Fifth Daniel C. Baker Jr. Memorial Lecture. Resident education: past, present and to where. The specialties in medicine and surgery developed slowly during the later 19th century and the early decades of this century. The American boards were the focal points for sponsoring specialty societies through which these developments occurred. The resident review committees have also played an important role. Otolaryngology resident education has developed into a progressively structured educational experience so that presently otolaryngology resident education is a broad experience in head and neck oncology, plastic and reconstructive surgery, otology, laryngology, rhinology, allergy and immunology, bronchoesophagology, teaching and research. Resident education is not static. The year of 1978 can be noted as the year of change, for the Resident Review Committee in Otolaryngology recommended that resident education be of five years in duration, one year being in surgery, three years in otolaryngology and one year being elective as to content. Such programming can be highly structured to meet a candidate's present and future needs in manpower, superspecialization and general otolaryngology. In this system superspecialization can and will be recognized and awarded through channels already established in otolaryngology. Manpower and general otolaryngology will also profit.


The aetiology of colonic suture-line recurrence. Cell viability studies have been performed on human desquamated colonic cancer cells obtained by both in-vivo and ex-vivo techniques, and on desquamated colonic cancer cells from an experimental animal model. There was no evidence of cell viability and I conclude that the hypothesis that suture-line recurrence occurs as a result of the implantation of desquamated tumour cells is of questionable validity. Field change in the colonic mucosa has been studied by examining the reactions of the mucosubstances in the goblet cells. A potential correlation between transitional mucosa at the anastomosis and the development of suture-line recurrence was found and warrants further study. The clinical problem has been investigated by the clinicopathological study of 16 patients developing suture-line recurrence in an attempt to discern the aetiology of each. In all but one the recurrence was due to incomplete excision of cancer or, in one instance, a second primary growth.


Transposition of muscle flaps for covering exposed bone in the leg. A muscle transposition technique for reconstruction of soft tissue loss and skin defects with exposed bone in the leg is described. Reconstruction with muscle flaps and freee skin grafts is a reliable and convenient one-stage operation. The gastrocnemius and soleus muscles were used to cover the upper and middle third of the leg. The method was used in 13 patients, and there were 3 failures in the series because of the impaired vascularity of the injuried leg. In 7 cases, including one failure, the soft tissue injury was associated with compound fractures. No functional disability was observed in the leg, ankle or foot after successful transposition of the muscle flap.


[Diagnosis of strongyloidiasis using the E.L.I.S.A. test (author's transl)]. An immunoenzymatic test, the E.L.I.S.A. test is used to diagnose human Strongyloidiasis. First results show that this reaction can complete other investigational methods already in use to diagnose this affection, i.e. coproanalysis and intradermal reactions, both in epidemiological studies and individual cases. In addition, the test is a good means of assessing the effectiveness of treatment.


Tracheo-arterial erosion complicating tracheostomy. Tracheo-arterial erosion occurred in 5 cases out of 816 tracheostomized patients, i.e. an incidence of 0.6%. The complication is serious and is nearly always fatal. In one case, treatment was successful, but the other four patients died as a result of massive haemorrhage. On the basis of these cases the factors leading to this complication and the possibilities of treatment are discussed. In one case the main cause of innominate artery erosion was the low lying tracheostomy. This patient was rapidly resuscitated, the blood volume was restored, bleeding controlled by direct finger pressure on the innominate artery and an emergency operation was performed immediately. The innominate artery was excluded from circulation and bypassed with an autogenous venous graft. The patient recovered and is doing well after a follow-up of two and half years.


[Gonadotropic activity in cultured hypophyses. 1. Adult male rats]. Adenohypophysial tissue of adult male rats was cultivated for 15 days, in order to eliminate influence from rats other organs, and to obtain a stable spontaneous gonadotropins release in culture medium. It was then stimulated from 15th to 25th day of culture with LH-RH and/or testosterone. LH-RH-induced effects : 2 to 6 times increased LH release, and 2 times increased FSH release, declined from 15th to 25th day, suggesting a loss of receptivity to the stimulating hormone. Testosterone had two direct effects on adenohypophysis : first, when added alone to the culture medium, it did not inhibited LH release and stimulated (x2) FSH release; second, it partially inhibited gonadotropin response to LH-RH.


[Gonadotropin activity of newborn rat adenohypophysial tissue in culture compared to that of adult rats (author's transl)]. It has been suggested that low circulating levels of androgens and gonadotropins found in impubertal subjects is due to a low -- setted feed-back regulation system, i.e. sensitivity of that system is higher than that of adult subjects. Cultures of adenohypophysial tissue of 2 to 6 days old male rats were performed and gonadotropins release compared to that obtained from similarly conducted adult male rats pituitary cultures (previous paper). Newborn rat hypophysis was more sensitive to factors stimulating LH release (LH-RH) and FSH release (testosterone). In contrast, testosterone inhibition of gonadotropins response to LH-RH was similar to that of adult tissue. Since trophic factors influence could not be totally excluded, it was concluded that pituitary tissue does not show marked variation of sensitivity with age.


Transmission of chronic spongiform encephalopathy with kuru plaques from humans to small rodents. An unusual case of spongiform encephalopathy was transmitted directly from a human to rats and mice. After serial passages, incubation periods were shortened to about six months in rats and four months in mice. Clinical symptoms were similar in rats and mice, including ruffled fur, arched back, bradykinesia, and hind limb paralysis. Pathologically, a spongy state, proliferation of astrocytes, and neuronal changes were observed. Electron microscopic observation of the parietal cortex of rats and mice disclosed many membrane-bound vacuoles in the neuropil, predominantly in dendrites. In the pons of mice, intramyelinic vacuoles and accumulation of extracellular fluid were prominent. The clinicopathological symptoms of the affected animals resembled those in other experimental spongiform encephalopathies, especially scrapie.


Viroimmunoenzymoassay for detection of anti-penicilloyl antibodies and penicilloyl residues: comparison of results obtained by radio-, viro- and enzymoimmunoassay. A new technic named viroimmunoenzymoassay is described. The principle is the same as the classical viroimmunoassay which uses as tracer a bacteriophage bound covalently to an hapten. Immuno-specific neutralization of these modified bacteriophages by an hapten antiserum allows to detect and to test hapten antibodies or the haptens with a great sensitivity. In the new technic the visualization of the bacterial lysis is estimated by measure of the amount of beta-galactosidase which is released into the medium by Escherichia coli BB bacteria. These are previously induced by isopropyl thiogalactoside or lactose. The method is applied to the assay of penicilloyl groups bound covalently with another molecule, and its performances are compared with three other classical immunological methods: the radio-, enzymo- and viroimmunoassay.


Inhibition of Clostridium botulinum by p-hydroxybenzoic acid n-alkyl esters. Twelve straight-chain esters, C(5) to C(14), C(16), and C(18), of p-hydroxybenzoic acid were prepared, and their melting points, solubilities in water at 25 degrees C, infrared spectra, dissociation constants (pK(a)), and activities against Clostridium botulinum were determined. These studies also included four commercial straight-chain esters, C(1) to C(4). The most potent activity was exhibited by undecyl and dodecyl esters, which are about 300 times as active as sodium nitrite. Quadratic and cubic equations were developed correlating the activity with pK(a) values and chain length of the esters, respectively.


Clinical and laboratory evaluation of cefamandole in the therapy of Haemophilus spp. Bronchopulmonary infections. A prospective, randomized, single-blind comparison of parenteral cefamandole and ampicillin was conducted in 27 hospitalized adult patients with pneumonia or purulent tracheobronchitis due to Haemophilus spp. Patients received either parenteral cefamandole or ampicillin in a dose of 1 g every 6 h. Cefamandole was as effective and safe as ampicillin. Of the 14 patients treated with cefamandole, 13 were considered cured, as were 12 of the 13 treated with ampicillin. One patient in each treatment group improved clinically but did not clear his sputum of Haemophilus spp. One patient treated with cefamandole had a recurrence of Haemophilus spp. bronchitis 9 days after cure. Adverse effects were more common in the cefamandole-treated group (50% versus 15%), but were mild and did not require discontinuation of therapy in any patient. The in vitro susceptibilities of 64 clinical isolates of Haemophilus spp. to 10 antibiotics were determined. Cefamandole was the most active of the cephalosporin-cephamycin antibiotics tested, inhibiting 98% of 61 non-beta-lactamase-producing isolates at 2 mug/ml and 100% at 4 mug/ml. Cefamandole inhibited the three ampicillin-resistant isolates at 2 mug/ml or less. Cephapirin, cefoxitin, and cephalothin were the next most active, whereas cefazolin and cephradine were the least active.


Inhibition of transpeptidase activity in Escherichia coli by thienamycin. Thienamycin was shown to be a more potent inhibitor than ampicillin of the enzyme peptidoglycan transpeptidase from Escherichia coli.


Rapid, simple enzyme immunoassay for gentamicin. An enzyme immunoassay for gentamicin is described. The assay is accurate and specific and needs only simple equipment.


In vitro model simulating the form of exposure of bacteria to antimicrobial drugs encountered in infection. A new model, which is designed to investigate the in vitro activity of antibiotics as a function of different concentration-time curves, is described. The antibiotic is allowed to diffuse through a membrane into a bacterial culture until a peak level is reached; the antibiotic is then removed by flow-assisted back diffusion. With this arrangement it is possible to expose bacteria to a changing concentration of drug while maintaining a constant volume of bacterial culture. Preliminary studies were carried out to investigate the response of a strain of Escherichia coli to gentamicin. The results indicate that bacteria surviving exposure to concentrations of gentamicin similar to those obtained during therapy may exhibit an increase in resistance to the antibiotic.


Mode of action of the azasteroid antibiotic 15-aza-24 methylene-d-homocholesta-8,14-dien-3 beta-ol in Ustilago maydis. Ustilago maydis sporidia treated with 0.1 mug of azasterol (15-aza-24-methylene-d-homocholesta-8,14-dien-3beta-ol) per ml appeared branched and vacuolated after 6 h of incubation. Sporidial multiplication, dry weight increase, and synthesis of protein, deoxyribonucleic acid, and ribonucleic acid were only slightly or moderately inhibited during the initial 3 h of incubation. An increase of free fatty acids was observed in lipid extracts of treated sporidia after incubation for 3 h or more. Ergosterol synthesis was completely inhibited within 1 h and there was a gradual decline of ergosterol content during 6 h which was accompanied by an accumulation of the sterol intermediate ergosta-8,14-dien-3beta-ol. The results indicate that toxicity of the azasterol results from specific inhibition of the reduction of the sterol C-14(15) double bond. A triarimol-tolerant strain of Cladosporium cucumerinum was tolerant to the azasterol, but an imazalil-tolerant strain of Aspergillus nidulans was not.


