than the minimal inhibition concentration of most gramnegative organisms. In 14 samples of the latissimus dorsi muscle no detectable tobramycin concentrations were found up two hours after injection of the same dose. The ratio of whole blood concentration and lung tissue concentration is 2 : 1. The measurement of tobramycin concentration in whole blood thus enables the concentration in lung tissue to be estimated. The results show--like all serum and tissue level assays--a high individual variation, which might be dependent on the non-defined factors of binding or metabolism, especially as during the examination period of two hours no concentration balance is accomplished between the two compartments. Administration of 80 mg tobramycin i. m. every six hours is recommended in patients with pulmonary infections due to gramnegative organisms.


Inactivation of netilmicin by carbenicillin. Netilmicin was added to human serum and stored at various temperatures and carbenicillin concentrations prior to bioassay. Inactivation of netilmicin increased with temperature and carbenicillin concentration. The order of inactivation of aminoglycosides was: tobramycin greater than gentamicin, netilmicin greater than amikacin.


Surveillance, prevention and control of hospital-acquired infections. III. Nosocomial infections as cause of death: retrospective analysis of 1000 autopsy reports. One thousand post-mortem reports were analysed retrospectively to see whether the patient had had a nosocomial or community-acquired infection and whether this led directly to or contributed to the patient's death. In 7.4% of all autopsies nosocomial infection was the direct cause of death. In 6.3% of the patients, nosocomial infection was a contributory factor leading to death. The most common hospital infections were pneumonia, septicaemia, peritonitis, meningitis, and hepatitis B. Most infections which led to or contributed to death were acquired in surgical wards. Patients with nosocomial infections, however, were more endangered by factors predisposing to infections (1.8 factors per patient) than patients without nosocomial infections (0.67 factors per patient). Sixty-three patients acquired an infection outside the hospital; in 70% of these patients, the infection was the main or contributory cause of death.


Anaerobic bacteria: evaluation of disc susceptibility to four cephalosporins. The disc diffusion technique was evaluated with 178 strains of anaerobes and four cephalosporins (cephalothin, cefamandole, cefazolin and cefoxitin). Good correlation in results was found in comparison with the agar dilution technique (p less than 0.001) with the exception of cefamandole and cefazolin against anaerobic cocci (p greater than 0.05). Choosing a breakpoint of 8 microgram/ml for distinguishing susceptible and resistant strains, we determined corresponding incubation, the rate of error is less than 1% for false susceptible and less than 5% for false resistant. However, some strains of anaerobic cocci required a 48 hour incubation period for allowing visible growth. Moreover, a great deal (60.5%) of overlapping zone diameters made interpretation of disc diffusion test difficult among Bacteroides fragilis strains classed as susceptible, intermediate and resistant occuring with cefoxitin. The results have shown that the cephalothin disk will not accurately predict susceptibility of B. fragilis to cefoxitin.


[Concentration in bone and haematoma of the aminoglycoside antibiotic tobramycin (author's transl)]. Tobramycin concentrations were assayed in the rabbit in serum during surgery and in serum, haematoma and bone tissue of the condyle of the femur in the absence of surgery. After a single i. m. injection serum levels were found to be 30% higher initially than in humans, but then dropped at a faster rate to zero. The hardening haematoma appeared to slow penetration of the antibiotic. The concentration in bone tissue was dependent on vascular supply. Surgery did not show any influence on the level of the concentrations.


