[Duodenal cancer. A clinical-pathological study]. Seven primary carcinomas of the duodenum were observed from 1973 to 1976 at the University Hospital Hamburg; four in females and three in males with an age between 32 and 69 years of age. The interval between the first symptoms (epigastric pain, jaundice, pruritus, diarrhea, and loss of weight) and surgical therapy (duodeno-pancreatectomy) averaged four months. All carcinomas were resected radically from the macroscopic (intraoperative) aspect as well as from the histological findings. Local tumour recurrences which proved fatal occurred in five patients within nine to twenty-one months. One patient died of peritonitis and another of pancreatitis. The diagnostic mode has been changed since the introduction of endoscopy and retrograde cholangio-pancreaticography (ERCP). The consistent inclusion of the duodenum in routine gastroscopy leads to the hope that more carcinomas of the duodenum can be detected early.


[Cranial complications in extension therapy of cervical fractures. Riechert's modification of extension therapy]. Cranial complications are reported in the treatment of cervical injury by Crutchfield skull caliper traction. The mechanical causes are discussed and a new skull caliper is demonstrated.


[Surgical management of fractures of the proximal end of the radius]. The problems of dislocated proximal radial fractures are discussed by presentation of 47 cases treated operatively. After operation, 74,6% of these patients had good results with complete elbow function. Special attention is paid to indication and possibilities of operative treatment as well as to intra- and postoperative complications.


[Fractures of the distal end of the femur and their management using condyle plates]. Forty-one patients with fractures of the distal end of the femur are investigated and the importance of the angular plate designed by the AO group for stabilization of these fractures is discussed. For good results it is necessary to have the complete set of instruments and to consider biomechanical principles for stable osteosynthesis, so that early active exercises can be performed. The operation is not always simple but is indicated considering the poor functional and anatomical results after conservative treatment or inadequate fixation.


[Computer-supported basic documentation at the accident-surgical clinic of the Hannover Medical School]. On the example of the computer-aided basic documentation at the Department of Traumatology Hannover, the necessity of constructive cooperation between the clinic staff and the medical data processors is shown. The system of basic documentation is primarily explained in its conception as far as the clinic is concerned. The fundamental principles, daily routine, and clinical application of this system are described, as are the tasks assigned to the clinical staff within the framework of medical data processing. The necessity of clinical staff quality controls by means of a computer short card is emphasized. The system has been in use for 3 years.


Large scale isolation of nuclei and nucleoli from vitellogenic oocytes of Xenopus laevis. A new method is described which allows the purification of large quantities of nuclei (germinal vesicles) from Xenopus laevis vitellogenic oocytes of different developmental stages. From the isolated nuclei, purified nucleoli were obtained. The isolated germinal vesicles are transcriptionally active showing endogenous RNA polymerase activity as well as a high level of activity with an exogenously added template.


Multiple complexes in human spermatocytes. Multiple complexes develop during metaphase I in normal human spermatocytes. Usually they form two separate bodies about 1 micron in diameter, composed of tripartite units and a denser matrix. The tripartite units are structurally identical to the components of the central space of synaptonemal complexes (SCs). Formation of the multiple complexes occurs by shedding of SC fragments from a few chromosomal regions at prometaphase I. The combined total length of central elements in each multiple complex is 1 to 3 micron. Multiple complexes remain as cytoplasmic, perinuclear bodies during telophase I and interphase of spermatocytes II, but they were not observed during or after the second meiotic division. Although multiple complexes are initially located in the spindle, they do not show microtubular attachments and seem to be passively moved towards the periphery.


Changes in the rectal mucosa induced by hypertonic enemas. The aspect of the rectal mucosa after administration of hypertonic enemas is occasionally confused with the macroscopic appearance of quiescent ulcerative colitis. Criteria for a diagnosis of enema reaction were derived from a retrospective series and tested prospectively on 11 healthy volunteers. Photographs and biopsies were obtained before and after administration of a sodium phosphate hypertonic enema. Three observers evaluated blindly the "before" and "after" macroscopic and microscopic pictures, graded the features, and made an overall diagnosis. In random studies, two observers mistakenly classified a macroscopic picture, but all correct histologic diagnoses of "before" and "after" biopsies. In decreasing order of discriminating power, the following features of an enema reaction were found to be useful: separation and mucous depletion of the glands (no observer variation), increase in mucosal fragility in 91 per cent of cases (82--100 per cent), edema of the lamina propria in 88 per cent (73--100 per cent), straightening of the basal membrane in 82 per cent (73--91 per cent) and an increase in extruded mucus in 70 per cent (18--100 per cent). In 39 per cent of cases (36--45 per cent), erythrocytes appeared focally in the lamina propria. The effects of hypertonic enemas can be recognized on biopsy.