Morphological changes of Escherichia coli induced by bicyclomycin. Electron microscopic studies with Escherichia coli revealed that bicyclomycin inhibits septum formation and converts the cells to filamentous forms. The antibiotic induced high undulation and numerous blebs of the outer membrane. Sometimes cytoplasmic contents leaked into the lumen of the bleb through a disrupted region of the membrane. Breakage of the outer membrane or blebs led to cell lysis. Electron-dense masses of amorphous material and vesicles were found in the cytoplasm.


Review of the current possibilities for arterial embolization in urology. Selective arterial embolization in urology is a new technique used in the management of a variety of urologic diseases. In the review of the literature on this subject the indications, techniques and materials used, and the complications are discussed.


Effects of pethidine and its antagonists on the newborn. Nalorphine and naloxone were compared as to their effectiveness as pethidine antagonists. 85 infants were divided into a control group containing 19 newborn babies whose mothers did not receive pethidine and the babies received no antagonist, and three groups in which the mothers all received pethidine and the babies had either no antagonist (24), nalorphine IV (16), or naloxone IV (26). All the babies were assessed by measuring their neurobehavioural states and respiratory functions. A further 12 newborn babies had naloxone plasma levels measured by radioimmunoassay. Although standard doses of nalorphine effectively antagonised the depressive effect on respiration induced by pethidine, there was a pronounced and undesirable excitatory agonist action. Naloxone was not observed to have any agonist activity, but the recommended IV dose (0.01 mg/kg) had only a slight and delayed antagonist action as measured by respiratory function tests. A more rapid and improved antagonism was noted after this dose was doubled (0.02 mg/kg). The plasma elimination-phase half-life of naloxone after intravenous cord injection was about 3 hours.20


Comparison of IV salbutamol with IV aminophylline in the treatment of severe, acute asthma in childhood. A double-blind test to compare IV aminophylline with salbutamol in the treatment of acute, uncontrolled asthma showed that both drugs were equally effective during the first 24 hours. Salbutamol caused a relative tachycardia. Hydrocortisone was given after 2 hours, but did not appear to affect the rate of recovery.


The recruitment of inflammatory cells using the skin-window technique. The chemotaxis of inflammatory cells induced by the skin-window technique using IgD as cytotaxigen or cytotaxinogen was studied in 16 patients with allergic contact dermatitis. Six patients with leg ulcer served as controls. By means of this method the recruitment of inflammatory cells with receptors for IgD could be shown.


Evidence for cell-mediated autoimmunity in patients with pemphigus vulgaris and bullous pemphigoid. Lymphoid cells from 4 of 5 patients diagnosed as pemphigus vulgaris (PV) and 6 of 7 patients diagnosed as bullous pemphigoid (BP) demonstrated specific cell-mediated immunity by the production of migration inhibitory factor (MIF) in the presence of autologous epidermal saline extracts. Clinical treatment of these patients with immunosuppressive agents resulted in a state of unresponsiveness of their lymphoid cells to similar concentrations of the antigen. Controls consisted of lymphoid cells from patients with bullous burns or various drug allergies which failed to show significant MIF production in the presence of autologous skin extract. These studies suggest that both PV and BP patients posses cell-mediated immunity (CMI) to their own autologous tissue antigens and this CMI may play a role in the pathogenesis of these diseases.


The treatment of recurrent malignant pleural effusion. Effective control of a recurrent malignant pleural effusion can greatly improve the quality of life of the cancer patient. At least a dozen different techniques have been advocated for controlling this common complication of malignant disease. The present review collects and examines the clinical results of all techniques designed to treat this problem. The pathophysiology and diagnostic evaluation of the effusion are also discussed. On the basis of comparisons involving effectiveness, morbidity, and convenience, we recommend intrapleurally administered tetracycline with thoracostomy drainage as the technique of choice. Instillation of a talc suspension with thoracostomy drainage is also a safe and effective technique and should be employed when tetracycline fails or is contraindicated.


Therapeutic value of anticonvulsant drugs in poisonings with an organophosphate. Therapeutic effects of phenytoin, pentobarbital, diazepam, trimethadione and phensuximide given as an adjuvant to atropine and obidoxime in fluostigmine intoxication were studied in the rat. It was stated that only trimethadione significantly elevated the LD50 value for fluostigmine in animals treated with atropine and obidoxime. None of the tested anticonvulsants raised the LD10 value above the LD90 value in animals treated only with atropine and obidoxime.


Antihypertensive comparison of furosemide with hydrochlorothiazide for black patients. Furosemide and hydrochlorothiazide were compared for treatment of black patients with mild to moderate hypertension in a randomized, open-label, crossover study design. Hydrochlorothiazide produced a significantly greater fall in mean arterial (24.7 vs 16.0 mm Hg, P less than .01) and diastolic (17.3 vs 10.1 mm Hg, P less than .01) blood pressure (BP) in 16 patients. Addition of methyldopa in nine patients produced a significantly greater fall in mean arterial (38.8 vs 31.9 mm Hg, P less than .05) and diastolic (28.9 vs 23.4 mm Hg, P less than .05) BP with hydrochlorothiazide vs furosemide. Renin status was categorized before and after treatment. Patients with low and normal renin activity were equally responsive to both diuretics. Hydrochlorothiazide caused a greater reduction in plasma potassium (0.26 mEg/L). Serum parathyroid hormone was not chronically elevated with furosemide. In this study, hydrochlorothiazide was more effective than furosemide for treatment of mild to moderate hypertension in black patients; renin classification did not predict diuretic responsiveness.


[The importance of mammography for the determination of tumor size in stage classification of breast cancer according to the TNM system (5-years-results) (author's transl)]. The influence of mammography upon stage classification according to the TNM system is evaluated in 590 breast cancer patients. By using tumour size measured on the radiograph instead of the tumour diameter determined by palpation it was possible to reclassify a significant proportion of cases in stage III. As much as 23% (52/228) of cases of stage III could correctly be grouped into stage II or I. The prognostic significance of this change is evident from the 5-year survival rates. The cases, removed from stage III by correction of the tumour size, show the same 5-year survival rates (65%) as cases primarily classified into stage I (64%) and II (63%). In view of these results we do recommend the use of mammography for stage classification, because it allows correction with prognostic significance.


[Valuation of autologous bone marrow transplantation in radio- and chemotherapy of malignant tumours (author's transl)]. This paper discusses the prerequisites of bone marrow autotransplantation performed as part of cancer therapy, the emphasis being on the condition of the patient, the facilities available to the institution for the treatment of cancer patients, the biology of the tumour, and the present possibilities of carrying out what is called superdose cancer therapy. The practical performance of a bone marrow autograft is based upon the withdrawal of bone marrow with indefinite vital stem cell preservation by deep cooling at a time when the tumour has not yet led to bone marrow metastasizing. The conserved bone marrow is used, in subsequent radiological and/or cytostatic superdose therapy, as a reserve in the case of extreme damage to hematopoiesis. The discussion of the current status of this method and the prospects for its general use reflects the whole spectrum of the problems associated with the most favorable procedure to be used, the type of superdose therapy to be employed, the time of regrafting, and the accurate assessment of the results obtained.


Immunosuppressive activity of ledakrin.

Immunosuppressive activity of ledakrin. The influence of the cytostatic drug Ledakrin on immunologic induction of PF and RF cells was studied. In low doses, the drug had a negligibly small effect on the numbers of PFC and RFC, but in high doses nearly entirely prevented their appearance. Cells producing IgM were more susceptible to this action than IgG-producing cells. Absence of a linear relation between the dose of the drug and its action was noteworthy. Drug-induced immunosuppression occured in "all-or-none" fashion. The possibility of oncostatic effect without interfering with the immunologic system is discussed.


Practical aspects of selection of streptomyces mutants. The methods of industrial strains selection on the basis of some regulatory mechanisms are presented. The selection of the producing S. erythreus mutants exhibiting higher activity for transformation of erythromycin C to erythromycin A is one of the examples for the practical use of the presented method. Some new techniques including isotopic methods are presented.


Antibiotics produced by Streptomyces olivaceus 142. Antifungal properties of antibiotic WR-142 FPG. Antifungal activity of antibiotic Wr-142 FPG was evaluated in vitro and in vivo. In vitro, the minimal inhibitory concentration (MIC) for Candida and Rhodotorula was 0.1 microgram/ml (preparation I) and 0.003 microgram/ml (preparation II). In vivo, experiments were carried out with model of subacute candidiasis in BALB mice. The criteria for antifungal activity of Wr-142 FPG were based on survival time of infected animals and numbers of live C. albicans cells in the kidneys and spleen of animals infected and treated with the antibiotics. Even a single intraperitoneal injection of Wr-142 FPG in mice with subacute candidiosis decidedly in prolonged survival time. Antibiotic Wr-142 injected subcutaneously on five consecutive days diminished the numbers of C. albicans cells, or even eliminated them entirely from the kidneys and spleens of the mice.


[Solitary bone cysts of the ulna (author's transl)]. The solitary bone cysts occurs most frequently in the upper humerus and femur in 75% of the cases, and it is very seldom located in the ulna, in 0.5--1.5%. This report deals with the treatment results of two children, five and six years old, suffering from solitary bone cysts of the lower end of the ulna. In one case a subtotal resection of the cyst was carried out and the defect was bridged with an autologous iliac bone graft. In the other case the patient was treated by curettage, and the defect was filled in with an autologous bone graft and cancellous bone out of the tibia. In both cases complete cure of the tumorlike lesion was obtained and no loss of function or deformity of the forearm was observed 12 and 16 years after operation. In the X-ray picture at that time there was no alteration on the length, form or structure of the bone.


[Usage of feeding yeast "Fermosin" grown on mineral oil distillate in animal nutrition. 2. Digestibility of the nutrients of Fermosin feeding yeast on broilers (chickens) and fattening pigs]. The digestibility of the nutrients of Fermosin was tested on pigs and the following values were ascertained: organic matter=86%, crude protein=89% and N-free extractives=83%. The net energy ascertained on the basis of the content of nutrients and the digestibility of the nutrients of Fermosin amounts to 617 energetic feed units for pigs/kg dry matter. The true digestibility of the amino acids of Fermosin was determined on pigs and chicken. For lysin the true digestibility was ascertained as 95% (pigs) and 73% (Broilers). Due to the different digestion abilities of the two animal species, corresponding differences in the digestibility of the other amino acids were found as well.


