Evolution in microcosm: the rapid somatic diversification of lymphocytes.

The characteristic task of the immune system is learning to respond specificially to entirely novel antigens. How it may do this is discussed under 6 headings. 1. -- Vertebrate and invertebrate immune strategies are contrasted. Whereas among invertebrates whole individuals appear to be selected for their immunological fitness, vertebrates have developed an internal population of lymphocytes among which variants arise and are selectively stimulated by antigen to give a response which protects the "host". 2. -- The genetic mechanism underlying this variation of lymphocytes is of great interest, but its discovery will not, given present ignorance of eukarote DNA, answer those questions about variation at the phenotypic level which are vital to the rest of immunology: e.g. when, how fast, and under what conditions do variantes arise? 3. -- A great deal of indirect evidence suggests that the production of entirely new variant lymphocytes occurs throughout life, particularly after antigenic stimulation. 4. -- Experimental approaches are discussed which might provide direct evidence for or against the idea of rapid variation among stimulated lymphocytes. The method used was based on detecting the cross-reactive specificity of antibody produced by single cells. 5. -- Evidence obtained with this technique is briefly described. There were two main kinds of experiment. In the first, rapid variation (at the rate of about one variation event per 30 divisions) was demonstrated within single clones of proliferating antibody-forming cells. In the second group of experiments, it was shown that certain uncommon antibody-forming cell specificities present at the peak of a primary response were entirely absent at earlier stages. 6. -- A new immunological paradigm may emerge from work on the generation of diversity and on active control of response. There may be relatively few types of lymphocytes with germ-line-coded receptors. These are stimulated by environmental antigens and mitogens, and perhaps by self stimulated by environmental antigens and mitogens, and perhaps by self antigens. Extensive proliferation and variation occurs, which in turn elicits suppressor reactions directed against antigen or against idiotypes of responding clones. The immune repertoire of the adult vertebrate is a product of the evolution of its lymphocytes under the competing pressures of antigenic stimulation and active suppression.


Comparative aspects of glycoprotein structure.

Glycoproteins have a wide distribution in nature and serve a vast number of functions. There are glycoprotein enzymes and hormones; glycoproteins are found in blood and secretions, in cell membranes, and in connective tissue. Of all the biologically occurring macromolecules the glycoproteins, which consist of carbohydrate moieties convalently linked to a polypeptide backbone, represent the most diverse group, ranging from substances in which the carbohydrate component represents less than 1% of the total weight to those in which it represents over 80% of the total. The proteoglycans, which are classified separately from other glycoproteins and include the chondroitin sulfates, dermatan sulfates, and heparin primarily carbohydrate in the form of numerous heteropolysaccharide chains attached to a polypeptide chain at closely spaced intervals. The sugars that commonly occur in glycoproteins include galactose, mannose, glucose. N-acetylglucosamine, N-acetylgalactosamine, sialic acids, fucose, and xylose. The proteoglycans also contain various uronic and sulfated amino sugars.


Evidence for multipotentiality of antibody synthesizing cells.

Immunization of mice with two unrelated antigens or antigenic determinants regularly results in the appearance of hemolytic plaque forming cells (PFC) of each specificity and of some PFC (1-4%) reacting to both determinants. Micromanipulation of individual double PFC appearing after immunization with trinitrophenyl conjugated sheep erythrocytes (TNP-SRBC) into media containing indicator erythrocytes (native SRBC and TNP-horse RBC) and a soluble specific inhibitor (TNP-BSA or soluble SRBC antigen), showed that the specific inhibitor suppressed the lysis of the corresponding indicator but did not interfered with the lysis of the unrelated indicator. Persistance of one specific activity in spite of complete inhibition of the other indicated that these double PFC synthesize two different antibody molecules. The destiny of double cells was studied in individual cell cultures by micromanipulating them into wells containing heavily irradiated normal mouse spleen cells and both determinants (TNP-SRBC). Those double cells which divided they generated in 24 hours monospecific daughter PFC (either anti-TNP or anti-native SRBC). Individually cultured monospecific PFC from mice immunized with one antigen (native SRBC) generated daughter PFC of the same specificity. By contrast, monospecific PFC from mice immunized with TNP-SRBC generated PFC of either the same specificity of (more frequently) of the one the other specificity. Thus, immunization with substituted erythrocytes resulted in the development of three clonotypes: two clones each composed only of cells of either specificity (amphispecific clonotype). For the maintenance of this amphispecific clone, continuous presence in the culture media of both antigenic determinants was necessary. Removal of the one for 48 hours (but not for 24 hours) abolished the generation of daughter cells of the same specificity.


1,4-Diaminobutane (putrescine), spermidine, and spermine.

As is evident from the above summary of the recent literature, plus many other papers not cited here, there is an extensive literature indicating the physiological significance of these amines. The most important studies can be summarized as follows. (a) Polyamines and their biosynthetic enzymes are ubiquitous. (b) Microbiological mutants have been described in which there is a definite requirement of polyamines for growth. (c) The concentration of polyamines and their biosynthesis enzymes increase when the growth rate increases. These increases usually precede or are simultaneous with increases in RNA, DNA, and protein levels. (d) Ornithine decarboxylase has a remarkably fast turnover rate in animal cells, and the level of this enzyme rapidly changes after a variety of growth stimuli. (e) Polyamines have a high affinity for nucleic acids and stabilize their secondary structure. They are found associated with DNA in bacteriophages and have a variety of stimulatory effects on DNA and RNA biosynthesis in vitro. (f) Polyamines stimulate protein synthesis in vivo and in vitro. (g) Polyamines protect spheroplasts and halophilic organisms for lysis, indicating their ability to stabilize membranes. Despite these observations, no specific mechanism has been firmly established for the action of the polyamines in vivo. It is clear that these compounds are physiologically important, however, and further work is necessary to establish the mechanism of their action.


The reovirus replicative cycle.

Soon after entry into their host cells ssRNA viruses form doule-stranded replicative intermediates. Most RNA viruses exist only transiently in this double-stranded form. Double-strand formation occurs irrespective of whether the genome is of the same or complementary polarity to viral mRNA. In contrast, reoviruses contain dsRNAs from the outset. Single, and not double, strands are the intracellular intermediates through which genetic information is transferred from parental to progeny reoviruses. Double strands are the repositories in which the information is stored. We emphasize this distinction because it permits dsRNA-containing viruses to replicate conservatively, a mode of replication that is not shared by any other viruses. One important consequence of the conservative mode of replication is that cellular enzymes never gain access to the reovirus genome but only to its ssRNA precursors.


Peroxidase-catalyzed halogenation.

Peroxidase-catalyzed halogenation reactions have been established as being important in the biosynthesis of the hormone thyroxine and in biological defense mechanisms. Recently these reactions have been recognized as valuable tools for the study of proteins as well as their arrangement in macromolecular structures. The pathways of peroxidase catalyses can be accommodated within the framework of the classical Chance-George mechanism. This implies that the initial steps of the reaction invariably involve oxidation of peroxidases by peroxides--and that the resulting derivative, compound I, is the oxidant of the halide ions. Such reactions may result either in the formation of hypohalous acids, or in halogenation of the enzyme apoprotein, followed by transhalogenation to substrate for halogenation. Chloro- and myeloperoxidases catalyze oxidation of all halide ions, except F-; oxidation of bromide and iodide is mediated by lactoperoxidase, but horseradish peroxidase only oxidizes iodide. All of the above enzymes except horseradish will oxidize the pseudo halide thiocyanate. The origins of this differentiation remain to be defined, but they presumably reflect significant variation in oxidation potential of different peroxidase-peroxide derivatives, rather than constraints on the peroxidase-donor interactions. As pointed out above, halogenation of the amino acids tyrosine and histidine or these residues in proteins can take place on the enzyme. This makes lactoperoxidase-catalyzed iodination selective. The amino acid residues in proteins that are iodinated depend not only on reactivity of the amino acid residue but also on its geometric location. Thus lactoperoxidase-catalyzed iodination can be a useful tool in the study of protein structure and function. It is also useful in establishing the geometric position of proteins within macromolecular structures. Thyroid peroxidase catalyzes iodination of thyroglobulin and is involved in a second important step, the coupling of the iodotyrosines to form thyroxine or triiodothyronine. A proposed mechanism for this reaction suggests that the oxidation is mediated by the iodoenzyme derivative mentioned above followed by a prototropic rearrangement and scission to form the ether bound of thyronine and a serine residue on thyroglobulin.


Why hemispherectomy?

A series of ten cases of infantile hemiplegia with behaviour disorders and with of without fits treated by unilateral stereotactic amygdalotomy is described. Out of the eight cases with fits good releif was seen in six and amelioration of the seizures in two. The behavioural disorders were well controlled in all the patients. When this procedure is compared with hemispherectomy, it is felt that operation of stereotactic amygdalotomy can be done as the procedure of first choice. Some hypotheses have been advanced to explain the modus operandi of the operation.


Contemporary methodology of stereotactic neurosurgery.

A survey of stereotactic operations from neurosurgical centres, one in Madras and the other in Bratislava, shows that many stereotactic operations are of the combined type. From a methodological viewpoint, stereotactic preformances may be divided into simultaneous, successive, symmetrical, asymmetrical, and one-sided, respectively. Thus, the stereotactic operation differs from the traditional concept that the patient may be cured by a single surgical performance. The stereotactic treatment usually consists of a succession of tactical steps, which make up the strategy of the whole treatment.


Treatment of psoriasis with topically applied tretinoin and steroid ointment.

The sequential application of tretinoin and a corticosteroid ointment was considerably more effective in the treatment of plaque-type psoriasis than either drug alone in a pilot study. The best results were obtained with 0.3% tretinoin followed by a potent corticosteroid ointment. Combined therapy was particularly efficacious in steroid-resistant psoriasis, including that on the palms, elbows, and knees. Irritancy from the high-strength tretinoin was a potentially troublesome side-effect. Care must be taken to avoid drug contact on areas that are easily irritated.


Pyoderma Gangrenosum and rheumatoid arthritis.

Two patients had pyoderma gangrenosum and rheumatoid arthritis. Biopsy specimens of the cutaneous ulcers in the patients showed a necrotizing vasculitis. Complement (C3) and immunoglobulins were not detected in the skin lesions. There was no important impairment of cell-mediated immunity observed.