Comparative clinical pharmacology of bacampicillin and high oral doses of ampicillin. Ampicillin is often used in high oral doses due to its incomplete absorption. The objective of this study was to compare the bioavailability of bacampicillin, a new prodrug of ampicillin which is nearly completely absorbed, to that of high doses of oral ampicillin. Single oral doses of bacampicillin 400 mg or 800 mg and ampicillin 500 mg, 1 g, or 2 g were given to 12 male subjects according to a cross-over design after overnight fasting. The median time after administration till the peak serum level was 0.75 and 1.0 hour with bacampicillin 400 mg and 800 mg respectively, as compared to 1.5, 2.0 and 1.5 hours for the ampicillin doses. The mean of the individual peak serum level after bacampicillin 400 mg, was 7.7 mg/l, which is higher than that after ampicillin 500 mg, 5.2 mg/l, and about the same as that after ampicillin 1 g, 7.6 mg/l. A slightly higher mean peak level was seen after bacampicillin 800 mg, 12.2 mg/l, as compared to ampicillin 2 g, 10.5 mg/l. The absorption rate was highest with bacampicillin, for which 90% of the absorption had occurred 1 hour after administration as compared to 2.5 hours after administration of ampicillin. The relative bioavailability was about 2--3 times higher after bacampicillin as compared to ampicillin. The data imply dose-dependent absorption of oral ampicillin in high doses as there seems to be a less than proportional increase in AUC. The urinary recovery after bacampicillin was 68--75% as compared to 25--41% after ampicillin. Higher doses gave a lower percentage recovery and this phenomenon was more pronounced with ampicillin.


[Investigations on the penetration of cefamandole into spinal fluid (author's transl)]. In 20 test persons spinal fluid was taken at intervals of 15, 30, 60 and 90 minutes after a single injection of 40 mg cefamandole/kg body weight in order to determine the levels of the active substance. Whereas in serum an average peak value of 248 mcg/ml was determined after ten minutes, there was no trace at all of cefamandole in the spinal fluid.


Rapid treatment of percodan addiction: a case report. This is a case study of narcotic addiction in which the patient was completely withdrawn from 12 to 20 Percodan tablets daily within 7 days. Signs and symptoms of the Abstinence Syndrome were minor and required minimal medication for their control. In addition, no electroshock treatment was necessary, nor were any other narcotic or other drug substituted for the Percodan.


Predicting success in a smoking control program. Using 10 independent variables, several of which had previously been related to smoking behavior, a regression equation was derived to predict success in a smoking control program. Thirty-one subjects were divided into the main and cross-validation treatment groups. Both groups participated in four 2-hour sessions. Taken individually, none of the predictor variables discriminated between successful and unsuccessful subjects. The regression equation, based on the five best predictors, accurately predicted direction of change of smoking rate 87% of the time.


Adolescent drug abuse and the development of behavior. Extensive research has revealed that illicit drug use often commences during adolescence, a critical period of physical and psychological development, and it is my intent to selectively focus upon some of the potentially significant interactions between illicit drug abuse and the development of behavior during the adolescent period.


Diversion of methadone: illicit methadone use among applicants to two metropolitan drug abuse programs. Newly admitted patients from two comprehensive drug abuse programs in the Baltimore area were queried concerning frequency of illicit methadone use and availability of illicit methadone for a 3-month period prior to their admission. The results showed that a significant percentage of applicants had used illicit methadone prior to seeking treatment, and that for the most part they were using "program methadone" presumably diverted from take-home medication from patients active in treatment programs in the Maryland area. The clinical and rehabilitative aspects of take-home medication are carefully assessed in relation to these somewhat disturbing findings.


Patterns of aspirin use among American youth. The use of aspirin was ascertained in several population cohorts. In the college age samples, aspirin had been used in the previous 48-hour period by one of every 4 students. Females reported a higher rate (33.2%) than males (16.9%). In the 4th to 12th grade samples, aspirin use was higher than other drugs with 39.6% of the 3,306 students sampled indicating that they had ingested aspirin during the previous week. In a 9--11 year-old category, 25% of these 4th to 6th graders used aspirin without parental knowledge. The relationship of aspirin use and drug education is discussed.


Arrests before and during methadone maintenance. The effect of methadone maintenance on criminal behavior remains ambiguous, in part because of major methodological problems with most studies. We attempted to approach the problem more precisely than previous studies by comparing official police arrest records of 100 heroin addicts for 1 year before admission with those for 1 year after admission. The total number of criminal charges decreased from 189 before admission to 129 after admission. Excluding vagrancy, because of a change in police arrest practice, we found only a 14% reduction in criminal charges. A statistically significant decrease of 40% occurred in one category, burglary and theft. Arrest frequencies were generally correlated with other outcome measures such as employment status and continuation in methadone treatment. The results suggest a modest reduction in criminal behavior as a result of methadone maintenance, with insignificant reduction in crime not directly related to narcotic addiction.