Mutagenic activity of cytostatic methyl hydrazones with different strains of Salmonella typhimurium. Experiments are performed to ascertain the mutagenic properties of four new cytostatic methyl-hydrazones in the Ames test using different strains of Salmonella typhimurium. As could be demonstrated all four hydrazones are mutagenic per se without a metabolic activation through rat liver microsomes (S-9 fraction). Whereas the beta-chloroethyl hydrazones B1 and B2 cause a base-pair substitution with the strains TA100 and TA1535 the methyl-hydrazones EB4 and CyB4 both cause base-pair substitution with TA100 and frameshift mutation with TA98. At both strains the mutagenic activity of Cy84 ist powerful. Furthermore, no relation could be detected between the mutagenic properties of the methyl-hydrazones and their alkylating behaviour on 4-(4-nitrobenzyl)-pyridine.


Salmonella meningitis. Occurrence in an adult. Salmonella meningitis is predominantly a disease of infants. An adult patient is described who had meningitis due to S typhimurium following a traumatic fracture of the first lumbar vertebra. A review of previous cases of Salmonella meningitis in adults revealed a predominance of infection due to S typhi prior to 1940 with a variety of other serotypes isolated since then. Only one of nine patients survived prior to the antibiotic era, but three of five patients with Salmonella meningitis since 1940 have survived.


Cryotherapy of Pseudomonas keratitis and scleritis. Three cases of perforated Pseudomonas corneal ulcers with scleral extension were treated with keratoplasty and cryotherapy to the remaining cornea and sclera. All three cases showed dramatic improvement. Cryotherapy of Pseudomonas keratitis in guinea pigs has been shown to be effective. Pseudomonas organisms seem to be susceptible to cryotherapy in vivo; there is no effect in vitro. Cryotherapy may prove to be a new tool in the treatment of Pseudomonas keratitis.


[Toxoplasma gondii: indirect immunofluorescence diagnosis in swine in the State of São Paulo, Brazil]. The frequency of anti-Toxoplasma antibodies in apparently healthy swine from Botucatu and from São Paulo industrial abattoir was assessed through the indirect immunofluorescence test using blood smears collected in filter paper. 225 (22.5%) of the 1000 samples examined were reagent with titles varying between 1:20 and 1:640.


[Anti-toxoplasma antibodies in bovine serums in Jaboticabal County; São Paulo, Brazil]. Sera of 204 cows in Jaboticabal, S.P., Brazil were examined by indirect immunofluorescent test for detecting anti-Toxoplasma antibody. Assuming titers from 1:64 as indicative of toxoplasmic infection it was observed 32.3% of positive reactions. The antibody titers even to 1:256 represented 7.8% of the reacting animals. The serological titers varied from 1:64 to 1:256. No clinical story could be correlated with the reacting animals and no isolation was performed.


Frontalis suspension in congenital ptosis using a polyfilament, cable-type suture. Fifty-five frontalis sling procedures were performed with use of 4--0 polyfilament, cable-type ophthalmic suture (Supramid Extra) as the material for suspension. Recurrences numbered 16, recorded through a follow-up period of one to ten years. Trauma accounted for five recurrences. A pattern of gradual droop of the lid operated on became most obvious between six and ten years postoperatively and accounted for six of seven recurrences during this period. These findings suggest that this suture material is a poor alternative to fascia lata for permanent frontalis suspension in patients with congenital ptosis and should be used only in unusual circumstances, or when a temporary procedure is indicated.


Juri flap procedure for the treatment of baldness. Two-year experience. I report a two-year experience using Juri procedure of transferring twice-delayed parietal-occipital flaps to balding areas of the scalp. These operations allow massive transfer of genetically determined permanent hair to the cosmetically deficient areas of the scalp, whether the condition of baldness is the result of injury or hereditary factors. These procedures require careful thought in planning the hairline and necessitate minor secondary procedures to achieve the most satisfactory results. I discuss concepts for the design of the flap, and describe modifications in the surgical techniques as compared with a previous report. The Juri operation, although extensive, gives the greatest amount of hair transfer in the shortest period of time and has resulted in satisfactory cosmetic results in all patients operated on.


The healing of wounds and scar formation under the influence of a tissue adhesion system with fibrinogen, thrombin, and coagulation factor XIII. The present paper reports the central role of fibrin (and specifically its pre-stage, fibrinogen), thrombin and coagulation factor XIII in wound healing and scar formation. The significance of these three factors had led to the development of a tissue adhesion system on a physiological basis, which can be applied in widely varying areas of surgery. The adhesive allows the exact, flat adaptation of the wound edges and thus promotes flawless scar formation. Two case reports complete the exposition.


[Clinical observations in electric stimulation of the ear (author's transl)]. For 20 years direct electrical stimulation has been used in cases of severe bilateral hearing loss or complete deafness to mediate acoustic percepts. The relevant literature is reviewed. While these attempts were initially thought to be unphysiological and unsuited for transferring speech, acoustic sensations were successfully conveyed even with the very simple unichannel electrodes through percutaneous signal transfer. Patients fitted with such simple systems were able to hear and distinguish environmental noise and speech, their lip reading as well as their speech improved. Speech discrimination was, however, impossible with such simple implants both on theoretical grounds and in practical terms, because frequency analysis is exclusively based on periodicity (up to 400 Hz). Designing bipolar multichannel electrodes which, when introduced into the scala tympani or the modiolus, produce discrete stimulation of several circumscribed groups of nerve fibers, was the logical consequence of earlier attempts along these lines, Implantation of these systems can be done along the transmeatal, meato-mastoidal or mastoidal approach. The electrodes can be implanted in bundles through the round window or into the modiolus; they can, however, also be introduced individually through several drill holes in the promontory for placement in the scala tympani and vestibuli. This produces a far more differentiated stimulation simulating a tonotopic pattern of stimuli. In addition to periodicity, the place principle can thus be utilized for frequency coding. While their dynamic range is rather poor (15 to 30 dB at best), multichannel systems, in theory, offer substantially more favorable conditions for speech intelligibility. Since current knowledge of speech coding is, however, inadequate, the degree of intelligibility obtainable is still insufficient for everyday life. Inspite of this flaw, such implants as are available today substantially benefit the patients, who are able to establish acoustic communications with their environment by distinguishing environmental noise from speech, to discriminate between male and female voices, to recognize musical rhythms and even to understand a few words. Indications for the implantation of prostheses, the requisite conditions and postoperative training programs are discussed. While cochlear implants are still experimental, they appear to be reasonably justified in selected cases, since they have been well tolerated by all patients treated sofar without causing any complications and since many of the data obtainable can only be collected in humans. It is, however, essential that experimental implantation be exclusively dealt with by specialized teams, which should evaluate such data as are available and translate them into practice as soon as possible. A routine impantation of hearing prostheses is currently unwarranted.


Galactose-1 phosphate uridyl transferase deficiency in the western grey kangaroo (Macropus fuliginosus; marsupialia): a model system for gene therapy studies. The western grey kangaroo (Macropus fuliginosus) was found to be deficient for galactose-1 phosphate uridyl transferase (GPUT). This species could be used therefore for studies of gene therapy techniques. An improved GPUT assay procedure was developed. It was found that phage particles injected intravenously remain in the blood of kangaroos until the particles are removed by the reticuloendothelial system or, if this system is overloaded, the particles are inactivated by the immune system four days later. No effective transgenosis was detected of the bacterial gal operon contained in the phage used.


[Physiological basis for a cochlear prosthesis (author's transl)]. For the attempt to develop a cochlear prosthesis, which allows some understanding of speech, it seems--at least for the first attempts--to be appropriate to mimic natural conditions as far as possible. The auditory nerve contains about 30,000 afferent fibres. Qualitatively, their behavior is similar but quantitative measures show considerably differences (2.3). Nothing certain can be said at present however about the spiral fibres originating from the outer hair cells. The quantitative differences between single afferents concern tuning, frequency selectivity, thresholds, intensity functions and--of particular interest for electrical stimulation--differences in timing of the activity pattern, brought about by differences in travelling time along the cochlear duct (2.3). The time differences seen in the activity pattern of different fibres are in the order of several ms (2.3.6;2.3.7). Actionpotentials elicited by natural acoustic stimuli show probabilistic behavior, that is they are not strictly determined. It is obvious that with artificial electrical stimulation not every surviving single fibre can be selectively stimulated. An electrode will always stimulate a group of fibres simultaneously. With any conceivable electrical stimulation all fibres in the suprathreshold region of the electrode will be synchronously activated (3.2); a fundamental difference to the natural situation. To estimate the number of channels, necessary to stimulate the auditory nerve with sufficient accuracy to allow speech perception we consider some psychoacoustic data. These have shown that the auditory system possesses the ability to differentiate a great number of different pitches, but on the other hand it is capable of integrating different frequency areas to a so called critical bandwidth. Sound energy falling into one critical bandwidth is integrated to a uniform auditory sensation. If one is to integrate various fibres of the auditory nerve to one channel of stimulation it seems to be adequate to use the critical bandwidth as a measure (3.1). According to this criterion 15 channels would have to be introduced into the speech region of the cochlea. This would allow 1.2 mm of cochlear length for each channel. Perfect electrical separation of the channels is required. Considering the severe distortions in neuronal activity pattern, introduced by electrical stimulation in comparison to the natural conditions it is not clear even whether the number given would be sufficient. On the other hand, current spreading would appear to prohibit any higher electrode density. As far as coding of sound parameters within one channel is concerned it is proposed that full use should be made of frequency analysis according to the place principle. In respect to coding of periodicity and loudness it is proposed to approach natural conditions as far as possible (3.3). Here delay times between the individual channels and a probabilistic character of the stimuli should be introduced to avoid dominance of periodicity pitch...


The treatment of breast cancer in a French anticancer centre. The complete protocol for the treatment of breast cancer at the Institute Gustave Roussy, Villejuif, France, is presented. Treatment is carried out by a multidisciplinary committee dealing with nearly one thousand new breast cancers annually. The protocol is based on initial classification by the T.N.M. system and by characteristics indicating "aggressive biological behaviour". Patients are separated into three broad groups for which the mainstays of treatment are surgery, radiotherapy, and chemotherapy. The rationale and results of the protocol are presented.