Bullous pemphigoid and associated malignant neoplasms.

To evaluate the significance of the association of systemic malignant disease with bullous pemphigoid, we reviewed the records of patients with bullous pemphigold seen at the Mayo Clinic between 1960 and 1972. Data from 73 patients with bullous pemphigoid were compared with data from 146 controls (73 with contact dermatitis and 73 with psoriasis) matched for age, sex, and calendar year of diagnosis. In the three groups, eight patients with bullous pemphigoid, 11 with contact dermatitis, and ten with psoriasis were found to have malignant disease within the period covering the five years before and five years after the diagnosis of the skin disease. These data indicate that pemphigoid does not seem to be significantly associated with malignant disease.


Infection, dermatitis, increased IgE, and impaired neutrophil chemotaxis. A possible relationship.

Eleven patients with recurrent bacterial infections were found to have impaired neutrophil chemotaxis. The infections were primarily staphylococcal abscesses involving the skin and the respiratory tract. All patients had chronic eczematour dermatitis and an elevated level of serum IgE. The peripheral blood eosinophil count was equal to or greater than 10% of the circulating leukocytes in 10 of 11 patients. Associated findings in some patients included  urticaria and oral or cutaneous Candida infection. These observations suggest a relationship between chronic dermatitis, elevated serum IgE level, eosinophilia, defective neutrophil chemotactic responsiveness, and recurrent pyogenic infections of skin and lungs.


Vesicular pemphigoid.

Seven patients had a chronic eruption of small vesicles that was initially considered to be atypical dermatitis herpetiformis. Histopathologic studies disclosed a subepidermal bulla that was compatible with either bullous pemphigoid or dermatitis herpetiformis. Immunofluorescence studies demonstrated deposition of IgG or C3, Or both, at the basement-membrane zone (BMZ) in six of seven patients. In four patients, circulating BMZ antibodies were detected also. We belive that these cases represent a vesicular form of bullous pemphigoid.


Persistent acantholytic dermatosis. A variant of transient acantholytic dermatosis (Grover disease).

A patient with unusual manifestations of transient acantholytic dermatosis (Grover disease) has lesions that have persisted for more than three years. Biopsy specimen showed histologic changes previously unreported in Grover disease. In order to emphasize that this condition is not always transient, we have titled this entity "persistent acantholytic dermatosis."


Bullous transient acantholytic dermatosis.

We have been three cases of a bullous variant of transient acantholytic dermatosis. Skin biopsy specimens showed histopathologic changes identical to pemphigus foliaceus, but immunofluorescent studies showed no tissue-fixed or circulating antibodies to intercellular antigens. The bullous eruption lasted a few weeks to several months and healed without scarring or recurrence. The lesions healed with topical and/or systemic corticosteroid therapy.


Leishmania tropica infections in travellers.

Oriental sore (acute cutaneous leishmaniasis) is usually a self-limited infection of the skin caused by the protozoan Leishmania tropica. This disease is endemic to the Mediterranean, Asia, Africa, and the Middle East, and is seen in this country among travellers and immigrants. We found four cases at the University of Michigan and diagnosed and treated the disorder. Some of the treatments currently recommended for this disease are potentially toxic, and none have been proved to be of real value. Uncomplicated, acute cutaneous leishmaniasis (L tropica) may best be managed by withholding treatment and observing the patient.


Diagnosis of Hirschsprung's disease by punch biopsy of rectum.

234 punch biopsy specimens of rectal tissue were taken from 112 children. In 94% of the patients the diagnosis of Hirschsprung's disease was confirmed or refuted by the first biopsy. There were no false-positive or false-negative results. One patient developed a serious complication, a pelvic haematoma.


Coliform meningitis in the newborn.

Thirty-six patients with coliform meningitis in the 15-year period 1960-1974 are reported. Only 9 patients survived unscathed though the other 5 survivors were not seriously affected. During the septicaemic phase of the illness the cerebrospinal fluid (CSF), though positive on culture, may be otherwise normal. Meningitis can ensue even when the patient is receiving antibiotics to which the organism is sensitive and the possible disadvantages of using a nondiffusible antibiotic must be appreciated. The CSF in Esch. coli meningitis can be persistently haemorrhagic which may cause difficulties in the initial diagnosis. It must be emphasized that infective illness in the newborn is often nonspecific in its presentation and that repeated bacteriological investigations are essential in neonates who are unwell.


Infantile cortical hyperostosis.

The genetic aspects of infantile cortical hyperostosis are discussed. A pedigree is presented, based on the history and clinical and radiological investigations of all living members of the family, with data from 11 cases with the condition in two generations, and one possible case from a third generation. The data suggest that an autosomal dominant gene with varying expressivity could be responsible in this family and, though the genetic outlook is unfavourable, it is fully balanced by the benign character of the disease. A chronic form of infantile cortical hyperostosis affecting 2 girls and 1 boy in the family is described with a follow-up of 3 to 5 years. There was no deterioration in the general state of health of the patients and no abnormality was detected in laboratory investigations. At the end of the second year of life, curving of the long bones was usually present radiologically and the appositionless corticalis was paper thin with extended marrow cavity. With increasing age the bowing of the bones became less noticeable (but can be permanent in some cases), the corticalis thickened, while marrow cavity volume decreased. In the marrow cavities the remains of insufficiently resorbed original hyperostoses were seen. All the affected bones exhibited both numerous Park's stress lines and osteoporosis, more marked in the bones of the lower extremities. Even these changes disappeared with increasing age. Neither the metaphyses nor epiphyseal ossification centres were affected by the condition.


Utilization of acrylate-embedded large tissue samples in dermatohistology.

A method of embedding tissue in synthetic material which has seldom been used in dermatohistology is described in this communication. This process combines the preparative advantage of slight artifactual alteration of organic tissue and readily reproducible sections between 1 and 3 mu in thickness with the feature of light microscopy that tissue slices of "normal" dimensions can be prepared without difficulty. It avoids the disadvantages of the small dimensions of the preparations required for the ultramicroscope. With few exceptions, all staining methods applied to paraffin slices can also be used.


[Effects of Candida albicans on wound-healing in an animal model (author's transl)].

The effects of Candida albicans on the healing of experimental wounds in rats was investigated. Granulation tissue developing in implated polyvinylchloride chambers was quantified. The amount of granulation tissue in the yeast-contaminated wounds is significantly less in comparison to controls. The inhibitory effect is directly proprotional to the amount of inoculated yeasts and dependes on the presence of living yeast cells. The repair of ulcers is supposedly retarded by yeast contamination, as has been suggested previously by clinical observation.


Steroids in the treatment of clinical septic shock.

A prospective (Part I) and a retrospective (Part II) study were used to determine the safety and efficacy of corticosteroids in the treatment of septic shock. In Part I, 172 consecutive patients in septic shock admitted over an 8-year period were treated with either steroid or saline: 43 received dexamethasone (DMP), 43 received methylprednisolone (MPS), and 86 received saline. The study was double-blind and randomized, and the three groups were compared for age, severity of shock, presence of underlying disease, and year of study. In the 86 saline-treated patients, the mortality rate was 38.4% (33/86); in the steroid-treated patients, it was 10.4% (9/86). With MPS the mortality rate was 11.6% (5/43), and with DMP it was 9.3% (4/43). Thus, overall mortality was significantly less in the steroid-treated group than in the control group. Further, there was no significant difference in mortality rate between the DMP- and the MPS-treated patients. In Part II, 328 patients were studied retrospectively. One-hundred sixty were treated without steroid, and 168 were treated with either DMP or MPS. Again, the two groups of patients were compared for severity of shock, underlying disease, age, and year of study. Mortality among patients treated without steroid was 42.5% (68/160) and among patients treated with steroid was 14% (24/168); there was no significant difference in mortality rate between DMP- and MPS-treated patients. In Parts I and II combined, complications occurred in 6% of steroid-treated patients with no significant difference between DMP- and MPS-treated groups.


Factors in the differential rate of arteriosclerosis (AS) between long surviving renal transplant recipients and dialysis patients.

In this study, the incidence of clinical and autopsy arteriosclerosis (AS) was studied in over 300 renal transplant patients (RTP) followed in our clinic up to 13 years post-transplant. Of 45 RTP followed a mean of 10.45 years, the incidence of clinical AS was 6% or 0.58% per year at risk. The incidence of death from AS was 2.2% over 10 years or 0.22% per year at risk. There was no apparent tendency for increase of the risk incidence with increasing time post-transplantation up to 13 years. This incidence of clinical and death-related AS in long term RTP contrasts sharply with a quite high incidence of both clinical and death-related AS in long-term dialysis patients as reported by Scribner's group and both the European and U.S. Dialysis Registry. Of our RTP surviving a decade or more, 77% have normal serum triglycerides and 92% are normotensive, again contrasting sharply with a 70-80% incidence of hyperlipidemia and a 60-80% incidence of hypertension in long-term dialysis patients. These studies suggest  that the high rate of accelerated AS in dialysis patients is largely reversed by successful renal transplantation, probably due to a lowering of both blood pressure and hyperlipidemia in the long-term RT patients. Practically, these results suggest that the superior survival of transplant patients over dialysis patients already evident at 10 year mark will widen further during the second post-transplantation decade.


Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors.

Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freund's adjuvant. The essential steps for the production of a safe, potent anti-human lymphoblast globulin (ALG) are: A) the use of early bleedings after immunization to reduce the titer of antibodies which react with red blood cells and platelets; B) careful absorption with human red blood cell stroma and platelets; C) stabilization with non-crystalline silica dioxide; D) chromatography through QAE sephadex to remove pyrogens, microaggregates and possible inhibitors of ALG activity; E) careful safety testing in animals for toxicity and pyrogenicity; and F) testing in vitro for sterility. Such a purified horse ALG (IgGab) can be administered safely intravenously to patients to supplement a standardized immunosuppressive regimen incorporating azathioprine and prednisone. Under these circumstances, allergic reactions are very rare, antibodies to horse IgG do not develop, skin tests to horse IgG remain negative, and immune elimination of circulating horse IgG from the human circulation cannot be demonstrated. The overall results of ALG patient survival and transplant function after 184 consecutive first cadaver transplants at the University of Minnesota demonstrate a statistically significant improvement in both parameters accompanying increases in ALG dose while rigidly utilizing standardized doses of azathioprine and prednisone. There is a significant reduction in the number of grafts lost to rejection; significant reduction in the number of rejection episodes; significant delay in the onset of rejection episodes; but there is no increase in septic loss of patients or kidneys. These efforts could be seen in the gross data or when subgroups controlling for patient age, tissue typing were analyzed. Excluding patients at high risk did not alter the results. The beneficial effects of ALG were particularly striking in good matches. In the highest doses, ALG may be dangerous for older patients with poor matches who develop an increased incidence of septic loss of kidney and/or life. Thus, ALG appears to be a useful adjunct in the early management of cadaver transplants by reducing the incidence and frequency of rejection episodes. The dose should probably be reduced in the older patients who receive kidneys from badly mismatched donors. One cannot conclude from this study that ALG manufactured in other centers by this or other techniques, will accomplish the same results since the multiplicity of factors involved in the success and failure of transplants must be controlled so that the influence of intravening variables in the assessment of ALG effectiveness can be assessed.


Treatment of rheumatoid arthritis: a review including newer and experimental anti-inflammatory agents.

Treatment of rheumatoid arthritis is often frustrating for patient and physician alike because of its chronic nature and our lack of knowledge about precise cause. It can be confused by the vast array of anti-inflammatory drugs now available, with new agents being added all the time. We present here an outline for a systematic treatment program that must be tailored to each patient's needs. It emphasizes a broad approach on the part of the physician and indicates that drugs comprise only one part of treatment. We review the drugs currently used in the treatment of rheumatoid arthritis and include discussion of those newer antiinflammatory agents that should be available shortly. A rational scheme for the use of these drugs is proposed.


Nosocomial Salmonella epidemic.

A patient admitted to the hospital with diarrhea due to Salmonella heidelberg subsequently developed fatal disseminated salmonellosis, despite vigorous antimicrobial treatment. Beginning five weeks after the initial patient's death, nine patients developed hospital-acquired S heidelberg infections characterized by diarrhea (in seven) and bacteremia (in two). A careful search for salmonellosis among patients and hospital staff revealed two asymptomatic excretors. Extensive culturing of samples from the environment did not show any contaminated objects or reservoirs. The epidemic ended after initiation of an energetic handwashing campaign and isolation procedures. The strain of S heidelberg isolated was resistant to chloramphenicol, ampicillin, and gentamicin. Especially interesting in the epidemic were the prolonged time between death of the index case and the appearance of nosocomial cases, the high fatality rate, and the marked antibiotic resistance.


Asymmetric distribution of concanavalin A binding sites on yeast plasmalemma and vacuolar membrane.

Isolated vacuoles of Saccharomyces cerevisiae did not bind Concanavalin A (labelled with tritium or with a fluorescent dye) unless the vacuoles were rendered permeable and their inner membrane surface made accessible. Yeast protoplasts, on the other hand, bound large amounts of Concanavalin A on their surface, and the number of binding sites was not increased after a gentle lysis expected to expose also the inner surface of the plasmalemma. It is concluded that both the plasmalemma and the vacuolar membrane carry Concanavalin A binding sites exclusively on the surface opposite to the cytoplasmic matrix.


DNA synthesis by Escherichia coli B/r/l synchronized and grown under conditions of slow growth.

Escherichia coli B/r/l was synchronized by a novel method and its growth was followed in a minimal salts medium containing glucose, acetate, aspartate or succinate as the sole carbon source. Thymine incorporation experiments showed agreement with the Cooper-Helmstetter model for DNA synthesis, during the division cycle, both in glucose grown culture with a doubling time 57.5 min and in acetate, aspartate and succinate where the doubling time was extended up to 90 min. The ratio C/C + D was identical or close to that predicted by the model. Prolonged growth of the synchronized cultures prior to each experiment was practised in order to ensure their physiological state without causing any considerable deterioration of synchrony.


Behaviour of Dictyostelium discoideum amoebae and Escherichia coli grown together in chemostat culture.

When Dictyostelium discoideum amoebae and Escherichia coli were grown together in chemostat culture damped oscillations in the population densities of the organisms occurred followed by a sudden increase in bacterial numbers and a concommitant decrease in the number of amoebae. After the system had come to equilibrium altering the dilution rate resulted in a monotonic change in the experimental variables to new steady state levels. A square wave increase in the concentration of limiting nutrient in the feed medium during the oscillatory phase of culture produced a sinusoidal response indistinguishable from that prior to the perturbation. The results are more complicated than those predicted by simple models of microbial predator-prey dynamics although they correspond most nearly to models which incorporate saturation kinetics.


Localization of mannan at the surface of yeast protoplasts by scanning electron microscopy.

The beta(1-3)glucanase of Basidiomycete QM 806 was used to prepare Saccharomyces cerevisiae and Candida utilis protoplasts. Plasma membranes isolated from S. cerevisiae contained a small amount of mannose and traces of glucose and ribose. Randomly distributed alpha-mannan was detected by scanning  electron microscopy at the surface of prefixed protoplasts using colloidal gold labelled with Concanavalin A as  a marker. C. utilis protoplasts were also marked with anti-mannan antibodies. Again the distribution of mannan was random. This experiment indicated also that plasma membrane mannan has the same immunochemical determinants as cell wall mannan. It is  hypothesized that mannan is mainly located in the outer layer of plasma membranes.


[Artificial intranasal bacterial invasion in the newborn calf. 1. Quantitative assessment of nasal secretion for certain groups of bacteria].

A technique has been developed for quantitative assessment of nasal secretion for the presence of specified groups of bacteria, as a contribution to microbiological treatment of the problem of artificial intranasal bacterial invasion in newborn and nursed calf. Some 10(6) to 10(7) bacteria were recorded from each gram of nasal secretion in calves exposed to natural bacterial invasion. Micrococci and green diplococci were very rare, with only 10(3) to 10(4) or hardly up to 10(5) bacteria per gram of nasal secretion. Streptococci were irregularly found in smaller counts. Bacteria of the coli group went up steeply on the second or not later than the third day of age, and the rise continued to the ninth day. Coliform germs accounted for high or even the highest percentage in total invasion during that period of time.


[Artificial intranasal bacterial invasion in the newborn calf. 2. Artificial bacterial invasion using gram-positive and gram-negative strains].

A micrococcal and a diplocaccal strain isolated from the nasal space of a clinically intact nursed calf were used for artificial bacterial invasion in the first phase of the experiment. Application of bacterial suspension prepared from those strains had no effect upon the rise of coli counts in the nasal secretion of nursed calves during their first days of age nor upon the morbidity or mortality of all 677 test animals in comparison to 665 controls. Therefore, an avirulent E.-coli strain was used in subsequent bacterial invasion experiments. The strain was retrievable up to the seventh day of age, the count having been about 10(5) bacteria per gram nasal secretion. Application of a bacterial suspension prepared from that E.-coli strain did not reduce morbidity and mortality among 820 test animals that were compared to 809 controls. Results are discussed in this paper with reference to literature.


Two dosages of imipramine in hospitalized endogenous and neurotic depressives.

Fifty-one newly hospitalized depressed patients participated in a double-blind comparison of two dosage levels of imipramine hydrochloride (150 mg vs 300 mg daily). Although some patients were suffering from neurotic depressions, they, together with the endogenous depressives, were a severely depressed group who required hospitalization. Improvement occurred with both dosage regimens, although a greater and more consistent improvement was noted in the 300-mg group than in the 150-mg group. There were a few differences between the response of the endogenous and that of the neurotic depressives, as assessed by the physician and self=rating scales. However, endogenous depressives who received 150 mg were overrepresented in the treatment failure group. A comparison of the response of deluded and nondeluded depressives indicated that the deluded patients responded less well than the nondeluded depressives, although half of the delusional group did respond to the treatment.


Paul Zweifel, pioneer fetal physiologist. A centennary tribute.

The demonstration by Paul Zweifel a hundred years ago (1876) that the fetus in utero consumes oxygen marks the beginning of the modern era of research on foetal physiology. The circumstances which led to the demonstration are reviewed, and its importance acknowledged anew as a tribute to Zweifel's many contributions to obstetrics and gynecology.


[Investigation of the dalcon shield by scanning and transmission electronmicroscopy and bacteriologic studies (author's transl)].

Bacteriologic studies and ultrastructural examination (scanning and transmission electron microscopy) was performed on twenty eight Dalcon Shields and the corresponding uteri. Microbiologic organism were detected in various degree. The results were compared with clinical results especially in regard to septicaemia in patients carrying the device.


[Isolation and characterization of the placental proteil pp1 (author's transl)].

The purification and characterization of the placental protein PP1 is described. The protein has been isolated from an aqueous extract of human term placentae using salt and ethanol fractionation procedures, gel filtration, preparative zone electrophoresis and chromatography on hydroxylapatite. PP1 sediments with 8.4 S and has a molecular weight of 160,000 daltons; it is composed of apparently four identical subunits, which have a molecular weight of 40,000 +/- 2000 daltons and are held together by non-covalent bonds. PP1 is a glycoprotein with a carbohydrate content of 2.7% and has the electrophoretic mobility of an alpha1-globulin. Immunochemical methods were used for the detection and quantitative determination of the protein. PP1 is not found in normal plasma or in erythrocytes; neither could it be detected in sera from pregnant women nor in sera from patients suffering from malignant diseases. PP1 is a tissue protein, but not specific for the placenta; it is also found in other human tissues. The average amount of PP1 extracted from one human term placenta was determined to be around 3 mg. Immunogluorescent studies revealed that the protein is located in the cytoplasma of the syncytium as well as in the stroma of the villi.


Puncture perfusion of small tissue pieces for scanning electron microscopy.

Small tissue pieces for scanning electron microscopy were punctured, before fixation, with a needle and perfused through the needle with Ringer solution. This puncture perfusion sufficiently eliminated blood and tissue fluid from the tissue and was of excellent value in cleaning the small samples which were hardly cannulated for vascular irrigation. Resin injection by this needle puncture method reproduced not the tissue spaces but, almost exclusively, the blood vessels.