Social effects of marijuana use in a recreational setting. Adult male volunteers with a prior history of either moderate (N = 12) or heavy (N = 14) marijuana use were systematically observed before, during, and after a 21-day period of free access to marijuana cigarettes. Data relevant to social interaction and recreational preferences were collected at hourly intervals. Moderate users consumed an average of 2.6 cigarettes per day and showed both acute and persistent (21-day) decrements in social interaction. Heavy users consumed 5.7 cigarettes per day but indicated fewer social reactions. The results suggested that marijuana inhibits social interaction in moderate users but behavioral tolerance in heavy users may mitigate this effect.


Narcotic antagonist treatment: clinical experience with naltrexone. Narcotic antagonist (naltrexone) treatment experience with 22 opioid addicts over a 29-month period shows that the mean duration of receipt of naltrexone was 6.2 weeks, and 12 subjects (55%) continued in treatment after cessation of naltrexone for an average of 5.6 weeks. Analysis of physical and behavioral measured revealed no toxicity, indicating that naltrexone appears to be a safe drug. Clinical evaluation of the patients receiving naltrexone suggests that ingestion of naltrexone provides a degree of external control, reducing the preoccupation with heroin and releasing energy for the pursuit of other goals. Subject follow-up at an average of 45.3 weeks after cessation of naltrexone indicated that 11 (58%) were known to be abstinent, and 9 (47%) subjects were employed compared with 3 (16%) employed at the onset of treatment.


The drug use index: a measure of the extent of polydrug usage. A drug use index (DUI) is constructed from actual usage data of 1,121 respondents (517 males and 604 females). It is proposed that this index represents a quantitative measure of the degree of involvement in polydrug use. Correlations between the DUI and use of 19 drugs or drug classes are reported. Furthermore, some applications of the DUI are demonstrated with specific reference to four psycho-personality tests.


Change in general and specific perceived locus of control in alcoholics as a function of treatment exposure. Fifty alcoholics successfully completing a 2-month rehabilitation program were administered the I-E Scale and a drinking locus of control scale during their first week in treatment and again the week prior to discharge from treatment. A test--retest non-alcoholic control group was administered the I-E Scale at a 7-week interval. Alcoholics were significantly more internal with regard to their behavior in general and their drinking behavior in particular at the close of treatment than at the onset. The control group evidenced no change. It was suggested that the alcoholics perceived internality was a function of exposure to treatment rather than a predisposing personality dimension.


The pharmaceutical industry: a further study in corporate power. This article represents an updated version of previous research conducted on the United States pharmaceutical industry. The unstated purpose of this article is to present new findings which supplement the earlier research. This article describes three aspects of the United States pharmaceutical industry: its strategy and structure within the world market, its global expansion beyond the territorial boundaries of the United States, and its interlocking directorates with banking institutions. The thesis presented here is twofold: first, the United States pharmaceutical industry has become increasingly integrated into larger and more heterogeneous production units operating on the world market; and second, the United States pharmaceutical industry has become increasingly linked to large United States banking firms through interlocking directorates.


Alternative forms of transport and their use in the health services of developing countries. During the past few years greater interest has been shown in ways in which the coverage of health services in developing countries might be increased. Frequently, it has been advocated that greater use be made of mobile health services, often using relatively sophisticated transport systems, including aircraft. The present article examines the uses to which mobility in health services has been put and the merits of different forms of transport, within the resource constraints and health "needs" of Third World countries. Our main conclusions are that for the majority of health service movement appropriate intermediate technology transport should be used (i.e. bicycle, animals, or motorcycles). The use of mechanical transport within health services with the highest benefit per unit cost is likely to be that employed in the regular supportive (not policing) visits to permanently staffed fixed basic care facilities by more highly skilled and scarce health personnel. Those clinics located closer to the regional base can usually be reached more cheaply by land transport, while those at a distance might justify the use of a light aircraft. Where aircraft are used in this supportive role, it is important they are integrated into the ongoing health services and tightly scheduled to lessen the risk of their diversion to less cost-effective activities.