Neutralization tests for dengue and Japanese encephalitis viruses by the focus reduction method using peroxidase-anti-peroxidase staining. Neutralization tests were made on 4 types of dengue (DEN) virus and Japanese encephalitis (JE) virus by incubation of serially diluted antisera and constant amounts of the viruses and then focus assay of surviving virus infectivity with peroxidase-anti-peroxidase (PAP) staining. Neutralization reactions were virtually completed in 2 hr on incubation of serum-virus mixtures at 28 C. A straight regression line was obtained on a probit chart by plotting the focus reduction rates at various dilutions of a given serum against the logarithm of the serum dilution used in the test. The slopes of the probit regression lines for the neutralization for DEN types 1 and 3 were similar, but differed somewhat from those for DEN type 2 and type 4. The slope of the line for JE virus was quite different from those for DEN viruses. Using these relations, the fifty percent focus reduction titer (FR50) of neutralizing antibodies of a given serum could be estimated from the focus reduction rates at several dilutions of the test serum when the latter was between 25-75% of the value of the control.


Action of human pepsins 1,2,3 and 5 on the oxidized B-chain of insulin. Human pepsins 1 and 2 attack the B-chain of oxidized insulin at pH 1.7 at the same bonds as does human pepsin 3. At pH 3.5, pepsins 1 and 2 attack insulin B-chain at essentially the same bonds as at pH 1.7, but more slowly. For all three enzymes, the first bond to be hydrolysed is Phe(25)-Tyr(26), followed simultaneously by Glu(13)-Ala(14), Leu(15)-Tyr(16) and Tyr(16)-Leu(17). Human pepsin 5, however, attacks Phe(24)-Phe(25) first of all, followed by Leu(15)-Tyr(16) and Tyr(16)-Leu(17). The results suggest that each pepsin has only one active site. Acid hydrolysis indicates that the sites of enzymic cleavage are not bonds with an inherent instability at low pH.


The specificity of some pig and human pepsins towards synthetic peptide substrates. 1. The peptidase activities of pig pepsins A and C and human pepsin and gastricsin were compared. 2. The peptides studied had the general formula A Leu Val-His-B. Hydrolysis at 37 degrees C and pH 2.07 occurred at the amino side of the leucine residue for all the enzymes and all the peptides. 3. When A was Ac-Ala the peptides were hydrolysed under these conditions slowly by pig pepsin C only. 4. Pig pepsin A and human pepsin were unable to hydrolyse the tyrosine-containing peptides under the conditions tested. Gastricsin (human pepsin C) had about one-third of the activity of pig pepsin C with these substrates. 5. The increase in the rate of hydrolysis caused by the extension of the chain by a single alanine residue was most marked for pig pepsin A and human pepsin.


Effect of fixation time on measurement of 2'-deoxyribonucleoside 5'-triphosphate pools in the rat embyro. Values for the concentrations of deoxyribonucleoside triphosphates in rat embryos on day 12 of gestation, determined by high-pressure liquid chromatography, were artifactually two to three times as high in embryos fixed by cooling in ice/water followed by freezing on solid CO2, in 20s, as in those more rapidly/fixed in liquid N2, in 1 s.


Increase in fibronectin in the deep dermis of involved skin in progressive systemic sclerosis. The distribution and amount of fibronectin in both involved and uninvolved skin from scleroderma patients and controls were compared by indirect immunofluorescence. A marked increase in fibronectin was found in the deep dermis of involved scleroderma skin, while the subepidermal papillary regions of all specimens revealed little variation in fibronectin content. The districution of the accumulated fibronectin appeared to parallel that of the accumulated collagen in the involved reticular dermis.


[Enzyme-immunoassay. New techniques for the photometric laboratory (author's transl)]. Enzyme-immunoassays (EIA) are a further development of the radioimmunoassay (RIA) employing enzymes instead of radionuclides as labels. This advance makes it possible also for the photometric laboratory to determine substances at extremely low concentrations. Heterogeneous EIA, mainly named ELISA (enzyme linked immunsorbent assay), are based on the same reaction principles as the analogous RIA. A characteristic feature is the bound-free separation, which is effected primarily by means of solid-phase techniques. The most sophisticated of these -- the solid-phase tube technique -- lets the immunological reaction take place on the inside wall of the reaction vial; the separation step is accomplished by simply emptying the vial. Heterogeneous EIA have a universal range of applications, from the determination of small haptens to the determination of macromolecular particles. Homogeneous EIA have so far been used only for the determination of haptenes. They require no bound-free separation step. The change in enzyme activity as a result of the enzyme-haptene-antibody reaction is proportional to the concentration of the haptene. In homogeneous assay systems, the photometric measurement is susceptible to interference by constituents of the sample material, whereas heterogeneous methods do not suffer from this disadvantage because the indicator reaction proceeds in an aqueous medium after the separation step.


[Principles of controlled trials (author's transl)]. Wrong interpretations of the results of experimental trials on animals and of clinical studies block up scientific progress in medicine and withhold the best possible treatment from the patient. They are caused by concomitant influences independent of or dependent on treatment. Such bias is avoided only by designing "controlled trials". Their definition and principles are discussed here. In clinical drug research these principles can almost always be brought into concordance with the demands of medical ethics.


[Restrictions and methodological considerations of multicenter trials (author's transl)]. Multicenter or cooperative trials should be initially evaluated for efficacy using criteria that in some way measure the degree to which the various centers are coordinated. The fundamental limitations of these studies can be traced to the inadequacy of coordination among the centers taking part in the trial. Whereas the structural homogeneity of the patient groups can be achieved by stratification and randomization within the centers, the organisational effort to prevent observer variation between centers is often underestimated. In this case the selection of the centers has a great bearing. More specifically their representativeness plays an important part in the interpretation of the apparent differences between the centers.


[Experimental design in phase I (AUTHOR'S TRANSL)]. Clinical pharmacology has its domain during phase I. The formalisation of phase I is not very advanced. Sometimes it is argued that the design of experiments during that phase is unnecessary. Just the opposite is true. Trying a new substance for the first time in man poses a special necessity for the design of experiments in a scientific context. Phase I is described in a formal way. The design of experiments with a single subject -- the first one to be exposed to a new substance -- is described. Finally Latin squares are dealt with as a useful tool for phase I.


[Errors in clinical data collection (author's transl)]. In the design of clinical trials the collection of the routine data is often not sufficiently defined. Numerous mistakes may occur in the registration of blood pressure, heart rate, body temperature, body weight, circumferences. The mistakes have to be prevented by standardization. In particular the intake of drugs especially during long-term medication has to be supervised.


[Neuroleptic infusion therapy with high-dosed fluphenazine (author's transl)]. 19 chronic schizophrenics who had previously been resistant to various neuroleptic treatment regimens, were given extemely high doses (ca. 300-500 mg daily) of fluphenazine. 2 infusions were given in the morning and in the afternoon. Therapy results, possible side effects and the transition to oral and i.m. (depot) modes of application are discussed. The above-mentioned extemely high doses of fluphenazine appear to be contra-indicated in depressive states and in cases of latent organic brain changes. Psychiatric state hospitals would be able to carry out this form of treatment in a special unit for "intensive care" in connection with appropriate social rehabilitative methods.


[Extrapyamidal side-effects with 1-day dosage of haloperidol (author's transl)]. In a double blind study, 30 in-patients (14 females, 16 males, ranging in the age from 18 to 55) suffering from an acute paranoid-hallucinatory syndrome, were treated with haloperidol for 30 days. 13 patients (3-day group) received 3 times a day 3 mg haloperidol (at 8 a.m., 12 a.m,, 5 p.m.) and 17 patients received 9 mg haloperidol only in the evening (9 p.m., 1-day group). Placebo instead of medication was given at the same time to the control group. Every 5 days the following assessments were performed: AMP 3 and 4, Webster and Simpson rating scales, handwriting tests according to Haase and psychometric tests according to Schoppe. In the 1-day dosage group the amount of anticholinergics were significantly reduced (2.4 mg biperiden/day compared to 4.6 mg/day in the 3-day group). The 1 daily application of neuroleptics is useful in treating acute psychosis. This treatment schedule has the advantages of sedation during the night, reduction of side-effects during the day, simpler and cheaper application form and induction of social activity.


[The incidence of abnormal EEG patterns with clozapine therapy (author's transl)]. During treatment with clozapine 59% of 127 patients showed abnormal EEGs. Remarkable are paroxysmal disturbances with sharp waves and/or SW-pattern in ca. 13%. Generalized tonic-clonic convulsive cereberal seizures were observed only twice.


[Pharmacogenic depressive syndromes in the course of schizophrenic psychoses (author's transl)]. Fluphenazine decanoate treatment causes significantly more depressive syndromes than does placebo. These depressions are primarily pharmacogenic. Depending on the intensity of symptoms patients are handicapped up to suicidal risk. Prophylactical treatment with neuroleptics, which is of great help in many cases, needs careful handling of individual dosage. In case depressive symptoms appear, first and best therapy is to reduce or even discontinue the application of the neuroleptic, later antiparkinsonian drugs should be added (or increased). Only when this regimen is unsuccessful or too slow, thymoleptics should be given carefully and temporarily. -- A schematized long-term neuroleptic treatment often causes needless inconvenience to the patients. Psychiatrists should use the spectrum of psychopharmacological drugs carefully, not only to bring a vita minima without relapse to the formerly schizophrenic patient but to help him live a life worth living after psychosis.


[Fluphenazine dihydrochloride--a multicenter trial on 660 patients (author's transl)]. Selected patients were treated with fluphenazine dihydrochloride. Summarizing the studies 51 investigators from 32 hospitals conducted, permits only a relative statement because, without doubt, also various additional social and psychotherapeutical treatments were employed. The findings, however, emphasize the authors' personal judgements considering fluphenazine dihydrochloride a qualified drug for psychiatric emergency cases and also particularly for the treatment of acute schizophrenic episodes. On account of the broadly disseminated identical findings about fluphenazine dihydrochloride further studies are being planned to which a scientific standard can be applied.


[Additional treatment to lithium prophylaxis of affective psychoses (author's transl)]. Ten endogenous-depressive patients under lithium maintenance therapy participated in a group behaviour therapy program for the modification of behavioural problems that are typical for this group of patients. The problem intensity as measured individually through a "problem barometer" as well as the score on the Pt-scale of the MMPI were reduced significantly over the ten treatment sessions. Concurrently, patients' self image regarding depressive components and social resonance improved. The effects were still present after a 3-month follow-up period. It is concluded that in lithium treated patients behaviour therapy methods can be used in the modification of typical behaviour disorders.