Immune processes in the course of infection with dysentery bacilli. I. Transfer of immunity by means of spleen cells.

Studies on the mechanisms of immune phenomena in the course of infections with dysentery bacilli in mice showed that injection of live Shigella sonnei phase I bacilli intravenously evokes the appearance in the spleen of cells by means of which immunity to a lethal dose of these microorganisms can be transferred into other mice. Immunity to a lethal dose of the bacteria was measured by the number of animals surviving the infection, and by the numbers of bacteria isolated from the organs of the animals. "Active" cells appeared in the spleen 4-8 days after immunization. Spleen cells obtained from mice earlier than 4-8 days after immunization, or from non-immunized mice, were inactive. The role of cell-mediated immunity, reactivity to endotoxins per se, and specific immunoglobulins in immunity to bacterial dysentery in mice are discussed.


Immune processes in the course of infection with dysentery bacilli. II. Transfer of immunity by means of serum.

The role of antibodies in immunity to intravenous infection with dysentery bacilli was studied in mice. Serum from animals immunized with a single dose of live dysentery bacilli obtained at a varying intervals of time after immunization transferred immunity to other mice infected with lethal doses of the same bacilli. Passive immunity transferred with serum was diffrentiated. Sera obtained 4 to 8 days after immunization of the donors with sublethal doses of live Shigella sonnei phase I bacilli protected lethally infected recipients by inhibiting multiplication of the bacilli in the spleen and liver. Highest protective activity of this type was found in sera obtained 6 days after immunization of the donors. Sera obtained after 11 days and later protected the recipients from death, but only negligibly inhibited growth of the bacilli in the internal organs of the animals. It is suggested that immunity to intravenous infection with dysentery bacilli in mice follows a biphasic course. In the first phase, between days 4 and 8 after immunization, cell-mediated immunity and a specific humoral factor play the main role. In the second phase, specific immunoglobulins of the IgG class afford protection.


Pancreatic cancer. The dismal disease.

Pancreatic cancer, the fourth commonest cause of death in the United States, has a very poor prognosis, is increasing in incidence, and, in most cases, is not detected before it has spread beyond the pancreas. Partial, or total, pancreatectomy has increased five-year survival in only a small fraction of cases. New techniques are helpful in earlier diagnosis, but patients have to be selected for examination long before clinical signs or symptoms develop. Elderly patients who use alcohol and tobacco excessively and female diabetics may be at higher risk. Pathologists should examine pancreasduct epithelium at autopsy in patients in the fourth to sixth decades for atypia, papillary hyperplasia, carcinoma in situ, or other possible precursor changes. Diagnostic tumor, or oncofetal antigens, or a biochemical difference in isozyme activities, hopefully, may be developed. Some combinations of surgery, chemotherapy, and radiation therapy may give better prognosis.


Infection of armadillos with Mycobacterium leprae. Ultrastructural studies of peripheral nerve.

Peripheral nerves of armadillos were studied 16 to 30 months after intradermal or intravenous inoculation with Mycobacterium leprae. Numerous bacilli were found within macrophages, Schwann cells, and perineurial cells; endothelial cells, pericytes and fibroblasts were involved as well. The bacilli were characteristically contained in membrane-limited vacuoles that were interpreted as being phagosomes. Some of the phagosomes contained granular, membranous, and vesicular debris considered to be bacillary degradation products, suggesting that lysosomal activity was present within the phagosomes. Multivesicular bodies, a few of which contained bacilli, were abundant in macrophages and perineurial cells. An unusual proliferation of irregular tubulovesicular profiles was noted, especially in Schwann and perineurial cell cytoplasm, surrounding and within phagosomes containing bacilli. The pattern of cellular involvement of neural structures with M leprae was similar to that observed in lepromatous leprous neuritis in humans.


Hepatic granulomas in leprosy. Their relation to bacteremia.

A clinicopathologic study of liver disease was conducted on 28 patients with leprosy who lived in Taiwan. None of the patients exhibited symptoms or signs of liver disease. Hepatic granulomas were found in 21 patients. Histologically, the infiltrates were epithelioid, foam cell, and histiocytic in type. Hepatic dysfunction was absent, except for mild sulfobromophthalein elevations in the severely infected cases. Hepatic granulomas correlated with the cutaneous reactions in lepromatous leprosy, but the association was poor for other stages of disease. Hepatic involvement varied with the severity of cutaneous infection and with the frequency and intensity of bacteremia. An estimated 1,000 to 10,000 acid-fast bacilli/ml of blood was required to generate the hepatic infiltrates.


Glomerular changes in dengue hemorrhagic fever.

Percutaneous needle biopsies were performed on the kidneys of 20 patients who had dengue hemorrhagic fever with some clinical manifestation of renal impairment. In ten cases IgG or IgM, or both, and C3 could be localized in the glomeruli, using the fluorescent antibody technique. In those cases in which immune complex was found, the biopsy had been done in the second week after the onset of fever. Electron microscopy showed focal thickening of the glomerular basement membrane, with hypertrophy of mesangial cells at the sites where the immune complex was shown. Dense, spherical particles, 40 to 50 nm in diameter, were found in 12 cases. Those particles were carried into the glomeruli by monocyte-like cells.


Surgery of the lower extremity in cerebral palsy: considerations and approaches.

This review of literature on surgery of the lower  extremity in cerebral palsy includes a discussion of the criteria for determining the appropriateness of surgical therapy in the cerebral palsied child and descriptions of the major types of procedures performed.


Efficacy of repeated pharmacotherapy in experimental acute poisonings with fluostigmine.

The effectiveness of repeated pharamacotherapy in acute poisonings with fluostigmine was studied in rats. It was demonstrated, that the second i.p. administration of obidoxime (40 mg/kg) was without effect. Repeated i.p. administration of atropine (10 mg/kg) shown marked efficacy only in animals treated previously with atropine (10 mg/kg) and diazepam (2.5 mg/kg). This procedure was without effect in animals treated just after intoxication with atropine (10 mg/kg) or atropine (10 mg/kg) and obidoxime (40 mg/kg). Subsequent administration of diazepam (2.5 mg/kg) or caramiphen (10 mg/kg) was without effect.


Simultaneous determination of influenza virus antihemagglutinin and antineuraminidase antibodies by means of the combined photometric ACU method I. conduct of test.

A modification of the photometric ACU (antibody concentration unit) method designated as combined ACU test is described by means of which the titers of both antihemagglutinin (AH) and antineuraminidase (AN) antibodies can be simultaneously determined, using intact homologous influenza virus. In addition, the constants describing the reactions of AH and AN antibodies with their antigens can be obtained. These constants were determined for a series of H2M2 and H3M2 influenza virus strains. This paper gives a detailed description of the conduct of test. The sensitivity and accuracy of AH antibody titration by means of the combinated ACU test was found to be the same as achieved by means of the original ACU test. The same conclusion was reached when comparing the titration of AN antibodies by means of the combined ACU test and of a modified ACU test which, in turn, has been found to be more sensitive and accurate than is AN antibody titration by the enzyme inhibition test. However, the sensitivity of AN antibody titration by the combined ACU test was found to decrease progressively as the ratio of AH to AN antibodies exceeded certain limits.


[A method of assessing the degree of vertical organization of cerebral cortical structures].

A method of obtaining a comparative quantitative evaluation of the vertical order of neurons in the cerebral cortex structures with the help ofinformational indices of the entropy and organization is proposed. The presence of the vertical column order of neurons is considered as a manifestation of a certain general regularly in the building of neural complexes. The morphological preparation (section) of the definitive process. The scheme of operations with the given record (morphological preparation) in the uork permits obtaining the values of the entropy and organization. In the example of the middle of layer III field 17 and sublayer III2 of layer 18 of the human new cortex it has been shown that the proposed method contributes to revealing the difference in the degree of the vertical order of neurons in these structures.


[Cortico-striate spinal degeneration. Report of a case with pathological and clinical findings suggestive of Creutzfeldt-Jakob disease].

A case suggestive of Creutzfeldt-Jakob disease in an adult with widespread lesions of the cerebral cortex, striatum and the spinal cord is reported. Anatomopathological studies showed neuronal degeneration, astrocytic proliferation, intense lymphoplasmocytic activity and slight spongiform degeneration. This inflammatory lymphocytic infiltration corroborates the hypothesis of viral etiology of this disease.


Acquired toxoplasmic chorioretinitis.

A patient developed an acquired toxoplasmic chorioretinitis 11 days after exposure to infected animals. As systemic manifestations of the disease, the patient had rhinitis, sore throat, muscular pains, fatigue, cervical lymphadenopathy, and cardiac symptoms, with highly elevated Toxoplasma antibody titers. During treatment with prednisone, the chorioretinal lesion progressed to the macular area, but improvement was seen when pyrimethamine and sulfonamide therapy was started. The importance of this case relates to the unusual occurrence of acquired infection with systemic manifestations in toxoplasmic chorioretinitis and to the possibility of the transmission of toxoplasmosis by trophozoites in excretions.


Granulomatous necrotizing retinochoroiditis caused by Sporotrichum schenkii. Report of a case including immunofluorescence and electron microscopical studies.

A middle-aged man had blurred vision, redness, and pain in the right eye. Ophthalmoscopic examination revealed slowly progressive necrotizing retinitis in the peripheral superonasal quadrant. The clinical impression was toxoplasmic retinochoroiditis, but lesions failed to respond to steroids, pyrimethamine, and sulfonamides. The eye was enucleated and, histopathologically, showed necrotizing granulomatous retinochoroiditis and optic neuritis, numerous cigarshaped, yeast-like organisms located within the necrotic retina and subretinally, and  a subretinal asteroid body. Organisms were identified as Sporotrichum schenkii by immunofluorescence techniques. Electron microscopical studies of the fungus disclosed an unusually thickened capsule with a well-developed cell wall, the outer portion of which exhibited a radiating pattern of granular filamentous material. The ability of S schenkii to cause endophthalmitis in a patient without apparent primary infection should be remembered in the differential diagnosis of a cryptogenic, slowly progressive intraocular infection.


Evaluation of the McCarey-Kaufman technique of corneal storage.