Well-differentiated adenoma at the anorectal junction. Twenty-six cases of patients having adenomatous polyps at the anorectal junction are presented. Most polyps in this region were well-differentiated, and atypical polyps were infrequently seen. Well-differentiated adenomatous polyps in the anorectal junction were larger in average size than ordinary colorectal polyps having the same grade of epithelial pseudostratification. The reason  adenomatous polyps at the anorectal junction grow to large sizes with only a relatively rare occurrence of malignant degeneration is discussed in relation to their specific location. Some well-differentiated adenomas were considered to develop secondarily in the bases of hemorrhoids or in pre-existing fibrous polyp that were the end result of hemorrhoids.


Osseous metastases from carcinomas of the colon and rectum. Of 765 patients with disseminated metastatic carcinoma of the colon and rectum treated at Memorial Sloan-Kettering Cancer Center during the ten-year period 1960--1970, 53 (6.9 per cent) had skeletal metastases. Of these, 14 (1.8 per cent) had osseous metastases only. In one case the osseous lesion was the first symptom of a cancer of the sigmoid colon, and one patient had metastasis in the fibula from a primary rectal cancer. In our series the incidences of osseous metastases were 8.9 per cent from rectal carcinoma and 5.1 per cent from colonic carcinoma. The mean period from manifestation of skeletal metastasis to death was 13.2 months.


Gardner's syndrome with duodenal adenomas, gastric adenomyoma and thyroid papillary--follicular adenocarcinoma. A case of a woman with Gardner's syndrome, originally manifested by multiple adenomatous polyps of the colon, is presented. She underwent subtotal colectomy at 14 years of age. Over the next 15 years she had a composite odontoma, an impacted supernumerary tooth, two epidermal inclusion cysts, multicentric paillary-follicular adenocarcinoma of the thyroid, two tubulovillous adenomas of the duodenum in which argyrophilic cells were a prominent feature, and an adenomyoma of the gastric antrum. The presence of all of these lesions in one patient expands the spectrum of lesions seen with Gardner's syndrome and supports the concept of a generalized abnormality of growth regulation as the cause of the syndrome.


Coloenteric fistulas.

Coloenteric fistulas. A ten-year experience with 12 cases of spontaneously occurring, preoperatively diagnosed coloenteric fistulas is described. Accurate diagnosis can be achieved most often by barium-enema examination. One-stage resection with primary anastomosis, to restore gastronintestinal continuity, is highly successful, and should be the procedure of choice.


WDHA syndrome caused by pheochromocytoma: report of a case. A case in which a pheochromocytoma secreted vasoactive intestinal peptide, causing WDHA syndrome, is reported. The patient, a 43-year-old woman, was seen because of intractable watery diarrhea, hypokalemia and weight loss. She was found to have a mass in the right adrenal area. Preoperatively, vasoactive intestinal peptide levels were elevated, and the diagnosis of WDHA syndrome was entertained. Exploratory laparotomy revealed a tumor of the right adrenal gland, measuring 15 x 15 cm, which was resected. Histologic examination revealed it to be a pheochromocytoma. Postoperatively, vasoactive intestinal peptide returned to normal. The patient had complete remission of symptoms, and has remained well since.


Hemangioma of the rectum: clinical appearance and treatment. A 53-year-old woman who had severe rectal bleeding was found to have a perirectal hemangioma as a source of the bleeding. Four years prior to this admission, she had undergone, in another hospital, hemorrhoidectomy, which had required resuturing several times in order to stop rebleeding. The diagnosis of hemangioma was established after extensive roentgenographic examination. The patient was treated with low-dose irradiation, divided into five consecutive sessions, to the affected area. The bleeding stopped, and the patient has been free of disease since treatment two years ago. The lumen of the rectum is not narrowed, the mucosa appears normal, and the elasticity of the rectal wall has been preserved.