[Routine EEG examinations accompanying lithium therapy over two years (author's transl)]. In 15 lithium-treated psychotic patients, the following variables were examined over two years at 6-monthly intervals; seru lithium levels, serum electrolytes, thyroid function, urinary creatinine and urea, and clinical EEG. The mean serum lithium level was 0.64 mval/l and did not change during the two years. When compared to the pretreatment EEG, visual analysis did not indicate any specific potentials, focal signs, or asymmetrical phenomena such as have been reported in the literature. Only at the beginning of treatment could a small increase in unspecific, abnormal changes be demonstrated, which, however, decreased during the following 18-month period of investigation.


Accelerated remission of the alcoholic organic brain syndrome with EMD 21657. Double-blind clinical and psychometric trials. The efficacy of EMD 21657--a derivative of a pyritinol metabolite--on the alcoholic orangic brain syndrome (OBS)) was investigated in a double-blind placebo-controlled study. 19 patients received 3X300 mg EMD, 21 patients 3X1 dragée placebo throughout 6 weeks. The two groups did not differ as to age, sex, weight, height, alcohol anamnesis and IQ. Investigations were carried out before and at the end of the 2nd, 4th and 6th weeks of drug treatment. While an overall evaluation by doctor and patient at the end of the therapy did not reveal any signficant differences, it was found by means of the global score and OBS score that the OBS improved under both substances, but significantly more so with EMD. Psychometric analysis demonstrated that EMD was superior to placebo in regard to general, associative and numeric memory, concentration and attention variability, psychomotor activity, affect and mood, while the Benton test and attention showed opposite findings. Side effects were observed more under EMD than placebo therapy and consisted of temporary headaches and dizziness. Our findings demonstrated that EMD 21657 has pronounced nootropic and some thymotropic effects.


[Piracetam and vigilance. A study of EEG changes and clinical effects in gerontopsychiatric patients (author's transl)]. The electroencephalographic and clinical effects of piracetam were studied in a group of 11 hospitalized gerontopsychiatric patients treated with a daily dosage of 4.8 g for 8--13 months. The EEG was evaluated by power spectral analysis, followed by a principal component analysis of frequency parameters. The statistical analysis of the resulting factor scores shows that piracetam induces significant EEG changes: decrease of slow frequencies, augmentation and acceleration of alpha-activity and increase of beta-activity. These EEG changes, indicating an increase in vigilance, correspond clinically to an improvement of communicative behavior and cognitive functioning.


[Bactericidal kinetics of cefazolin, cefoxitin and amikacin alone and in combination (author's transl)]. The in vitro activity of cefazolin, cefoxitin und amikacin alone and in combination was determined via membrane filtration against E. coli (n = 2), K. pneumoniae (n = 2) and of cefoxitin and amikacin against Proteus vulgaris (n = 1). Therapeutically achievable concentrations of cefazolin (10 micrograms/ml), cefoxitin (10 micrograms/ml) and amikacin (10 micrograms/ml) lead to a rapid bactericidal effect against all of our strains. The combination of cefazolin (10 micrograms/ml) and amikactin (5 micrograms/ml) and cefoxitin (10 micrograms/ml and amikacin (5 micrograms/ml) was synergistic against only one of the 2 K. pneumoniae strains. Cefoxitin and amikacin were antagonistic against the P. vulgaris strain but synergistic against both E. coli strains.


Comparative study of the clinical effects of vincamine + glycerol versus glycerol + placebo in the acute phase of stroke. The treatment of the acute phase of stroke creates a difficult problem to the clinician. The presently used drugs lead to controversial results. The progress in knowledge of the pathogenesis of cerebral damage underlines the determinant role of the metabolic deficits in the ischemic areas. The effect on the clinical symptomatology of patients in the acute phase of stroke was studied during a double-blind comparative clinical trial with an alcaloid of Vinca minor (Pervincamine) which acts favorably against disturbances of oxydative glucose metabolism and of cerebral microcirculation. 20 patients divided into two homogeneous groups received during 5 days either Pervincamine (4 ampoules of 3 ml = 60 mg vincamine p.d.) + glycerol, or glycerol + placebo administered by i.v. infusion. Clinically the results indicate a greater improvement of the neurological status (objectivated by a neurological scale) with vincamine treatment than with placebo. Statistically the analysis confirms the highly significant effect of vincamine on motility of lower and upper limbs (p less than 0.02) and the significant effect on cranial nerves (homonymous hemianopsia and conjugated deviation of eyes) (p less than 0.05) and on the sphincter control level (p less than 0.05).


A controlled study of the analgetic effect of two non-steroidal anti-inflammatory drugs in cancer pain. With a subjective response technique the analgetic activity of two non-steroidal anti-inflammatory agents which greatly differ in kinetics is compared. The double-blind cross-over trial was carried out in 18 patients of both sexes suffering from pain due to malignant tumours who received single doses of 200 mg indoprofen and 250 mg naproxen p.o. Both compounds were efficacious and there was no difference in the duration of their activity in spite of the great difference between their half-lives.


[Dedo and Fishman technique for laryngeal release in cervical tracheal reconstruction (author's transl)]. The Authors report two cases of tracheal tumor operated with laryngeal release and tracheal mobilization following Dedo and Fishman. They discuss the indications and describe this technical procedure which has proved successful in obtaining a suture without traction also for 4 cm sleeve resection of trachea.


[A tissue bank: aspects concerning its promotion and organization (author's transl)]. In spite of continued improvement in the production of artificial tissues, there are still many instances where replacement of the damaged part by a natural tissue grafts would be preferable. It is to satisfy this requirement that tissue banding has been developed. In this paper a brief description of the preparation of tissue grafts currently being carried out in the Yorkshire Regional Tissue Bank is given and the philosophy of tissue banking from a financial and scientifical point of view is explained.


[Bacampicillin, a new semisynthetic antibiotic for oral administration in the treatment of urinary tract infections (author's transl)]. The Authors report the results obtained administering 2.4 g/die of bacampicillin in a group of 30 patients suffering from both primary and secondary infections of the genito-urinary tracts. The antibiotic displayed excellent tolerability and therapeutic effectiveness, determining in almost all the treated cases either the resolution or, at least, significant improvement of the inflammatory course; only two patients, as a matter of fact, showed mild side effects.


Atherosclerosis in lemmings and voles fed a high fat, high cholesterol diet. Two species of lemmings and two species of voles were fed a high fat, high cholesterol diet for several months. Clethrionomys rutilus had a moderate (2x) rise in serum cholesterol while Microtus oeconomus had a marked increase (5x); Dicrostonyx stevensoni and Dicrostonyx rubricatus had extreme increases (8x and 11x, respectively). Typical lesions of atherosclerosis were observed in all species, but D. rubricatus had significantly more severe lesions. Hepatic fatty infiltration was the principal pathologic lesion found besides atherosclerosis in those test rodents which died spontaneously.


Aortic valve replacement in a case of Ehlers Danlos syndrome. A case of Ehlers Danlos syndrome is described in a 54-year-old Caucasian male. He had calcific aortic valve disease and dilatation of the ascending aorta. An aortic valve replacement was performed using a Starr prosthesis.


Marrow autotransplantation accelerates haematological recovery in patients with malignant melanoma treated with high-dose melphalan. In a Phase I study, melphalan 140 mg/m2 was administered to 8 patients with disseminated malignant melanoma. Marrow was removed from the patients immediately before melphalan administration and returned i.v. 8 h later. Studies on marrow culture and melphalan pharmacokinetics predicted that this was a safe time to administer non-cryopreserved marrow. Four patients received lower doses of i.v. melphalan without autologous marrow. In the group receiving autologous marrow the time for recovery of peripheral-blood granulocytes to 800/mm2 or greater was significantly less (P = 0.01) than in those not receiving marrow. In 7 patients the tumour showed evidence of response to the drug and there was 1 complete remission. This treatment deserves investigation in patients with tumours more sensitive to drugs than melanoma.


A statistical study of sarcoma complicating Paget's disease of bone in three countries. Details of sex, age at presentation and anatomical site of sarcoma complicating Paget's disease of bone were recorded from the literature for white patients in Australia, the United Kingdom and the United States over the period 1978--77. Evidence is presented to suggest that sex and tumour-site distributions are free from bias, except possibly for the skull. There was a male predominance for all sites except the skull, where the odds ratio of sarcoma compared with other locations is more than twice as high for females as for males. No national differences emerged in the sex ratio of patients. In Australia a latitudinal effect was observed. Whereas the percentage of males with uncomplicated Paget's disease was essentially constant, those with sarcoma showed a decrease with increase in latitude from Queensland to Victoria. This was attributable to tumours of the skull. Patients with bone involvement above the waist were significantly younger than those with affected feet, legs or pelvic girdle.


Dihydrocholesterol-induced gallstones in the rabbit: evidence that bile acids cause gallbladder epithelial injury. Rabbits fed a diet containing 0.75% dihydrocholesterol for 7 days develop bile acid allodeoxycholic (ADCA) and deoxycholic acid (DCA) stones in the gallbladder. In this model, inflammatory changes in the gallbladder mucosa are often observed even before stones are formed. Within 3 days of the lithogenic diet, abnormalities of platelet function were detectable. Platelet aggregation upon addition of adenosine diphosphate (ADP) was impaired. At the same time the red cells became crenated and developed thorny spicules (echinocytes). This morphological changes was associated with intracellular dehydration and excessive loss of potassium. These changes coincided with a rise in serum ADCA and DCA and preceded a slow rise in serum cholesterol. In vitro incubation studies also suggested that the bile acids had probably caused membrane injury to the platelets and red cells. It is concluded that changes in the bile ADCA and DCA probably induce gallbladder epithelial injury in this model of experimental cholelithiasis.


Lactoperoxidase activity in guinea-pig milk and saliva: correlation in milk of lactoperoxidase with bactericidal activity against Escherichia coli. The lactoperoxidase (LPO) activity in guinea-pig milk and saliva has been investigated in sows suckling normal young, and young orally infected with Escherichia coli. There was a 5-fold increase in activity in milk during the 3--4 weeks of lactation; infection of the young did not alter this. There was no comparable increase in lactoperoxidase activity of saliva during this same period, either in the infected or non-infected group. The antibacterial activity of milk from sows suckling normal young increased with the lactoperoxidase, and this bactericidal activity could be reversed by LPO inhibitors such as penicillamine and cysteine but not by addition of sufficient iron to saturate the lactoferrin. In milk from sows suckling infected young, bacteriostatic activity occurring in samples from about 14 days after infection needed iron or both iron and penicillamine (or cysteine) for reversal, indicating that both the antibody-lactoferrin system and the LPO system may be involved in the infected state.