Health microplanning in the developing countries: a systems approach to appropriate technology. A method of systematically planning the technical details of personal health care in the developing world is described. In contrast to national health plans of the traditional kind--"macroplans"--those for health technology have to be minutely detailed. They have therefore been termed "microplans". (They have also been called health care packages, but this term has other usages). A microplan is defined as an integrated set of components (instructions for technologies, equipment lists, teaching aids, evaluation instruments, etc.) prepared nationally to support a particular health care subsystem. The rationale for a microplan is that the whole is more than the sum of its parts. A microplan is itself a system in two senses. First, the technologies in a given microplan need to be organized so as to support one another. Second, the components in a microplan must themselves be integrated into a system. A microplan can be applied to induce change and so improve the technical quality of existing services. It can also be used to train new workers. More importantly, it ties educational programs to service needs. Since the technology for dealing with disease is so similar all over the developing world, once a "master microplan" for a particular subsystem has been prepared, it can be adapted readily to the needs of individual countries.


Occupational mobility of health workers in the United States. This article presents data from the 1970 U.S. Census Public Use Sample on occupational mobility patterns and labor force separations for health occupations. Turnover among health workers is significantly lower than in the labor force in general. Occupations with the strongest occupational attachment are those predominately male occupations that require the heaviest investment in training. Those with the highest attrition rate are traditionally female occupations that require relatively few skills and are often viewed as entry points for possible upward mobility.


Sexism and racism in the American health care industry: a comparative analysis. By drawing on a wide range of material, a picture emerges of extensive abuse, discrimination, and exploitation of women and ethnic minorities at the hands of the American health industry. The numbers of minorities and women in professional schools and among the "elite" strata of the industry remain disproportionately low. As patients, they receive often inferior, insensitive treatment. Overall, there is a remarkable similarity in the situation of women and minorities, a condition which reflects the pervasiveness of racism and sexism in American institutions and ideologies.


Use of gentamicin to prevent intestinal side effects of lincomycin therapy. Mild to severe and persisting diarrhea and even colitis have been reported as a side effect of therapy with lincomycin and clindamycin. An alteration in the normal bowel flora with an overgrowth of coliforms and other antibiotic-resistant bacteria has been postulated as a mechanism for the development of diarrhea. Investigations were undertaken in men to observe whether the simultaneous administration of gentamicin was capable of preventing lincomycin-associated intestinal disturbances. Of the 30 subjects treated only with lincomycin 11 (36.6%) developed diarrhea. Of the 18 subjects treated with lincomycin and simultaneously with oral gentamicine, none developed diarrhea. Results of bacteriological examinations indicate that in subjects treated with lincomycin, some potentially pathogenic bacteria, like coliforms and clostridia, are still present in intestinal flora; the simultaneous absence of bifidobacteria and bacteriodes could result in the abolishment of the host resistance to the noxious activity of these endogenous bacteria, as some reported data of the literature suggest. Coliforms and the majority of clostridia strains are not present in subjects treated simultaneously with gentamicin.


Renin-aldosterone system and urinary electrolytes after amiloride, hydrochlorothiazide and the combination. Plasma renin activity (PRA), urinary aldosterone excretion (U-Ald) and electrolyte excretions were studied after a placebo (P) (n = 47) and during the following day randomly after amiloride (A) (5 mg, n = 18), hydrochlorothiazide (H) (50 mg, n = 12) and hydrochlorothiazide + amiloride tablets (HA) (50 + 5 mg, n = 19). After A no change in PRA or in U-Ald could be found in 24 hr. After H an increase in PRA was found, but not until 24 hr, and U-Ald was increased during 8--24 hr. HA possessed a higher saluretic effect than H, but the excretion of potassium was lower. PRA increased in 8 hr after HA and a further increase was seen until 24 hr. U-Ald had already increased after HA during 0--8 hr, and U-ALD was higher during 8--24 hr and 0--24 hr than after H. After HA a positive correlation was found between the increases of sodium excretion and PRA; between U-Ald and PRA a positive correlation was also found; but between potassium excretion and PRA or U-Ald there was no correlation. The results suggest the priority of natriuresis in the regulation of renin release after H and HA. The stronger reaction of the renin-aldosterone system after HA than after H thus may result from the faster and higher natriuretic potency of this combination in acute study.