We present our evaluation of the McCarey-Kaufman (M-K) method of corneal storage. Sixty-six rabbit corneas were stored in the M-K medium at 4 C for periods of four, eight, and 12 days. Endothelial viability was assessed, using the specular microscope, the phenomenon of temperature reversal, and known inhibitors of endothelial cell function. Our results support those of McCarey and Kaufman, who showed that rabbit corneas will remain viable when stored by this technique. We were unable to support the contention that M-K medium-stored corneas are functionally superior to those corneas stored in moist chambers in the conventional manner. An unsuccessful attempt was made to correlate the function of the endothelium with either its morphological appearance as seen through the specular microscope or changes in ultrastructure as shown by transmission electron microscopy.


Intraocular copper foreign bodies. Use of dexamethasone to suppress inflammation.

In an attempt to prevent the intense inflammatory response to intravitreal copper foreign bodies in the rabbit eye, varying dosages of dexamethasone sodium phosphate were administered daily via the subconjunctival route. The steroid appeared to behave systemically and had similar effects in both the injected and the noninjected  eyes. Its effect was similar also regardless of the concentration of copper within the foreign body. Nine days of dexamethasone therapy prevented a substantial number of copper foreign  bodies from becoming totally encapsulated during that time. Furthermore, a delay in the onset of the inflammatory response to the foreign body was noted. In a few instances, inflammation was completely suppressed during  the entire course of therapy.


Did George Washington die of quinsy?

After his second term as first president of the United States, George Washington retired to his Mount Vernon estate in 1796. It was there that he suddenly fell ill and died in December of 1799 after an illness lasting only 21 hours. His problem was first diagnosed as "quinsy" and later modified to "Cynanche trachealis". A review of the signs, symptoms, and clinical course of his fatal illness suggests that the cause of death was most likely an otolaryngologic emergency known as "acute epiglottitis."


Lymphomas of the masticator space.

Lymphomas that involved the masticatory space occurred in three patients. In one patient, the masticator space remained the sole manifestation for many years; in the other two patients, the masticator-space involvement was a local manifestation of constitutional disease. In all three patients, excisional biopsies and microscopical tissue examinations were carried out because of a mass deep to the parotid gland. The symptoms and signs are quite similar to those manifested in patients with infection. Surgical procedures other than incisional biopsy are not indicated. Irradiation and chemotherapy appear to be the treatments of choice.


Mucociliary function of the eustachian tube: assessment by saccharin test in patients with dry perforations of the tympanic membrane.

The mucociliary function of the Eustachian tube was assess in 44 patients with dry perforations of the lympanic membrane by means of the saccharin test. A saccharin crystal was placed on the mucous membrane of the middle ear as close to the orifice of the Eustachian tube as possible, and the time taken for the patient to taste the saccharin was measured. The function of the Eustachian tube was also assessed by means of the aspiration test and by the Valsalva maneuver. No relationship was found between the results of the saccharin test, aspiration test, and the Valsalva maneuver. However, a correlation seems to exist between the hearing improvement obtained as determined by the postoperative air-bone gap, the positive or negative results of the saccharin test, and (in cases with positive saccharin test) the saccharin perception time.


Computerized tomography of the head: a preliminary report on its use in the diagnosis of internal auditory canal and cerebellopontine lesions.

Computerized tomography (CT) of the head in rapidly replacing other procedures in the diagnosis of lesions of the cerebellopontine angle and the internal auditory canal. The quality of the information is such that CT may become the only procedure necessary for the diagnostic examination. It substantially diminishes time, expense, and possible radiation hazard to the patient.


Dr Alexander Graham Bell--audiologist and speech therapist.

Alexander Graham Bell is best known for his role in the invention of the telephone. However, he had a lifelong involvement in speech therapy and audiology besides many other medical investigations. He was also awarded an honorary MD degree from Heidelberg University. In this, the 100th anniversary of his invention of the telephone, his life and some of his medical interests are briefly reviewed.


Joseph Leidy: his contributions to otology.

Few men of science have contributed more to our understanding of the workings of nature than Joseph Leidy. Philosopher, anatomist, paleontologist, botanist, educator, and natural scientist in the purest sense of the work, Leidy's interest in the humanities and in all aspects of nature lent itself to his exact descriptions of new species and unchartered anatomic realms. His insistence on man's acquaintance with nature fostered a humanistic and sensitive approach to life, something that needs more emphasis today. This communication deals with Leidy's life, his philosophy, and his unique dedication to the study of nature. An appreciation and understanding of his anatomic expertise, particularly of the temporal bone, hopefully will sensitize the modern otologist to the heart and mind of one that preceded him.


Aneurysmal bone cysts.

Ten cases of aneurysmal bone cysts in various parts of the body are presented. Their features are analysed and the relevant literature is reviewed.


The treatment of intoed gait in spina bifida patients by lateral transfer of the medial hamstrings.

The operation of lateral transfer of the medial hamstring muscles is described. Its applicating in the management of intoed gait in spina bifida is discussed, and the results of eight such operations, performed on four children, are recorded. The operation was effective in correcting the intoed gait in all; however, there was no activity in the transferred muscles in one child.


The effect of dazomet on salmonellas on artificially contaminated eggs.

Salmonellas were isolated from the surface of only 1 of 21 artificially contaminated eggs after they had been treated with dazomet. By comparison salmonellas were isolated from the surface of 13 of the 21 untreated eggs. Penetration by the salmonellas through the shells to the shell membranes resulted from the immersion of warm eggs in a cold suspension of salmonella cells. While the dazomet treatment reduced the incidence of salmonellas within the shells and shell membranes, elimination of salmonellas from all eggs was not achieved. However, the numbers of surviving salmonellas on the eggs were small; a count of 4 per shell being recorded compared to greater than 110,000 per shell of the untreated eggs. The failure to achieve complete elimination of salmonellas within the shell and membranes appeared to be due to inadequate penetration of the fumigant to these structures.


Fluorescent antibody test in diagnosis of ulcerative enteritis.

A direct fluorescent antibody (FA) test to demonstrate the presence of Clostridium colinum in cryostat sections of liver and intestine from chickens with ulcerative enteritis ("quail disease") was investigated. Both field cases and experimentally infected birds were studied by FA, bacterial isolation of the clostridium, and histopathology. The FA test proved highly specific for Cl. colinum. It was concluded that the described direct FA procedure offers simplicity and speed over bacterial isolation procedures for etiologic diagnosis of ulcerative enteritis.


Examination of poultry litter for Salmonellae by direct culture and fluorescent antibody technique.

Direct culture and fluorescent antibody (FA) procedures were used for examining approximately 6200 samples of poultry floor or nest litter for salmonellae. Each sample was cultured directly in tetrathionate brilliant-green (TBG) broth, incubated at 42 C for 48 hours, and plated on brilliant green (BG) agar. The FA procedure was conducted from pools of 4-8 samples prepared by transferring 1 ml supernatant from TBG at 24 hr into 50 ml of either gram-negative (GN) broth, selenite cystine, or selenite brilliant-green sulfapyridine. After 6 hr of incubation at 42 C, BG agar plates were streaked from each pool, and smears were prepared for FA. Salmonella was isolated by plating from 268 of 854 pooled units. Recovery was 97% by direct culture, 86% from GN broth, and 57% from the selenite secondary enrichments. In the FA procedure, GN broth was superior to either of the selenites as the secondary medium from which to prepare smears, giving more FA-positive pools, a higher percentage of confirmed positives, and a lower percentage of false negative pools. FA examination of litter samples can be expedited by using sample pools. A major deficiency of the FA technique was the high percentage of false-positive reactions as judged by inability to isolate salmonellae. From litter cultured directly in TBG, salmonellae were isolated from 97% of the total number of pools culturally positive by combined culture methods.


Clinical trial with a new substance (PLP 100-127) in order to asses therapeutic efficacy and dependence creating properties.

The objectives of the study have been to evaluate the therapeutic efficacy of PLP 100-127 (6-(4-methyl-l-piperazinyl) morphanthridin) on patients with moderate to severe insomnia, to evaluate safety and tolerance of the drug and to investigate whether or not the drug may have dependence producing properties through the possible development of mental and/or physical dependence. A clinical-therapeutical long-term comparsion as a double blind cross-over investigation between PLP 100-127 and nitrazepan is presented. 30 patients at Gaustad hospital, mainly long-term patients with the diagnosis of schizophrenia, were selected for the trial, which lasted for 38 weeks. There were 9 drop outs, mainly due to relapse of psychotic symptoms. PLP 100-127 seems to have a favorable effect on moderate and severe insomnia in patients suffering from severe mental diseases. It seems to be well tolerated in these groups of patients. No signs of dependence producing properties have been observed by the observation method here presented.


The specificity of a 7 alpha-hydroxy steroid dehydrogenase from Escherichia coli.

1. Thirty-eight steroids were tested as substrates for a 7 alpha-hydroxy steroid dehydrogenase preparation from a strain of Escherichia coli; an improved method of making the crude enzyme is described. 2. Steroids having a 7 alpha-hydroxyl group in the molecule were substrates except (a) when the 5 beta-cholan-24-oic acid side chain was shortened to less than four carbon atoms and (b) in certain cases when sulphate ester groups were present in the molecule. 3. For testing with the enzyme, a new specimen of 7 alpha-hydroxy-3,12-dioxo-5 beta-cholan-24-oic acid was made, which had properties different from those previously described.


Replication of the deoxyribonucleic acid of multiple-drug-resistance factor in Escherichia coli.

1. It was shown that a system previously described for labelling R-factor DNA during transfer to an irradiated recipient strain of Escherichia coli did not allow high selectivity in the incorporation of thymine into R-factor DNA. 2. Lack of selectivity was shown to be due to cross-feeding from recipient to donor strain. 3. An improved system using a nalidixic acid-resistant recipient strain is described in which incorporation of thymine into the DNA of donor cells is minimized by addition of nalidixic acid after completion of transfer of the plasmid during conjugation.


Histopathological and pharmacological studies on the action of a new anti-inflammatory agent (BR 700).

The effect of a new anti-inflammatory agent, 2-phenyl-4-p-chlorophenyl-thiazol-5-ylacetic acid (BR 700) on the development of cover slip granuloma was studied. The drug decreased macrophage emigration and delayed some characteristic processes of the mononuclear cells.


[The influence of pivmecillinam on the human gut flora (author's transl)].