Successful maintenance immunotherapy by BCG of non-Hodgkin's malignant lymphomas: results of a controlled trial. Forty-eight patients less than 65 years old, suffering non-Hodgkin's malignant lymphomas with one or more criteria of poor prognosis, were priorly placed in complete remission by an association of chemo + radio + chemotherapy. They were then randomized to receive either BCG in weekly scarifications for 3 years or no further treatment. Five patients were excluded (four after pathological reassessment); 43 are thus evaluable. There were 13 relapses out of 23 control patients and three relapses out of 20 treated patients (0.01 less than P less than 0.025). This difference is more distinct for clinical stages I and II (0.01 less than P less than 0.025) than for stages III and IV (not significant). Eight patients died in the control group whereas there was only one death in the treated group (0.025 less than P less than 0.05). These results indicate than BCG is useful in maintaining remission in about 40% of the cases and also in increasing their survival, especially in patients with clinical stages I or II.


Detection and quantification of platelet-bound antibodies with immunoperoxidase. The use of immunocytochemical techniques enables one to quantify antibodies bound to cell membranes. We have tested the platelets of subjects with immune thrombocytopenic purpura by this method. The washed platelets were incubated in the presence of antiglobulin conjugated with an equimolar amount of peroxidase. The fixed peroxidase was revealed and quantified by an enzymatic reaction using orthodianizidine-H2O2. From the results the number of immunoglobulin molecules per platelet was calculated. The test was calibrated so as to eliminate non-specific fixation of the reagent. Under these conditions the platelets of subjects with idiopathic thrombocytopenic purpura bound a much large amount of detectable immunoglobulin (800-21 000 molecules per platelet) than those of normal subjects (235 +/- 74 sites per platelet) or subjects with non-immune thrombocytopenia (395 +/- 203 molecules per platelet).


Surgical management of carcinoma of eyelids and periorbital skin. An appraisal of a personal series of 115 unselected and surgically treated cutaneous cancers of palpebral region is presented. Histological confirmation of the diagnosis and adequacy of excision was obtained for all lesions. Seven of the 8 patients with doubtful clearance were successfully treated with further surgery very soon. Complications were few, the incidence of reoperations low, and cosmetic as well as functional results were mostly satisfactory. Tumour recurred in 1 case (0.87%). Two patients had a poor cosmetic result. Seventy-nine cases (69%) were treated as day cases under local anaesthesia even for major repairs like full-thickness reconstruction of two-thirds of the lower eyelid and repairs with large full-thickness skin grafts of up to 20 x 55 mm by a new simple technique of graft fixation. The use of longer-acting local anaesthetics in oculoplastic surgery is described. Attention is drawn to the dangers of using direct wound closure for repair.


A ptosis repair of aponeurotic defects by the posterior approach. A simple posterior approach operation for correcting ptosis due to a disinsertion of the aponeurosis of the levator palpebrae superioris muscle is presented. Müller's muscle is restored to its normal length. Pull-out sutures are used which give some postoperative control of eyelid level and allow the procedure to be done under general anaesthesia if required.


Hydrogen transfer in catalysis by adenosylcobalamin-dependent diol dehydratase. Studies [bachovchin, W. W., et al. (1978) Biochemistry 17, 2218] of the mechanism of inactivation of adenosylcobalamin-dependent diol dehydratase have led to the development of a general method to describe the kinetics of a reaction pathway containing a reservoir of mobile hydrogen. Analysis by this method of catalytic rate measurements for mixtures of 1,2-propanediol and 1,1-dideuterio-1,2-propanediol supports a mechanism involving an intermediate with three equivalent hydrogens, in which hydrogen transfer from this intermediate to product is the major rate-contributing step. Other results using tritium as a trace label [essenberg, M. K., et al. (1971) J. Am. Chem. Soc. 93, 1242] are considered in light of these deuterium isotope studies.


Isoleucyl transfer ribonucleic acid synthetase. Steady-state kinetic analysis. A steady-state kinetic analysis was conducted of the overall aminoacylation reaction catalyzed by isoleucyl-tRNA synthetase. The patterns of Lineweaver-Burk plots obtained indicated that tRNA adds to the enzyme only after isoleucyl adenylate formation and pyrophosphate release. These kinetic patterns were consistent with the bi-uni-uni-bi Ping Pong mechanism generally accepted for this aminoacyl-tRNA synthetase, but they could also be accommodated by a mechanism in which a second molecule of L-isoleucine added to the enzyme between isoleucyl adenylate formation and aminoacylation of tRNA [Fersht, A.R., & Kaethner, M.M. (1976) Biochemistry 15, 818]. The values of the kinetic parameters favor the latter mechanism. The results of this kinetic analysis indicated that the affinity of isoleucyl-tRNA synthetase for Mg.ATP was enhanced upon binding of L-isoleucine and vice versa. It also indicated that the affinity of the enzyme for L-isoleucine is decreased upon binding tRNA and vice versa. The values of dissociation constants calculated for each of the substrates by this study generally compared well with those determined by other authors using a variety of kinetic and equilibrium methods.


Isoleucyl transfer ribonucleic acid synthetase. Competitive inhibition with respect to transfer ribonucleic acid by blue dextran. The inhibitory effects of blue dextran and a small dye molecule derived from it (F3GA-OH) on the steady-state reaction catalyzed by Escherichia coli isoleucy-tRNA synthetase have been studied. Blue dextran gave uncompetitive inhibition with respect to Mg.ATP, mixed inhibition with respect to L-isoleucine, and competitive inhibition with respect to tRNA. The small dye molecule (F3GA-OH) was also competitive with respect to tRNA. These inhibition patterns were not consistent with the bi-uni-uni-bi Ping Pong mechanism generally accepted for aminoacyl-tRNA synthetases. They were consistent with a mechanism in which a second L-isoleucine is bound after isoleucyl-AMP synthesis and before transfer of the isoleucyl moiety to tRNA. Enzyme-bound L-isoleucine lowered the affinity of the enzyme for blue dextran approximately fivefold, a value comparable to the ninefold lowering of the enzyme's affinity for tRNA upon binding L-isoleucine. The affinity of the synthetase for F3GA-OH (K1 = 1.0 X 10(-7) M) is approximately fivefold higher than its affinity for blue dextran (K1 = 5.3 X 10(-7) M). These results indicate that blue dextran and its derivatives may be useful for kinetic and physical studies of polynucleotide binding sites on proteins as well as NAD and ATP sites.


Studies of yeast phenylalanine-accepting transfer ribonucleic acid backbone structure in solution by phosphorus-31 nuclear magnetic resonance spectroscopy. Approximately 17 diester phosphates from the backbone structure of yeast tRNAPhe give rise to phosphorus resonances, which are resolved in its 31P NMR spectrum. To localize these diester phosphates within the tRNA structure, 31P NMR spectra of several chemically or enzymatically modified yeast tRNAPhe species were recorded. To this end selective modifications were performed in the anticodon, the DHU, and the T psi C loop. Modifications, performed in different loop regions, give rise to perturbation of different characteristic 31P resonances. The 31P spectra were correlated with the corresponding 1H NMR spectra of the ring N hydrogen-bonded protons and interpreted in view of the X-ray results obtained on yeast tRNAPhe. It is concluded that the diester phosphate groups, which experience an unusual shift, can be accounted for in the X-ray structure in terms of hydrogen-bonded phosphates groups and diester phosphates with a diester geometry, deviating from the normal double-helical conformation.


Mechanism of action of D-serine dehydratase. Identification of a transient intermediate. Static absorbance measurements of D-serine dehydratase from Escherichia coli taken at 2 degrees C show that during the steady-state course of D-serine conversion the absorption maximum of the Schiff base of the cofactor pyridoxal 5'-phosphate (pyridoxal-P) is shifted from 415 to 442 nm. Furthermore, the progress curve of intermediates was monitored by stopped-flow techniques at wavelengths ranging from 320 to 500 nm. A point by point construction of successive spectra from these stopped-flow traces at various time intervals after the start of reaction resulted in a series of consecutive spectra exhibiting two isobestic points at 353 and 419 nm. The half-time of the absorbance changes occurring at 330 and 455 nm was found to be 6.5 ms, suggesting the observation of a single, enzyme-bound intermediate. The spectral data with substrate and inhibitors provide evidence that the intermediate is the Schiff base of alpha-aminoacrylate and pyridoxal-P. The proposed assignment is strongly supported by experiments of apodehydratase with transient-state analogues which exhibit a similar absorbance shift on binding to apoenzyme. Moreover, these results suggest that the phosphate group of the substrate--pyridoxal-P complex serves as the main anchoring point during catalysis. A reaction mechanism of the D-serine dehydratase is presented.


High-resolution phosphorus nuclear magnetic resonance spectra of yeast phenylalanine transfer ribonucleic acid. Melting curves and relaxation effects. In a continuation of our studies on structural effects on the 31P chemical shifts of nucleic acids, we present 31P NMR spectra of yeast phenylalanine tRNA in the presence and absence of Mg2+. Superconducting field (146 MHz) and 32-MHz 31P NMR spectra reveal approximately 15 nonhelical diester signals spread over approximately 7 ppm besides the downfield terminal 3'-phosphate monoester. In the presence of 10 mM Mg2+, most scattered and main cluster signals do not shift between 22--66 degrees C, thus supporting our earlier hypothesis that 31P chemical shifts are sensitive to phosphate ester torsional and bond angles. At 70 degrees C, all of the signals merge into a single random coil conformation signal. Similar effects are observed in the absence of Mg2+ except that the transition melting temperature is approximately 20 degrees C lower. Measured spin-lattice and spin-spin relaxation times reveal another lower temperature transition besides the thermal denaturation process. A number of the scattered peaks are shifted (0.2--1.7 ppm) and broadened between 22 and 66 degrees C in the presence of Mg2+ as a result of this conformational transition between two intact tertiary structures. The loss of the scattered peaks in the absence of Mg2+ occurs in the temperature range expected for melting of a tertiary structure. An attempt to simulate the 31P spectra of tRNA Phe based upon the X-ray crystallographically determined phosphate ester torsional agles supports the suggestion that the large shifts in the scattered peaks are due to bond angle distortions in the tertiary structure.