Biochemical evaluation of succinic acid therapy in urolithiasis. Reports of Melon et al. [7] and Hodgkinson [4] regarding the efficacy of succinic acid or its derivative (salt) in reducing the endogenous synthesis of oxalate are conflicting. The possible application of succinic acid as a potential inhibitor of oxalate synthesis, and the biochemical alterations resulting therein, has been studied in 10 idiopathic stone-forming patients (6 primary stone-formers and 4 recurrent stone-formers) and in 21 normal adult rats. In rats no significant changes in oxalate excretion were observed during the 4 weeks of succinic acid administration (500 mg/100 g BW/day) and 2 weeks therafter. In the clinical trial of 3 months, where stone-formers were given 20 g/day of succinic acid, the post-therapy values of urinary oxalate excretion showed a singificant drop ( less than 0.001) as compared with those of pretherapy--recurrent stone-formers showing a more marked decrease (63%) than primary stone-formers (49%).


The role of diet on 5-fluorouracil toxicity. In three experiments performed at two month intervals, rats eating a nutritionally adequate defined-formula diet (DFD) exhibit a remarkable similarity in the response to 5-FU as measured by survival time, leukopenia and weight loss. Conversely, the corresponding control groups eating the standard Purina rat food show a different degree of tolerance to 5-FU, which varies from a level similar to that of the DFD groups to twice that value. It is suggested that certain protective factors against 5-FU toxicity present in natural food are absent in formula diets produced on the basis of standard requirements for normal growth and nutrition. The present studies indicate that such protective factors are neither vegetable fibers nor arachidonic acid. The importance of food intake in experimental toxicology and clinical pharmacology is emphasized.


The effect of Org GC 94 on thrombocyte function, blood coagulation and the fibrinolytic system in man. The effect of a 14 day treatment with Org GC 94 in rising dosage to a maximum of 45 mg/day on thrombocyte function, blood coagulation and the fibrinolytic system was investigated in 16 healthy volunteers in a double-blind comparative trial with placebo. At the same time the influence on some liver function tests and on the general condition of the subjects was followed. Analysis of the data obtained in tests pertaining to platelet function, blood coagulation, fibrinolysis and liver function did not indicate unwanted or harmful effects of Org GC 94. No significant difference in effect between Org GC 94 and placebo was detectable. The general physical condition including appetite and body weight was not affected by Org GC 94. A mild, transient sedative effect of the maximum dose of Org GC 94 is likely and some influence upon concentration (decrease) and mood (indifference or elevation) in some subjects cannot be excluded.


[Pharmacokinetics and bioavailability of naftidrofuryl capsules in man]. We have studied the pharmacokinetics of a single dose of naftidrofuryl in man. Two phases of diffusion have been observed, 11,0 +/- 2,6 respectively 26,5 +/- 3,61. This indicates that the drug is not extensively bound to tissues but mainly distributed throughout the extracellular space. The bioavailability of its oral form, gelatin capsules, is good, if in the same person the area under the plasma curves after oral administration is compared to the one after intravenous injection.


Pharmacokinetic aspects of digoxin in patients with terminal renal failure. IV. Clinical implications of own observations with a recent review of literature. Digoxin dosage regimens for patients on chronic intermittent hemodialysis (CIH) were calculated from pharmacokinetic data of digoxin in these patients between the during hemodialyses. Especially when a maximal digitalisation is not necessary an administration of 0.125 mg digoxin only on days without hemodialysis will be adequate. The regimens should be considered as a suitable starting-point in therapy as individual differences in bioavailability, apparent volume of distribution. clearance and sensitivity may necessitate an individual correction. The place of hemodialysis in the management of severe intoxications will also be discussed. Besides, it is advised to use digoxin instead of digitoxin in patients on CIH.


Phenytoin disposition in smokers and nonsmokers. Smoking habit did not affect the disposition kinetics of intravenously administered phenytoin. Phenyoin was given to 8 smokers and 8 nonsmokers and plasma concentrations of phenytoin were determined over a three day period by GLC and RIA techniques. Nonlinear least squares computer fit of the plasma concentration-time data yielded coefficients of a biexponential equation for calculation of half-lives (t1/2beta), clearances (ClB) and volumes of distribution. There were no statistically significant differences in these parameters with respect to either sex or smoking habit. However, more variable t1/2beta's were noted in the smoking group. No differences in serum protein binding between smoking and nonsmoking groups were found. Serum thiocyanate concentrations were used as a measure of smoking habit. There was no significant correlation between thiocyanate concentrations and t1/2beta or ClB. Attemps to correlate phenytoin ClB with basal metabolic rate also failed.