The effect of pivaloyloxymethyl ester of 6-beta-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid (pivmecillinam, FL 1039) on the gut flora of human subjects was investigated at different doses. Following administration of 1.2 g or 2.4 g/die E. coli and other enterobacteriaceae species were markedly reduced. The response of enterococci and bacteroides species showed no uniformity. No overgrowth of the gut flora by Pseudomonas, Staphylococci or Candida was observed. Meanwhile it has been possible to inspect stool specimens of a patient who was suffering from a septicaemic Salmonella infection and was treated with a combination of pivmecillinam-HCl 4 X 800 mg/pivampicillin-HCl 4 X 350 mg/die for one month. After disappearance of Salmonellae during therapy enterobacteriaceae decreased to amounts of 10(2)--10(4), all strains of which were highly susceptible to mecillinam.


[Betaines of quaternary salts of pyridine-2-and -4-aldoxim (author's transl)].

The monobetaine derived from the AChE-ractivator bis-[4-hydroxyiminomethyl-pyridinium-(1)-methyl]-either dichloride (obidoxim; Toxogonin), was shown to be in solution an intramolecular CT-complex. Some betaines of quaternary salts of pyridine-aldoximes were isolated.


Characteristics of patients with serum antibodies to extractable nuclear antigens.

A distinguishing feature of the mixed connective tissue disease (MCTD) syndrome is the presence in the serum of antibody in high titer to ribonucleoprotein (RNP). To determine whether this was an exclusive observation, a large rheumatic disease population was surveyed for the presence of antibody in high titer to extractable nuclear antigens (ENA) including RNP. Of 650 sera examined, 440 (from 240 patients) had antinuclear antibody. Only 39 patients had serum antibody to ENA in titers greater than or equal to 1:200 dilution. In 16 the anti-ENA was shown by RNAse digestion to be anti-RNP. Although many clinical and laboratory characteristics were similar in these two groups, the patients more closely resembled the previously described MCTD syndrome and, importantly, less often had severe renal and central nervous system disease manifestations. Thus the presence of serum antibodies to ENA that are predominantly RNAse-sensitive (anti-RNP) helps to identify a rheumatic disease syndrome and also appears to have prognostic value.


[On the efficacy of carbocromen in the treatment of myocardial infarction (author's transl)].

Comparative clinical trials on 100 infarcted patients have demonstrated the therapeutic superiority of 3-(2-diethylamino-ethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensain). 50 patients were treated eith carbocromen and 50 with papaverine as controls. Overall improvement under the influence of carbocromen was observed. Carbocromen eliminates ischemic pain, in contrast to papaverine, without any change in blood pressure even in the case of i.v. administration. The typical pathological changes in the ECG were normalized more rapidly and disturbances in the cardiac rhythm have been observed in only one case in the carbocromen group, while in the papaverine group extrasystolic arrhythmias, paroxysmal fibrillation and disturbances in atrioentricular conduction often occurred. Acute cardiovascular insufficiency in carbocromen treated patients was observed in only one case, but in 6 patients of the papaverine group. Out of the patients who displayed the same unfavorable prognosis, 6 patients died of the papaverine group and only one of the carbocromen group. By all patients carbocromen was well tolerated and there were no side-effects. Due to the results of our investigations the application of carbocromen in the treatment and prophylaxis of myocardial infarction is of advantage.


Significance of persisting serologic abnormalities in SLE.

The significance of abnormal serum anti-DNA and complement levels persisting in SLE patients on treatment has been explored. Instances when serologic abnormalities returned to normal were followed by a significantly longer mean duration of remission. When anti-DNA persisted at abnormal levels, a more severe exacerbation was likely to follow, although this result was not the case for persisting hypocomplementemia. These data did not result from two variants of SLE, one mild and one severe, because druation of remission correlated directly with dosage of steroid. Randomly discovered abnormalities in anti-DNA and complement levels were of limited predictive value, because they frequently persisted for over 1 year before exacerbations occurred. Hypocomplementemia resolved spontaneously without recognizable exacerbation in nearly half the observed instances.


Comparison of the complement-fixing activity of antinuclear antibodies in lupus nephritis, mixed connective tissue disease, and scleroderma.

Complement-fixing antinuclear antibody (CFANA) titers were measured in 18 patients with lupus nephritis and were compared to titers in 22 patients with scleroderma and mixed connective tissue disease (MCTD) who had comparable ANA titers but lacked nephritis. CFANA titers were higher in SLE patients with nephritis than in a control group of SLE patients without nephritis but were no higher than in scleroderma or MCTD. Thus the striking differences in the prevalence of nephritis among these patients with high titer ANA cannot be explained by differences in complement fixation by these antibodies.


Effect of fenoprofen calcium on acute gouty arthritis.

Twenty-seven patients with thirty-six joints affected with acute gouty arthritis were treated with fenoprofen calcium for a duration not exceeding 8 days and with a variable dose not exceeding 3.2g daily. The results indicated that fenoprofen calcium was an effective drug in these patients. Side effects were modest.


[Further results of a multi-centre clinical trial with the oral antidiabetic drug glisoxepide (author's transl)].

The oral antidiabetic agent 1-(hexahydro-1-H-azepin-1-yl)-3-(p-[2-(5-methyl-isoxazol-3-carboxamido)-ethyl]-phenylsulfonyl)-urea (glisoxepide, BS 4231, Pro-Diaban¿) was studied in a multi-centre open clinical trial comprising 4337 patients and was found to be an effective therapeutic agent for maturity-onset diabetics. About 66% of the patients had been pre-treated with oral antidiabetics. 54.7% of those 3572 patients treated with Pro-Diaban for at least 3 months achieved stabilization, which was classified according to strict criteria as "good", 73.4% achieved at least "satisfactory" stabilization. 12.5% of the cases dropped out after having received at least 12 mg/day because of inadequate efficacy of Pro-Diaban; 51.9% of these patients dropped out in the first 3 months (early failures 6.9% of the total case number). 61.9% received their daily dose in one portion, 29% in two and 10% in three portions. 98% received maximally 16 mg, 70% maximally 8 mg, and 42% 4 mg per day. Hypoglycaemic episodes led in 0.9% to a termination of the trial. In 1.22% of the cases the trial was terminated because of side effects, in 0.18% of cases they consisted of allergic or suspected allergic complaints and in 0.69% they consisted mainly of gastro-intestinal symptoms. Of the side-effects which did not lead to a termination of the trial, dizziness, headache and nausea were the relatively more frequent symptoms. An analysis of the laboratory data under consideration of pathological and normal initial and subsequent values showed that under the influence of Pro-Diaban pathological data reverted to normal more frequently than initially normal values changed to pathological ones. The analysis of laboratory and blood pressure data from 4 subgroups of patients, e.g. patients with diseases of the liver or the kidneys and hyperlipaemic or hypertensive patients, revealed that those data of special interest in each subgroup had mostly improved or remained unchanged under Pro-Diaban.


Areca nut: a review.

Areca cattechu Linn is commonly known as areca nut or betel nut. It is a very widely cultivated plant in eastern countries like India, Bangladesh, Ceylon, Malaya, the Philippines and Japan. The importance of this nut is due to its use for chewing purposes. It had an important place as a pharmaceutical in Ayurveda--the ancient Indian system of medicine--also in the Chinese medicinal practices. The pharmaceutical importance of areca nut is due to the presence of an alkaloid, arecoline. Synthetic arecoline hydrobromide is also shown to possess numerous pharmacological properties. Chewing of "betel quid" or areca nut is a typical oriental habit. Betel quid comprises betel leaf, areca nut, catechu, lime and sometimes also tobacco. It is shown that there exists a correlationship between betel quid or areca nut chewing habit and oral cancer. A number of investigators have been able to produce cellular changes such as leukoplakia by application of betel quid or areca nut extract to the buccal mucosa of different  animal.


[Methodological problems of the clinical research on rhythms in depressive patients (author's transl)].

The working hypothesis is discussed that desynchronized rhythmic functions are at the root of endogenous depression. Methods and problems of the clinical research on rhythms in depressives are concerned with the assessment of data, experimental conditions, technical procedures and the personality of the depressive patient in his predicament. Investigations of groups of patients are considered critically, the necessity of intraindividual long-term studies is emphasized.


[Studies on a novel antidepressant (viloxazin) by means of time-series analysis of TV data].

19 depressed patients were treated with viloxazin (n = 9) or  amitriptyline (n = 10) in a double-blind-trial. TV-tapes were produced for each patient on day 0, 10 and 20. These tapes were analysed with respect to the intensity of depression by 4 independent raters under the condition of a time-blind analysis. These 3 TV-tapes could easily be discriminated in the sense of a decreasing depressivity. The results suggest that the effect of viloxazin has a shorter delay than that of amitriptyline.


[On the dose-effect relationship in the therapy with piracetam (author's transl)].

The effect of piracetam therapy with different dosages was studied in a double blind trial against placebo on its effect in psychoorganic syndrome of old age. 78 patients (61 females, 17 males) on the average of 73.2 years, showed statistically significant differences between piracetam therapy at a dosage of 3 X 1600 mg per day und placebo after a six week peroral therapy while no statistically significant differences between piracetam therapy at a dosage of 3X800 mg per day and placebo were found.


[Comparison of the effects of the anthracene derivative danitracen (WA335-BS) and amitriptyline in depressive patients (author's transl)].

9,10-Dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol (danitracen, WA 335) is a substance with a stronger peripheral and partly central antiserotonin and antihistamine effect than cyproheptadine. In 5 different hospitals, WA 335 (3 X 1 mg/die) was investigated versus amitriptyline (3 X 50 mg/die) in a double-blind study in 116 depressive patients of different nosology. In the end of the investigation period (20 days), under WA 335 treatment 67.7% and under ami-riptyline treatment 66.7% of the patients showed an improvement of 50% = decrease in the Hamilton depression score. However, a decrease of 50% in the selfrating scale (von Zerssen) was only shown by 57% of the patients under WA 335 administration and 51% under amitriptyline administration. There were no significant differences seen as regards course and side effects of the two drugs. Like amitriptyline, WA 335 shows sedative properties at the beginning of therapy.


Clinical and pharmacological effects of treatment with a new antidepressant.