Sloughage of the anus and lower rectum following aortic graft replacement: report of a case. The successful management of a near-complete sloughage of the anal outlet following aortic graft replacement is reported. Oxygenation in the immediate postoperative period along with appropriate antibiotics may be beneficial in preventing such sloughage. Embolic phenomena or bacterial growth, or both, may have been factors in causing the extensive sloughage.


[Macrocytic anaemia with folic acid deficiency in hypothyroidism (author's transl)]. Three different kinds of anaemia are seen in hypothyroidism: (1) normocytic, normochromic anaemia; (2) microcytic, hypochromic anaemia; (3) macrocytic normochromic anaemia. The latter is either a true pernicious anemia, which occurs fairly frequently in Hashimoto's thyroiditis, or maturation disorder of erythropoiesis as a result of folic acid deficiency. In three patients with primary hypothyroidism and macrocytic anaemia there were decreased levels of serum folic acid. After short-term administration of folic acid and 1-year of thyroxine the blood picture became normal in two of the patients.


[Thrombectomy for acute renal-vein thrombosis (author's transl)]. Three personal cases are presented to indicate the growing need for thrombectomy as a method of treatment of renal-vein thrombosis. In addition to known causes of renal-vein thrombosis (e.g. iatrogenic, post-traumatic) there is the so-called spontaneous renal-vein thrombosis especially in newborns. The possibility of renal-vein thrombosis must be considered in the presence of sudden, circumscribed pain in the flanks, haematuria and albuminuria, large kidney shadow radiologically, loss of renal function.  Reported cases and the three personal ones suggest a trial of thrombectomy. It is not known how long the kidneys can tolerate venous occlusion. But the personal observations suggest that even occlusion lasting for serveral days may be reversible. In one patient with renal-vein thrombosis after unrecognised misplacement of a Mobin-Uddin filter into the right renal vein, surgical restoration of venous drainage after several weeks indicates that long-term observations are necessary to judge final results.


[Reduction of dislocation of transvenous pacemaker electrodes taking intracardiac ECG potentials into account (author's transl)]. For the assessment of stable positions of the electrodes radiographic control, threshold measurements and methods provoking dislocation are used. There is an average dislocation rate of endocardial electrodes of 7-11%. As a further parameter for intra-operative assessment of a stable electrode position intracardiac R-potentials were measured with the stimulation electrode. While QRS complexes in the surface ECG remain unchanged, intracardiac electrocardiograms show an alternating height of the R-amplitude from one ventricular action to the next. From these differences (deltaR) a stable electrode position can be assumed as long as deltaR is small (our patient group 2.12mV+/-1.05MV). Large differences (6.9mV+/-1.7MV) indicate a non-optimal fixation of the electrode tip. The dislocation rate including the post-operative exit block could be reduced below 2% by consideration of the R-amplitude alterations.


[CSF lactate and EEG changes in comatose patients with various medical conditions (author's transl)]. EEGs were recorded and initial CSF and blood lactate measurements (135) made in 104 patients who were in coma of differing severity from a variety of medical conditions. There were two patterns: in one, the CSF lactate alone was due to cerebral tissue hypoxia; and in the other factors, such as cerebral haemorrhage, meningitis or lactacidosis were predominantly present. In those with cerebral hypoxia there was a connection between the severity of the disease picture and the level of CSF lactate. In extreme cases with dissociated cerebral death, there was a mean CSF lactate concentration of 11.78 +/- 1.66 mmol/1. The prognosis of coma with concentrations above 9 mmol/l is, therefore, poor if not hopeless. To some extent one may draw prognostic conclusions from lower concentrations but this is not possible in individual cases. There was no definite correlation between the severity of EEG changes and the level of CSF lactate in coma, although there was some relationship to the degree of cerebral hypoxia. In case of meningitis, CSF lactate allowed differentiation between bacterial and viral cause, the average concentration in the former being four times normal.


Biliary ascariasis.