Clinical pharmacokinetic study of procetofene, a new hypolipidemic drug, in volunteers. The clinical pharmacokinetics of a new hypolipidemic drug, procetofene (Lipanthyl), have been determined in 10 normolipemic volunteers after a single 300 mg dose and repeated 300 mg fractioned doses (b.i.d.) during 10 days, followed by an additional single dose (300 mg) on day 11. The peak plasma level of procetofenic acid, the circulating active metabolite, was observed after 4 or 6 hr. A steady-state plasma level above 10 microgram/ml was reached on day 5 and maintained to day 10 on continued fractioned administration. This mean plasma level was not reached during the single-dose study. A double-exponential plasma decay curve was observed in volunteers after repeated doses: alpha phase, 5.27 +/- 1.05 hr; beta phase, 21.73 +/- 1.07 hr. As shown by the urinary excretion data, the drug is poorly absorbed by the digestive tract, i.e., only about 30% is absorbed.


Excretion of methylergometrine (methylergonovine) into the human breast milk. Methylergometrine concentrations in the maternal plasma and breast milk were determined by a radioimmunoassay during continuous treatment with 0.125 mg of methylergometrine 3 times daily. On the fifth postpartum day at 8:00 a.m. the patients (n=8) took 2 tablets of Myomergin (0.250 mg of methylergometrine) orally, and the levels in the plasma and milk were determined at 1 and 8 hr after the drug administration. Measurable amounts of the drug were found only in 5 out of 16 milk samples. It was concluded that this oxytocic drug does not appear in the breast milk in quantities sufficient to affect the infant. No cumulation in the plasma or in the breast milk was found.


The effect of intravenously administered proxyphylline and Baralgin on the contraction of the human gallbladder. In subsequent studies 300 mg of proxyphylline (Group 1) and 1 amp Baralgin (Group 2) were administered intravenously to 20 patients in order to study the relaxing effect of proxyphylline and Baralgin on the contracted gallbladder in connection with routine oral cholecystography. After the standard contraction meal (200 ml cream) the intravenously administered proxyphylline had no relaxing effect on the human gallbladder, whereas Baralgin caused a significant dilation. The dilation effect lasted throughout the whole study period (60 min). Proxyphylline concentrations in the serum, determined by gas-liquid chromatography, proved to be on the therapeutic level which is said to be effective in the treatment of obstructive pulmonary disease. Because with proxyphylline no dilation effect on the gallbladder was found, the clinical spasmolytic response to proxyphylline during an acute attack of pain in a patient suffering from gallstones seems to be questionable. Baralgin caused a significant dilation effect on the gallbladder, and it seems to be a useful agent in an acute gallstone attack.


Chronopharmacokinetics of ethanol. III. Variation in rate of ethanolemia decay in human subjects. Five male human subjects were administered repeated oral doses of ethanol approximately four hours apart and were examined for venous ethanol levels during the third and fourth hours after each dose. Estimates of the slopes of the apparently linear ethanol disappearance curves exhibited statistically significant variation along a 24-hour time scale within 4 of the 5 subjects, as well as among individuals. Prior findings on one of the subjects were confirmed. It is proposed in general that pharmacokinetic parameters may vary in accord with the physiologic circadian phase at the time of drug challenge.