Comparison of the effects of increased intracellular calcium and antidiuretic hormone on active sodium transport in frog skin. A study with the calcium ionophore A23187. The addition of the Ca2+ ionophore A23187 (1 microM) to the inside solution of the frog skin resulted in an approx. 40% transient increase in the active influx of Na+ and ionic conductance, which decayed to an approx. 13% steady-state stimulation after 1--2 h. A23187 had no effect from the outside solution. A23187's stimulatory action is most likely the result of the ionophore's ability to increase intracellular Ca2+. This contention is supported by the following experimental results: (1) reintroduction of Ca2+ into a Ca2+-free inner solution stimulated Na+ transport only in the presence of A23187: (2) Mg2+ would not mimic these effects, and (3) EGTA in the inner solution would inhibit the A23187 response. The stimulation of active transport and ionic conductances elicited by A23187 were found to be very similar to those caused by antidiuretic hormone. Several lines of evidence suggest that A23187 may by-pass steps in the normal antidiuretic hormone stimulatory process: (1) A23187 and antidiuretic hormone are apparently non-additive; (2) A23187 acts three times faster than antidiuretic hormone; (3) A23187 stimulates antidiuretic hormone-insensitive frog skins, and (4) results from other laboratories indicate that A23187 does not increase cyclic AMP concentrations. It is speculated that an increase in free intracellular Ca2+ may be a step in the normal antidiuretic hormone stimulatory process. This increase in intracellular Ca2+ may in turn stimulate active sodium transport by increasing the Na+ permeability of the outer 'rate-limiting' membrane.


The effect of altered ergosterol content on the transport of various amino acids in Candida albicans. Candida albicans cells have low levels of ergosterol when grown in ascorbic acid-supplemented media. When cells are grown in hydroquinone-supplemented media, the ergosterol levels became higher as compared to normal cells. The uptake of lysine, glycine, glutamic acid, proline, methionine and serine is reduced in hydroquinone-supplemented cells. In contrast to hydroquinone-supplemented cells, the rate and level of accumulation of these amino acids are higher in ascorbic acid-supplemented cells. Nystatin-resistant isolates of C. albicans with low ergosterol contents also exhibit an increased rate and level of accumulation of these amino acids. The uptake of phenylalanine and leucine remained unaffected by such a change in ergosterol levels brought about by different supplementation of the media. The results demonstrate a correlation between ergosterol levels and amino acids uptake. Contrary to various reports, the rate of K+ efflux does not seem to correlate with the amino acid uptake in C. albicans cells.


An inducible proline transport system in Candida albicans. 1. When Candida albicans cells were preincubated with proline or grown in the presence of proline as the sole nitrogen source they exhibited a rapid increase in the influx of proline (the inducible transport system). 2. The induction appeared to be specific for proline and also demonstrated in other Candida species. 3. Both the inducible and constitutive proline uptake systems exhibited similar characteristic features. 4. The nature of the inducer for proline uptake in C. albicans appeared to be free proline. 5. The development of the inducible proline transport system was dependent on concomitant synthesis of RNA and protein and the induction was not affected by glucose or any other carbon sources used.


Variant forms of matrix protein in Escherichia coli B/r bearing N plasmids. Plasmids of the N incompatibility group have been found to decrease or virtually eliminate the synthesis of the 36,500 dalton outer membrane matrix protein of their Escherichia coli B/r hosts (Iyer, R. (1977) Biochim. Biophys. Acta 470, 258--272 and Iyer, R., Darby, V. and Holland, I.B. (1978) FEBS Lett. 85, 127--132) or modify its composition. Although the 34,000 dalton tol G protein is slightly increased in some strains, it is identical in composition to the homologous protein from the plasmidless host. In three of five N+ strains the synthesis of the modified matrix proteins depends on the temperature of cultivation of the strains in which they occur. The alterations to the matrix proteins are non-identical and do not affect the expression of several plasmid-coded functions including those of sensitivity to the N plasmid-specific filamentous bacteriophage IKe (Khatoon, H. and Iyer, R. (1971) Can. J. Microbiol. 17, 669--675), or their interbacterial transfer via conjugation to appropriate recipient strains. Thus, although the significance of the variant matrix proteins in N+ strains with respect to plasmid-mediated functions remains unclear, N plasmids nevertheless provide a convenient system which might be used to elucidate the events that precede the insertion of this protein into the outer membrane of E. coli B/r hosts.


Resolution of the coenzyme B-12-dependent dehydratases of Klebsiella sp. and Citrobacter freundii. Diol dehydratase (1,2-propanediol hydro-lyase, EC 4.2.1.28) and glycerol dehydratase (glycerol hydro-lyase, EC 4.2.1.30) are shown to be distinct, separable enzymes that occur individually or together in different strains of Klebsiella sp. Anaerobic growth with propan-1,2-diol induces diol dehydratase alone, whereas glycerol fermentation induces both enzymes in K. pneumoniae ATCC 25955 and in Citrobacter freundii NCIB 3735. The dehydratases can be resolved by polyacrylamide-gel electrophoresis or separated by anion-exchange chromatography alone. Sucrose density gradient centrifugation failed to distinguish the enzymes and indicated a molecular weight of 1.9 . 10(5) for both. The enzymes can be assayed individually, even when present in the same crude extract, using the 67-fold difference in their Km values for coenzyme B-12. For both enzymes inactivation kinetics are observed with glycerol as substrated, and monovalent cations influence both the inactivation rate and catalytic rate of the reaction.


Purification and characterization of the extracellular proteinase of Serratia marcescens. The extracellular proteinase produced by a depressed strain of Serratia marcescens ATCC 25419 was purified and characterized. This produces more than 10-times the amount of extracellular proteinase produced by other strains of Serratia tested. The purified enzyme was prepared from the culture supernatant by (NH4)2SO4 fractionation and DEAE-cellulose chromatography. The purified enzyme has an so20,w of 3.95 and is a monomer of molecular weight 51,900. The proteinase has a broad pH optimum in the alkaline range with a maximum at pH 9.5. The enzyme will utilize a number of proteins as substrate. The products of digestion are primarily in the size range of tripeptides to hexapeptides. Peptides containing a sensitive bond and a minimum size of size amino acids are hydrolyzed. The proteinase is inhibited by chelating agents but unaffected by sulfhydryl or serine reagents and is devoid of esterase activity.


Age-dependent increase in the formation of prostaglandin I2 by intact and homogenised aortae from the developing spontaneously hypertensive rat. The prostaglandin I2 biosynthetic capacity of aortae from spontaneously hypertensive rats of various ages (1, 2, 3, 4, and 5 months) was investigated. An age-dependent increase in enzyme activity was observed reaching maximum by three months of age which correlated well with the age- related increase in the systolic blood pressure. These results support our notion that the enhanced aortic synthesis of the potent vasodepressor prostaglandin I2 by the spontaneously hypertensive rat likely represents an adaptive mechanism for the attenuation of the sustained elevation in blood pressure in this animal model.


Comparison between the in vivo rate of metabolism of prostaglandin I2 and its blood-pressure-lowering response after intravenous administration in the rat. Intravenous bolus injection of prostaglandin I2 in the Inactin-anaesthetised rat produces a slow dose-dependant vasodepression which reaches maximum approximately 15 s. after injection. Administration of 9 beta-[3H1]-prostaglandin I2 by the same route followed by serial arterial sampling and TLC analysis revealed a slow conversion into one less polar metabolite starting after 20 s and reaching 40% by two minutes in the circulation. These experiments indicate that prostaglandin I2 survives pulmonary transit for a sufficiently long time to elicit a biological action. Thus its continuous systemic vascular synthesis could play an important role in the control of hypertension.


Cord factor (trehalose-6-6'-dimycolate) of in vivo-derived Mycobacterium lepraemurium. Harvests of Mycobacterium lepraemurium obtained from livers of moribund infected mice yielded M. lepraemurium cell walls that were extracted with solvent to provide crude M. lepraemurium cell wall lipids. By solvent fractionation and chromatography on DEAE cellulose and cellulose, a cord factor-like glycolipids contaminated with mycoside C was obtained. Additional solvent treatment provided the purified glycolipid, which was identified as 6,6'-trehalose dimycolate, by infrared and chromatographic comparison with authentic samples from M. tuberculosis, by identification of trehalose and specific mycolates of M. lepraemurium, and by permethylation analysis. This constitutes the first unequivocal identification of cord factor as a product of in vivo-derived mycobacteria.


Catabolite inactivation of phosphoenolpyruvate carboxykinase in spheroplasts from Saccharomyces cerevisiae. Catabolite inactivation of phosphoenolpyruvate carboxykinase was studied in yeast spheroplasts using 0.9 M mannitol or 0.6 M potassium chloride as the osmotic support. In the presence of potassium chloride the rate of catabolite inactivation was nearly the same as that occurring in intact yeast cells under different conditions of incubation. However, in the presence of mannitol, catabolite inactivation in spheroplasts was prevented. The mannitol inhibition of catabolite inactivation was released by addition of ammonium or phosphate ions. At a concentration of 0.3 M ammonium or 0.06 M phosphate ions, the maximum rate of catabolite inactivation in spheroplasts suspended in mannitol was achieved and was comparable with that observed in spheroplasts incubated in 0.6 M potassium chloride as the osmotic stabilizer. Sodium sulfate (0.04 and 0.4 M) or potassium chloride (0.06 and 0.6 M) did not release the mannitol inhibition of catabolite inactivation in spheroplasts. In intact yeast cells, 0.9 M mannitol, 0.08 M ammonium or 0.1 M phosphate ions did not influence the rate of catabolite inactivation. The nature of the effect of mannitol, ammonium and phosphate ions on catabolite inactivation in yeast spheroplasts is discussed.


Degradation of proteins in steady-state cultures of Escherichia coli. The degradation of proteins in Escherichia coli was investigated in cells grown under steady-state conditions in a glucose-limited chemostat. During the first 24 h, approximately 25% of pulse-labeled proteins were degraded and after 72 h up to 58% of the proteins were broken down. To examine the stability of subcellular components steady-state cultures were labeled with an initial pulse of [14C]leucine, 24 h were allowed for turnover of these proteins, and the cells were then labeled with a short pulse of [3H]leucine. By this double-label protocol, the labile proteins were preferentially labeled with [H]leucine and had high 3H/14C ratios, while the more stable proteins had lower 3//14C ratios. The 3/-labeled proteins were degraded approximately five times as rapidly as the 14C-labeled proteins in exponentially growing cells. The relative stability of subcellular fractions was determined by comparing their 3H/14C ratios to the ratio of the cells at harvest. The soluble fraction contained the most labile proteins, while the ribosomal and membrane fractions were at least as stable as the average cell protein.