The novel tetracyclic piperazino-azepine compound Org GB 94 (Tolvon, Tolvin) in a dose of 20 mg three times daily was found to be of save markedly and significantly less side-effects. Patients with reactive depression and those with endogenous depression reponded equally well to Org GB 94. No correlation was found between plasma levels of Org GB 94 and either clinical effects or side-effects. Org GB 94 did not alter the tyramine pressor response, in contrast to amitriptyline.


[Double-blind comparative study on the effects of lofepramine and amitriptyline in depressive outpatients (author's transl)].

The anticholinergic side-effects of tricyclic antidepressants are unpleasant for the patients. Lofepramine, a new tricyclic antidepressant, has in animal studies been shown to have weak anticholinergic effects and a low acute toxicity. The aim of the present study was to see whether these pharmacological properties led to a lower rate of side-effects in depressed patients. In a double-blind trial 40 outpatients were treated with lofepramine or amitriptyline. Assessments were made with the Hamilton Scale, the Wakefield Self-Assessment Scale and a Side-effect Scale. 33 patients completed the trial. Both drugs proved effective. There were small differences in favour of lofepramine both in therapeutic efficacy and frequency of side-effects.


[Doubleblind study with the novel antidepressant viloxazine versus imipramine in 50 in-patients (author's transl)].

In this double-blind study on 50 depressive patients viloxazine in dosages between 150-300 mg/die, showed to be a very active and well tolerated thymoleptic substance. Its profile of activity seems similar to that of imipramine. The differences in favour of viloxazine were: a more rapid onset of its effect, a more balanced stimulation of energetical level versus clearing up to depressed mood, evident better results in patients aged over 50, fewer drop-outs on account of complications (especially confusional states or psychotic symptom provocations) and fewer side-effects such as vegetative disfunction, vertigo, and weight increase. More initial fatigue reactions, slight sleep disturbances and 3 hypertensive transient reactions must be emphasized on the side of viloxazine.


[Are anticholinergics indispensable in the long-term therapy of neuroleptic-induced Parkinson syndrome? A withdrawal study (author's transl)].

53 patients with a neuroleptic-induced parkinson syndrome were suddenly withdrawn from their antiparkinson medication without changes in neuroleptic medication. All but 10 patients had been given antiparkinson drugs for more than 1 year. Slight and constant deterioration in their condition occurred in 4 female patients within 1-3 weeks following withdrawal. The neuroleptic dose was increased in 7 patients, a slight transient deterioration of the parkinson symptoms occurring in 2 cases. Investigation into the longitudinal course of the disease revealed that the intensity of symptoms is not always steady, but that certain variations occur. Our results confirm similar available studies in that the incidence of relapses in cases of neuroleptically conditioned Parkinson's disease is very low in patients with anti-parkinson medication for long period; this incidence of relapses amounts to 8% in our study.


[Proceedings: D-Amphetamine in manic syndrome (author's transl)].

Six manic patients were acutely treated with 30 or 50 mg d-amphetamine, respectively. There was no intensification in any of these patients of gross manic behavior or single manic symptoms. Conversely, there was sedation and considerable reduction of manic symptomatology in all of them. This effect lasted for 1 to 3 h only. The clinical subgroup "elated-grandiose" was significantly, the subgroup "paranoid-destructive" was not significantly influenced. "Drive" and "mood" were similarly reduced. There was, however, no complete recovery from mania.


[Double-blind study on the therapy of postural hypotension in psychotic patients under psychotropic medication (author's transl)].

13 psychotic patients developing various degrees of postural hypotension during neuroleptic or antidepressant treatment were additionally given either placebo or a mineralocorticoid or a sympathomimetic drug. As shown by Schellong tests during therapy the best effect on postural hypotension was achieved by the mineralocorticoid. The statistical evaluation of the randomised study was significant.


[Long-term tranquilizers - an alternative in medical practice (author's transl)].

Over a period of 7 to 12 weeks we studied 3 series of 274 patients with depressive and somatic complaints treated with the long-acting neuroleptic fluspirilene in a dosage of 1-1.5 mg weekly. By means of various rating scales it was compared to diazepam in regard to its tranquilizing effects. Fluspirilene showed good activating and antidepressive qualities, which were superior to those of diazepam, whereas somatic complaints responded equally well to both drugs. The indications for a long-acting tranquilizer with the advantage of a controllable application are being discussed.


Focal glomerulonephritis.

Focal glomerulonephritis show a pathologic involvement of some glometuli and a normal aspect of the others. It happens in many different kidney diseases as SLE. Shonlein-Henoch syndrome, Goodpasture syndrome, recurrent hematuria. Although focal by light microscopy there is a diffuse pattern of immunoglobulins revealed by immunofluorescence techniques. There are clearly several different pathogenetic mechanisms and the factors which deterline the focal nature of the entity are poorly understood.


[Proliferative diffuse glomerulonephritis (author's transl)].

Some aspects of the diffuse proliferative glomerulonephritis have been examined: initial renal failure, evolution of the lesions, crioglobulinemia. Thirty-five of 88 cases presented high urea levels, in 3 of them with acute renal failure transient hemodialysis treatment was needed, only one case progressed toward chronic renal failure. Anatomic alterations either in the case of exudative or proliferative damages improved but not up to complete healing: mesangial tickening and local proliferation has been observed. Crioglobulinemia was found in 14 of 21 cases. The disappearance in two cases of the crioglobulinemia was accompanied by a significative improvement of the hystology; a persistent crioglobulinemia usually accompanies unmodified histologic alterations.


[Kidney preservation methods (author's transl)].

The results of preservation of the two kidneys of the same animal by two different techniques and then reimplanted on the same femoral artery, have been compared. The two methods are the following: 1) Short starting perfusion by Collins solution and than cold storage a 4 degrees C in the same solution. 2) Continuous perfusion by machine supplied by pulsatile pump, oxigenator, cooling. The first more impressive result by using continuous perfusion is the possibility of nullifying the effects of warm ischemia up to 30'. Kidney preservation with continuous perfusion is like to give less problems in the postoperatory period. Some weeks after transplantation however, the problems seems to increase in comparison with kidneys stored in Collins solution and not rarely sudden GFR decreases or anurias without immunologic rejection has been observed. Cautious conclusion should advise to use Collins solution when there has not been a long warm ischemia.


Microvascular thrombosis in the pathogenesis of chronic renal disease.

Haemostatic involvement in the pathophysiology of renal disease has been evaluated kinetically. Renal microvascular platelet destruction is characteristic of several different pathologic processes in which there is damage to intrarenal endothelial cells. The hemostatic abnormalities may be partly modifiable by drugs which inhibit platelet function, rather than by anticoagulant, but there is as yet no evidence that interruption of platelet consumption will cause improvement in renal function.


Results of total correction of the tetralogy of Fallot. Long-term haemodynamic evaluation at rest and during exercise.

Postoperative haemodynamic evaluation was performed on 15 patients 7 to 14 years (mean, 11 years) after total intracardiac repair of Fallot's tetralogy. The average age of the patients at the time of postoperative catheterization was 20 years (range 12 to 29) and they were all asymptomatic. Before operation 11 patients were severely cyanosed and disabled and 4 had mild cyanosis with anoxic spells. The cardiac output and right heart pressures were measured at rest and after 5 minutes of submaximal exercise on a bicycle ergometer. It was shown that the degree of residual obstruction of the pulmonary outflow tract was slight and that the right ventricular/pulmonary arterial systolic gradient (RV/PA gradient) exceeded 20 mmHg (2-6 kPa) at rest in only 3 patients. The mean cardiac index at rest was 5-4 l min-1 m-2 which increased to 8-3 l min-1 m-2 during exercise. The response of the cardiac output during exercise was either normal or supranormal in 14 of the 15 patients. In the remaining patient the response was marginally below the normal range. Pulmonary valvular regurgitation was present in 8 patients but there was no detectable difference in the cardiac function of these patients compared with patients with competent pulmonary valves. Six of the patients investigated had also had cardiac catheterizations performed 1 to 4 years after operation. The results of the present study show that remarkably little change has occurred in their haemodynamic status in the intervening years. Though these results are encouraging, further studies are required to determine the eventual outcome of the RV pressure and volume overload.


Effects of trace anaesthetic gases on behavioural performance of volunteers.

Nitrous oxide and halothane, in concentrations as low as 50 p.p.m. and 1.0 p.p.m. respectively, caused measurable decrements in performance in psychological tests in healthy male volunteers. Nitrous oxide alone caused similar effects. The functions apparently most sensitive to these low concentrations of anaesthetic agents were visual perception, immediate memory, and a combination of perception, cognition and motor responses required in a task of divided attention to simultaneous visual and auditory stimuli. These effects were absent in subjects exposed to nitrous oxide 25 p.p.m. and halothane 0.5 p.p.m.


Immune-mediated reactions to althesin (alphaxalone).

Measurements of complement conversion and white cell variations were made on sequential blood samples obtained from a single volunteer following repeated administration of Althesin. The results suggest a mechanism by which a clinically significant hypersensitivity reaction to the drug might be mediated. Studies of patients receiving routine anaesthesia revealed a very high incidence of subclinical "hypersensitivity" reaction, some of which appear to be immune-mediated. These reactions occurred irrespective of whether the patients were induced with Althesin, methohexitone or propanidid.


The effects of adding adrenaline to etidocaine and lignocaine in extradural anaesthesia I: block characteristics and cardiovascular effects.

The addition of adrenaline 5 mug/ml, 1 : 200 000 to 1% etidocaine hydrochloride administered extradurally (L2-3) shortened significantly the onset time for sensory blockade, particularly with respect to the spread of the analgesia from the injection site, and shortened the already rapid onset of motor block. Etidocaine hydrochloride 1% plain caused a slower onset of block, laster longer and produced more profound analgesia over the caudal dermatomes than did 2% lignocaine hydrochloride. The motor block from plain etidocaine was more profound in its extent and lasted longer than that caused by lignocaine. With regard to cardiovascular variables, there were no significant differences between subjects receiving the plain etidocaine and the plain lignocaine. However, subjects receiving etidocaine with adrenaline exhibited increased cardiac stimulation and a decrease in total peripheral resistance over the first 150 min.


Supplementation of general anaesthesia with narcotic analgesics.