In vitro sensitivity testing of cells of histologically typified ovarian carcinomas and carcinoma of corpus with 3H-cyclophosphamide-metabolites in the serum of man after massive dose therapy. Cells of a carcinoma of the uterine corpus and of five ovarian carcinomas were cultured in vitro with monolayer and sandwich methods, respectively. After 24-hours-incubation with serum samples of patients treated with a massive dose of 3H-cyclophosphamide (60 mg/kg body weight i.v.)-the samples were taken at different times after application-these cultures with a chromatographically defined content of free metabolites were interpreted, guided by morphological criteria. Incubation of the cultures with serum samples taken 5 hours after application of the massive dose turned out to be a practical system for detection, before the start of therapy, of the sensitivity of malignant tumors to cyclophosphamide. Statements about the proliferation kinetics of the malignant cells, about the active ultimate form of the antitumor agent and its way of action, which are not guaranteed experimentally, are largely eliminated by this method. The justification for using 4-hydroxy- and 4-hydroperoxy-cyclophosphamide to test the sensitivity of malignant cells in vitro to cyclophosphamide was critically examined.


Concentration behavior of carbamazepine in bile and plasma of man. The concentration in plasma and bile of carbamazepine was determined in four humans with Kerr's T-tube drain after an oral administration of a single dose of 400 mg of Finlepsin (carbamazepine). The mean plasma half-life time was 25 (15-31) hr. The concentration time curves in bile and plasma were parallel with the bile to plasma concentration ratio of 0.62 (0.24-0.82). A negative linear correlation between the lithogenic index and the bile plasma concentration ratio was found. It is suggested that the concentration of carbamazepine in bile is influenced by the saturation of biliary micelles with cholesterol. The amount of carbamazepine eliminated by bile within 72 hr was 4.1 +/- 1.9 mg, i.e., 1% of the administered dose. It is concluded that there is no significant enterohepatic circulation of carbamazepine.


Systemic reactions to topically applied drugs. Topical drugs can be absorbed percutaneously in sufficient amounts to cause untoward systemic effects. Generally speaking, infants and young children appears to be more vulnerable than adults. It has been shown that the prolonged and extensive use of topical corticosteroids can induce iatrogenic hypercorticism and that they may also impair the patients ability to cope with stress. Furthermore, the relatively limited use, areawise and timewise, of agents such as phenol, resorcinol, salicylic acid, hexachlorophene, boric acid, mercurials, and podophyllin may suffice to elicit dire systemic reactions.


Auricular calcification.

Auricular calcification. Auricular calcification in two patients was discovered by palpation and x-ray of the pinnae of the ears. In one patient auricular calcification was locally secondary to chronic inflammation, while in the other patient systemically secondary to adrenal insufficiency, a systemic factor.


Clinical and pathologic observations in dermatitis cruris pustulosa et atrophicans. A group of 81 patients with dermatitis cruris pustulosa et atrophicans, a common condition among Africans in Northern Nigeria, is analyzed. The significance of such predisposing factors, as repeated application of oily substances, trauma and seasonal variations are discussed.


Chromoblastomycosis: cure by cryosurgery. Chromoblastomycosis was successfully treated by cryosurgery in a 55-year-old white man. Depigmentation within the scar precludes an entirely successful cosmetic result.


Lichen myxedematosus. Treatment with cyclophosphamide. Lichen myxedematosus is a rare, chronic, progressive disease of unknown etiology characterized histologically by mucin deposition in the upper one half of the dermis and is in many cases associated with a serum paraprotein. We report the third case of lichen myxedematosus which has been treated with oral cyclophosphamide. Our case, as one of those previously treated, lacked the characteristic paraprotein. Therapeutic response consisted of improvement, but not complete resolution of the skin findings.


Multiple comedonal papule of the nose.

Multiple comedonal papule of the nose. Two unique patients are described with a smooth papule on the nose containing comedones and being preceded by trauma.


Clinical pharmacology of systemic chemotherapeutic agents in skin neoplasms. Considerable progress recently has been made in the systemic chemotherapy of disseminated skin neoplasms. Several agents are particularly useful in this regard: the nitrosoureas, methotrexate, actinomycin D, and dacarbazine. This paper reviews their pharmacologic disposition in man. The nitrosoureas have short plasma half-lives; however, they are extensively degraded to metabolites that persist in the body, and are only slowly excreted. Highly soluble in lipids, the nitrosoureas penetrate significantly into the central nervous system. Actinomycin D is only minimally metabolized in vivo; its elimination from the plasma shows a prolonged slow phase with a half-life of 36 hours; but its excretion is even slower than expected about 30% in a week. A potent inhibitor of dihydrofolate reductase, methotrexate exhibits a multiphasic plasma disappearance, and accumulates in tissues with high dihydrofolate reductase activities. At the normal therapeutic dosages, methotrexate is eliminated by the kidneys as the unchanged drug; appropriate dosage modifications are mandatory if renal function is compromised. Dacarbazine has a relatively short plasma half-life, and is rapidly excreted partly as the unchanged drug; it undergoes extensive biotransformation in the body. Like other antitumor agents, these drugs may cause gastrointestinal toxicities and myelosuppression; in addition each drug can have its own individual organ toxicity.