Dynamics of glucose-induced plasma insulin increase in the rat fetus at different stages of gestation. Effects of maternal hypothermia and fetal decapitation. The effect of glucose on the release of insulin from the pancreas of 19.5- to 21.5-day-old rat fetuses has been studied in utero. Fetal hyperglycemia was induced by a square-wave glucose infusion into pregnant rats over a period of 150 min. The infusion of glucose raised the fetal blood glucose concentration to that of the mother and induced a rapid increase of plasma insulin levels on day 19.5 of gestation. There was a progressive rise of the insulin response as the gestation proceeded, with an increase of the two phases of the hormonal secretion. Maternal hypothermia induced by pentobarbital anesthesia decreased markedly the insulin response to hyperglycemia in the mothers and their fetuses. In fetuses decapitated on day 18.5 and studied on day 21.5, the increase of plasma insulin concentration after a 1-hour hyperglycemia was similar to that in the littermate control fetuses.


Kinetics of changes in lymphoid organ weight and the cellular composition under leukosis of the latter, inoculated with different amounts of cells. The authors studied the kinetic pattern of weight change in lymph glands, spleen, thymus, and their cellular composition during the development of mouse reticulosarcomatosis and Shvets' leukosis when the transplant contained different numbers of tumor cells. They found that during the development of reticulosarcomatosis, the weight of lymph glands and their content of lymphocytes and plasmocytes undergo enormous changes; the weight of the spleen and its content of lymphocytes increase gradually while the kinetic curve of plasma cell changes presents two maxima. During the development of Shvets' leukosis, the weight of spleen and lymph glands and their lymphocyte content change enormously while the number of plasmocytes rises exponentially. In every case, the authors determined a definite dependence of the reaction of lymphoid organs on the size of the transplantate.


Dopamine receptor stimulating agonists in the treatment of Parkinson's disease. In this article, the clinical actions of the principal dopamine receptor stimulating agents (apomorphine and its derivatives; piribedil, rye-ergot derivatives) are discussed on the basis of their biochemical and pharmacological properties.


Vacuolar pool of magnesium in cells of the yeast Saccharomyces cereviciae. Cytochemical analysis and the fluorescence spectra of yeast cells indicate the existence of a vacuolar pool of magnesium and manganese in Saccharomyces cerevisiae. It was suggested that the tonoplast of yeast cells contains a system of transport of Mg++ and cations of divalent metals, which participates in the regulation of the level of these ions in the cytosol.


Osteopetrosis reconsidered as a curable immune disorder. Osteopetrosis is a unique model for investigating osteoclast formation from lymphocytes and more precisely from T-lymphocytes. In the pathogenesis of this condition, a thymic impairement must be postulated. The cure of several osteopetrotic animal mutants and an infant suffering from juvenile malignant osteopetrosis by injecting normal marrow are the first examples of the successful management of a bone disorder by cell injection.


Adjuvant therapy in colorectal cancer. (A randomized trial comparing radio-chemotherapy and radio-chemotherapy combined with the methanol extraction residue of BCG, MER). Fifty-three patients with colorectal cancer Dukes' B2 and C were randomized after surgery. One group was treated by radio-and/or chemotherapy and the second by radio-and/or chemotherapy and MER. After 24 and 36 months a significant longer disease free interval, lower recurrence rate and better survival was found in the group treated by radio-chemo- and immunotherapy. Treatment was well tolerated and there were few local side effects from the MER injections. The long time efficacy of this adjuvant treatment whether it increases the cure rate or only delays recurrence does require longer follow-up.


Haemostasis during transvesical prostatic adenomectomy. A controlled trial on the effect of drugs with antifibrinolytic and thrombin-like activities. Blood loss, plasma fibrinolytic activity, prothrombin, P.T.T., and fibrinogen plasma levels were measured in 30 patients subjected to transvesical adenomectomy. These parameters were evaluated during 7 consecutive days after the operation. Ten patients received the antifibrinolytic substance (AMCHA), ten patients received Bothrops Jararaca venom extract, and ten patients served as controls. The results show that the coagulating fraction of Bothrops Jararaca snake venom reduces intraoperative bleeding without influencing the haemostatic balance. Postoperative haematuria could be reduced by antifibrinolytic agents.


Havelock Ellis and his 'Studies in the psychology of sex'. The life of Havelock Ellis is described; his personality and life experiences are related to the writing of his major work. Important sections of the 'Studies' are summarized and their relevance to contemporary sexology is emphasized.


Randomised trial comparing buprenorphine and diamorphine for chest pain in suspected myocardial infarction. Buprenorphine, a new powerful analgesic agent, was used to treat chest pain in patients with suspected myocardial infarction. Initial studies showed no significant changes in systemic or pulmonary artery blood pressure or in heart rate after intravenous buprenorphine. Sublingual buprenorphine also appeared effective in relieving pain, but its onset of action was considerably delayed compared with the intravenous route. A randomised double-blind controlled trial of equivalent doses of buprenorphine and diamorphine showed no significant difference between the drugs in terms of pain relief and duration of action. The occurrence of nausea, vomiting, and other side effects was similar in the two groups. The onset of action of buprenorphine was slightly but significantly slower than that of diamorphine. Since buprenorphine seems to be comparable with diamorphine in action and is not a controlled drug, it may prove useful in both general and hospital practice.


Preparation of beta-cells from fetal bovine pancreas: characterization of insulin biosynthetic activity. Dispersed cell preparations enriched in beta-cells were obtained by collagenase digestion of fetal bovine pancreas and separation by Ficoll gradient centrifugation. These cells actively incorporated [3H]leucine into proinsulin and insulin. Incubation of these cells in the presence of the arginine analogue, L-canavanine, resulted in the inhibition of conversion of newly formed proinsulin to insulin and the appearance of a radioactive component of molecular weight 11,000-12,000. Incorporation of [35S]methionine into this component was detected in the presence of canavanine, an event not observed in control incubation. Canavanine thus induced the formation of a component possessing molecular weight and compositional properties expected for preproinsulin. Further characterization of cellular products by polyacrylamide slab gel electrophoresis in sodium dodecyl sulfate showed a highly labeled band corresponding to molecular weight 18,000-20,000 which might be involved in insulin biosynthesis.


The effects of prostaglandins on secretion of glucagon and insulin by the perfused rat pancreas. The secretion of both glucagon and insulin by the isolated perfused rat pancreas was significantly stimulated by 10(-7) M PGH2. Experiments to show that the stimulated secretion was mediated by conversion of PGH2 to TXA2 or TXB2 revealed no correlation between the amount of secretion and the amount of thromboxane formed. Conversion of PGH2 with a crude platelet thromboxane synthase preparation caused a progressive loss of ability to secret insulin, whereas the capacity to stimulate release of glucagon remained at about one-half the maximal level. This relatively stable and selective secretagogue action on the alpha-cells appeared to be due to the formation of PGD2 by the platelet preparation. Direct administration of PGD2 confirmed this interpretation and showed clearly that this prostaglandin is a potent secretagogue for glucagon with little activity in stimulating the release of insulin. Our results have shown high and relatively equal stimulation of secretion by alpha- and beta-cells with exogenous PGE2, PGF2 alpha, and PGH2, little or no secretion by either cell type with TXA2, TXB2, or PGI2, and a unique selective stimulatory action of PGD2 upon the alpha-cell.


Dicarboxylic acid transport in Escherichia coli K12: involvement of a binding protein in the translocation of dicarboxylic acids across the outer membrane of the cell envelope. We have previously found that the dicarboxylate transport system in Escherichia coli K12 is an active transport system and that at least one binding protein and two cytoplasmic membrane transport components are involved in the uptake of dicarboxylic acids. Recently, through surface labelling studies, some dicarboxylate binding proteins were found to be exposed on the cell surface. In the present paper, we demonstrate that the dicarboxylate transport component located in the outer membrane can be inactivated by two different kinds of nonpenetrating inhibitors, viz. proteases, and diazosulfanilic acid. These inhibitors seem to act on the dicarboxylate binding protein. By adding this protein to inactivated cells or to transport-negative mutants, we have succeeded in reconstituting the dicarboxylate transport system. These findings suggest that the dicarboxylate binding protein found on the cell surface plays an essential role in the translocation of dicarboxylic acids across the outer membrane.


Microtubules, colchicine, and lymphocyte blastogenesis. We have studied the time course of disassembly of microtubules of resting and stimulated mouse lymphocytes caused by the drug colchicine, as well as the effect of this compound on DNA and RNA synthesis of human and mouse lymphocytes. Fine-structure studies with the electron microscope showed a great increase in number of microtubules resulting from stimulation of mouse lymphocytes by the mitogenic lectin Con A. The presence of a network of microtubules was demonstrated in resting lymphocytes by use of the technique of immunofluorescence; this technique was not effective for the study of the microtubules of stimulated lymphocytes in the blast stage. The disappearance of microtubular networks in some cells (approximately 25%) was caused by the protocol of colchicine treatment used in many laboratories (30 min at 10(6) M); a 6- to 8-h treatment was required to cause all cells to lose their microtubules. It is indicated in these findings that there is need for extreme caution in implicating microtubule disruption as the cause of certain colchicine effects, such as that on the Con A-induced inhibition of receptor-ligand migration. The addition of colchicine to stimulated cells at varying times of culture caused marked inhibition of DNA synthesis provided that sufficient time (approximately 20 h for maximum inhibition) elapsed between addition of the drug to the stimulated culture and assay of DNA synthesis. Our data on the time course of inhibition of DNA synthesis by alpha-methyl mannoside (alpha MM) and by colchicine do not exclude the possibility that the latter compound may act partially by affecting the commitment of stimulated lymphocytes to DNA synthesis but they show that it can inhibit well after commitment is complete. The later the time of assay of thymidine incorporation, the more disparate were the curves relating the effects of alpha MM and colchicine to DNA synthesis of human cells. In the case of mouse splenic lymphocytes, there was no resemblance between the time course of the alpha MM and of the colchicine effects. Synthesis of RNA after 12 h of culture of stimulated human lymphocytes was also sensitive to colchicine.