Four analgesic drugs--fentanyl, phenoperidine, morphine and pethidine--were compared in a double-blind trial involving 113 patients paralysed and ventilated with nitrous oxide and oxygen. The differences between the drugs were relatively small. There were only slight differences in "duration of action", a term which is questioned in this context. Pethidine appeared to have a slightly longer duration of action than the other drugs. The problems inherent in studying analgesics in this manner are discussed.


Cardiac arrhythmia during outpatient dental anaesthesia: the advantages of a controlled ventilation technique.

Two techniques for endotracheal anaesthesia in dental outpatients have been compared: a spontaneous ventilation technique using nitrous oxide, oxygen and halothane, and a controlled ventilation technique using nitrous oxide and oxygen, with tubocurarine and fentanyl. The latter technique has several advantages: abolition of arrhythmias induced by surgery, more rapid and hence safer recovery, avoidance of suxamethonium, and avoidance of atmospheric contamination with and possible sensitization to halothane.


The effect of suxamethonium alone and its interaction with gallamine on the indirectly elicited tetanic and single twitch contractions of skeletal muscle in man during anaesthesia.

Simultaneous measurements of tetanic and single twitch contractions of the adductor politics muscle in man were made during neuromuscular blockade induced by suxamethonium (0.2 mg/kg) under nitrous oxide, oxygen and pentazocine anaesthesia. 2. After a suitable control period, suxamethonium (0.2 mg/kg) was given intravenously and the same dose was repeated 15 min later. After a further 15 min gallamine (0.2 mg/kg) was administered intravenously. When recovery from gallamine reached a plateau on the tetanic contraction recording a third injection of suxamethonium was given. 3. In most patients, suxamethonium (0.2 mg/kg) caused a partial blockade of the single twitch and complete blockade of the tetanic contraction. In every instance, the tetanic contraction was more depressed and recovered more slowly than the single twitch which not only recovered promptly but also showed overshoot. 4. After gallamine marked antagonism to suxamethonium block developed and this was greater with the single twitch than with the tetanic contractions. 5. Tetanic-tension fade was observed after every injection of suxamethonium and the degree of fade was dependent on the frequency of the tetanic stimulation.


Comparative trial of propranolol and practolol in hyperthyroidism.

The possible role of practolol in the management of hyperthyroidism has been studied by comparing it with propranolol. 2. In a double-blind cross-over trial, propranolol (40 mg), practolol (120 mg) and a placebo four times daily for one week were compared in twenty-one hyperthyroid patients by sequential analysis. 3. Judged by their effect on the symptoms and signs of thyrotoxicosis, both propranolol and practolol were significantly better than the placebo but no clear distinction could be made between the two active compounds. 4. Propranolol and practolol reduced heart rate by 24 and 17% respectively compared with placebo. 5. Patients generally preferred propranolol or practolol to placebo but this preference did not achieve significance with either drug. 6. Only in its effect on heart rate was practolol significantly inferior to propranolol, and it would appear to be a useful alternative to propranolol in the management of the peripheral manifestations of hyperthyroidism.


Comparison of the effects of acebutolol (Sectral) and practolol (Eraldin) on airways obstruction in asthmatics.

The effects of oral practolol (Eraldin, I.C.I. Ltd) (300 mg) and acebutolol (Sectral, May & Baker Ltd) (300 mg) were compared in a placebo-controlled, crossover study in ten asthmatics. 2. Pulse rate, forced expiratory volume in one second (FEV1) and specific airways conductance were measured before and after a bronchodilator and the same procedure was repeated after taking acebutolol, practolol or placebo. 3. A mean increase in resting airways obstruction and reduction in bronchodilator response were evident with both drugs. The differences were statistically significant only after acebutolol for the logarithm of specific conductance. Mean plasma levels of the two drugs were similar. The response to both drugs was similar in the same patient and unrelated to severity of asthma. Mean reduction in resting pulse rate was statisitcally greater after acebutolol compared with placebo but not after practolol compared with placebo. 4. In any individual the beta-adrenoceptor blocking response is unpredictable and any beta-adrenoceptor blocking drug must be used with extreme caution in asthmatics.


Pharmacokinetic and pharmacological studies with tolamolol in man.

Pharmacokinetic and physiological variables were measured in six healthy subjects after intravenous and oral administration of tolamolol. 2. After intravenous injection of tolamolol (20 mg), there was a biphasic decline both in plasma concentration and attenuation of maximum exercise tachycardia. First and second phase half-lives of plasma concentration were 7 min and 2.5 h respectively. WReduction of maximum exercise tachycardia declined from 32 beats/min at 2 h to 19 beats/min at 8 hours. Clearance of tolamolol from blood ranged from 0.8-1.41 min-1. 3. After the oral administration of tolamolol (100 mg), the average volume of distribution was 220.1 and plasma concentration half-life 1.8 hours. After ten eight-hourly doses of 100 mg there was no accumulation of tolamolol and the half-life of plasma clearance was unchanged. 4. Hydroxytolamolol was detected in plasma in two of six subjects after oral tolamolol. 5. There was a significant positive correlation between reduction in maximum exercise heart rate and logarithm of plasma concentration of tolamolol after both oral and intravenous administration.


Hepatic drug-oxidizing enzyme systems and urinary D-glucaric acid excretion in patients with congestive heart failure.

Drug-oxidizing enzyme systems in liver biopsy samples and the urinary excretion of D-glucaric acid were studied in two different groups of patients with cardiac insufficiency. 2. In one group of six patients, the activities of drug-metabolizing enzymes had decreased considerably as compared with the control values, but in four liver samples from patients treated with oral hypoglycaemic agents for their diabetes, activities were higher than in control samples from ten patients. 3. In the other group of seven patients, the urinary excretion of D-glucaric acid (isolated by ion-exchange chromatography) was 60% lower than in the control group of nine humans, whereas in four patients taking antiepileptic agents excretion rate was higher than control values. 4. Because the age distribution was markedly different between cardiac insufficiency and control groups, it is difficult to conclude, if the impairment of drug metabolism was a consequence of the old age or of the disease process. However, drug-oxidizing enzyme systems seem to be inducible also in old age. 5. The results support further the opinion that the urinary excretion of D-glucaric acid may be one useful index in assessing an individual's capacity to metabolize foreign compounds especially in the patients with lowered drug metabolizing capacity.


Phenylbutazone: a clinico-pharmacological study in rheumatoid arthritis.

A clinical trial of phenylbutazone in high dose (300 mg daily) and low dose (50 mg daily) is presented. 2. By analysis of the data by different methods, significant differences in clinical efficacy were shown between the two therapeutic regimes. 3. A relationship between the clinical effect and plasma level of phenylbutazone was demonstrated. 4. Some problems in the interpretation of plasma level-clinical effect correlates are discussed.


The administration of cephradine to patients in renal failure.

Cephradine was given to two control and twenty subjects with varying degrees of renal failure. Serum levels at various times were recorded and side-effects noted. Recommendations for dosage schedules for subjects with renal failure have been made.


Control of epilepsy with a single daily dose of phenytoin sodium.

Fifty-three patients in an epileptic centre have been studied. All were receiving phenytoin and many were also receiving other antoconvulsant drugs. 2. Thirty-six patients took part in a three month cross over study. There was no significant change in the frequency of epileptic seizures or in the late morning serum concentration of phenytoin when the treatemtn was changed from two to three spaced doses of phenytoin sodium/day to a single dose at 12.00 hours. 3. Seventeen patients acted as a control group. They received phenytoin sodium as two or three spaced doses/day throughout the study. There was no significant change in the frequency of epileptic seizures or in the late morning serum concentration of phenytoin between the first and second three month periods of observation. 4. It is concluded that the total daily dose of phenytoin sodium may be given once daily without reduction of the anticonvulsant effect.


The planning of a clinical trials workshop.

The groundwork involved in the planning and running of a Clinical Trials Workshop using a computerized simulation exercise called 'Instant Experience' is described in detail. 2. Groups of six or seven students, each with an experienced tutor, are set the problem of designing a clinical trial protocol for a given drug. By using a computer programme, results can be generated for these designs according to pre-set rules laid down by the organizers. 3. The game itself acts as a vehicle for emphasizing the practical and theoretical problems associated with clinical trials. Further valuable information can be imparted during the group discussion periods when the trial design is being developed and during analysis of the results. 4. Limitations of this type of workshop include the need for students to have a working knowledge of clinical medicine and pharmacology, the competence of the tutors and organizers and the technical problems associated with computers and a comparatively rigid computer programme. 5. The value of this type of workshop lies in its ability to allow students to apply themselves to practical problems in clinical trials and to make mistakes with no harm to the patient.


In vitro and in vivo evaluation of T and B lymphocyte functions in AKR mice.

To investigate whether AKR spontaneous leukaemogenesis is associated with a reduction in functional activity of T lymphocytes, the PHA response of AKR blood cells at different ages up to and including the preleukaemic period was studied. No significant differences were observed among young, adult and preleukaemic donors. In addition, the in vitro and in vivo AKR lymphocyte functions were compared with those of CBA lymphocytes by means of their response to stimulation with T and B lymphocyte selective mitogens (PHA, Con A and LSP respectively), and their response to immunization with thymus dependent (SRBC) or independent (LPS) antigens. We observed in vitro that while the B lymphocytes responded normally to mitogen, an intrinsic hyporeactivity to mitogens characterizes the T lymphocytes. Moreover, AKR mice exhibited a reduced in vivo response to both thymus dependent and independent antigens.


5-year follow-up of cytotoxic chemotherapy as an adjuvant to surgery in carcinoma of the bronchus.

This report gives the 5-year findings of a double-blind study of long-term cytotoxic chemotherapy as an adjuvant to surgery in patients receiving busulphan or cyclophosphamide for carcinoma of the bronchus compared with a group receiving a placebo. Of 243 patients initially allocated busulphan, 234 cyclophosphamide and 249 placebo, 28%, 27% and 34% respectively were alive at 5 years. There were significant associations between mortality from bronchial carcinoma and histological involvement of the resected intrathoracic nodes and the histology of the tumour. Haematological toxicity, especially thrombocytopenia, was frequent and severe in the busulphan series, and low platelet counts continued long after chemotherapy was stopped.