Basal cell epithelioma in a vaccination scar. A 42-year-old woman developed a superficial basal cell epitheliol in a smallpox vaccination scar. After reviewing similar reports in the English literature, I believe any unusual change occurring in a vaccination scar, either simultaneously or years later, should be viewed as a possible malignancy and treated accordingly.


Pathologic investigation of cutaneous stretch. Unevenly stretched skin of the back of rats resulted in microscopic as well as light microscopic features of wounding with subsequent repair as a result of the trauma due to this type of stretch. In skin evenly stretched, dermal collagen was markedly thickened and homogeneous as compared to controls. The increased thickness of evenly stretched skin despite its increase in surface area is consonant with views indicating that stretch may increase the synthesis of diminish the degradation of dermal collagen. The validity of this conclusion, however, is dependent upon the premise that the evenly stretched skin is also "wounded" since this latter would be required to account for the rapid turnover of collagen in these rather acute experiments. This implies a defect at a molecular or biochemical level since no qualitative structural alterations were detected by the conventional techniques employed.


Erythema chronicum migrans in three soldiers. Three cases of erythema chronicum migrans in soldiers who had returned from active duty in Central Europe were seen within a ten-week period in San Franciso. Typically, the lesions cleared in less than five days with penicillin in two cases and erythromycin in another.


Symmetrical lividity of the palms and soles. Symmetrical lividity (SL) was the term coined by Pernet in 1925 for symmetrical, bluish-red plaques on the soles of the feet, accompanied by hyperhidrosis and not corresponding to areas of pressure or patterns of innervation. We report two patients with a persistent eruption of the palms analogous to that described by Pernet on the feet. Unlike most reported cases of SL, our patients did not respond to topical drying treatments, but one patient partially responded to tretinoin. There appear to be two forms of SL: transient, which responds to drying; and persistent which does not respond to drying. The hyperhidrosis studied in one of our two patients was significantly greater within the plaques of SL than the normal palm. While we could suppress the hyperhidrosis with topical therapy, this failed to clear his hyperkeratosis or eliminate the livid color.


The nevus comedonicus syndrome: a case report with emphasis on associated internal manifestations. A 14-year-old boy with nevus comedonicus, multiple congenital abnormalities of the spine, and a central nervous system disorder is described. The associated abnormalities previously reported with nevus comedonicus are summarized. Thorough evaluation of patients with nevus comedonicus may disclose the occurrence of certain internal abnormalities in syndromic association.


How not to pin a hip.

How not to pin a hip. Errors in judgement and technique are responsible for increased failure rates in fractures around the proximal femur. The advanced age of the average patient jeopardizes even the best hip pinning. Proper understanding of mechanics, operative techniques, and the natural course of those fractures will lower the incidence of failures.


Pancreatic necrosis and acute pancreatitis. With reference to 115 cases of acute pancreatitis which were either operated on or confirmed, the authors stress the seriousness of the lesion to the glandular parenchyma; it is also difficult to recognise during peroperative exploration. The necrosis, which is sometimes limited to the peripheral and interstitial tissue, sparing the gland itself (its prognosis is less serious) has led many surgeons to perform surgical excision. However, the problems encountered postoperatively have given rise to doubts a posteriori as to whether this is legitimate. Reference is made to the decapsulation of the pancreas described by Romanian authors, and a method for future operative diagnosis of glandular necrosis is proposed.


Study of nonspecific lymphocyte transformation in urologic cancer patients. Blast-cell transformation of lymphocytes in response to phytohaemagglutinin was examined in patients with urologic tumours and with nonmalignant urologic processes. A significant depression of immune reactivity was found in the malignant cases. The practical aspects of the findings are discussed.