Biliary ascariasis. The presenting clinical features of a series of cases of biliary tract ascariasis are described, in particular the characteristic colicky pain which occurs. The term 'ascaritic biliary pain' is introduced for the symptom diagnostic of live Ascaris adult worms inside the biliary passages. Methods of diagnosis before, and in the course of, operation are discussed and seem adequate. The management of worms discovered in the bile ducts, and those in the proximal small bowel, is described.


Single dose therapy of giardiasis with tinidazole and metronidazole. In random order, a single dose of either tinidazole or metronidazole, calculated as 50mg/kg body weight, was given to 100 children with symptomatic giardiasis. Follow-up was done for 16 days and consisted of 4 clinical, parasitological and biochemical assessments at intervals of 4 days. The actual mean dose of the drugs received by the patients was 55.5 mg/kg of tinidazole and 52.0mg/kg of metronidazole. Success, i.e. parasitic clearance and symptomatic relief, was achieved in 80% of patients given tinidazole as opposed to 36% of patients given metronidazole (p less than 0.01). Moreover, control of diarrhoea and negative stool conversion for G. lamblia occurred earlier with tinidazole than with metronidazole (p less than 0.01). The incidence of gastrointestinal side-effects was 12% for tinidazole and 4% for metronidazole. Neither drug caused any abnormality of the blood count, blood urea, urine analysis or liver function tests.


Tinidazole in the treatment of trichomoniasis, giardiasis and amoebiasis. Report of a multicentre study. An open multicentre trial was undertaken in 8 countries to assess the efficacy and tolerance of short course treatment regimens of tinidazole Trichomoniasis: of 859 patients with trichomonal vaginitis given a 2g single dose of tinidazole 717 (95.2%) were cured. Side-effects occurred in 82 patients (9.5%) and in 12 were regarded as severe. Giardiasis: of 74 children with symptomatic giardiasis given tinidazole in a single dose of approximately 50 mg/kg body weight, 65 (88%) were parasitologically and symptomatically cured. 2 (2.7%) complained of side-effects, none of which was severe. Intestinal amoebiasis: of 502 patients, comprising 458 adults and 44 children, with symptomatic intestinal amoebiasis who received tinidazole as a single daily dose on 2 to 3 consecutive days, 477 (95%) were parasitologically cured with complete or marked improvement in symptoms. Side-effects occurred in 50 patients (10%) and in 11 were regarded as severe. Amoebic liver abscess: 82 patients were given tinidazole in single doses of 2g on 3 consecutive days. The response was rated as excellent in 60 and good in 17 (overall cure 93.9%). Side-effects occurred in 9 patients (10.9) and in 2 were regarded as severe. These findings confirm the efficacy and tolerance of short regimens of tinidazole given in single daily doses.


Surgical drainage of amoebic abscess of the liver. 45 cases of amoebic abscess of the liver which were managed, over a period of 17 years, by surgical drainage are reviewed. The clinical presentation, diagnostic procedures performed, and morbidity and mortality are presented. From the results the following indications for surgical intervention are recommended: presence of an obvious liver abscess; persistence or aggravation of symptoms and signs during or following medical treatment, or persistence of symptoms with an inconclusive result from diagnostic procedures.


Anthelminthic effect of oxantel and oxantel-pyrantel in intestinal nematode infections. 704 patients with intestinal nematode infestation were treated with oxantel and oxantel-pyrantel in either liquid or tablet form, at doses from 10 to 25mg/kg. All were given the drug or drugs as a single dose. In 699 patients with trichuriasis cure rates between 64 and 93% were obtained and there were egg reduction rates of between 90 and 100%. The best results were obtained using oxantel, either alone or in combination with pyrantel, at 15 to 20mg/kg. Only 2 of 152 patients with ascariasis were not cured after a single dose of pyrantel (given as oxantel-pyrantel) of 10, 15 or 20mg/kg, and both these patients were from the group given the lowest dose. Only mild side-effects were noted. The combination, oxantel-pyrantel is a safe and effective treatment for multiple intestinal nematode infection.


A comparative study of the effect of oxantel-pyrantel suspension and mebendazole in mixed infections with Ascaris and Trichuris. A comparative trial was carried out in 4 orphanges in Seoul, to compare the anthelminthic efficacy of oxantel-pyrantel suspension and mebendazole tablets against mixed infections of Ascaris lumbricoides and Trichuris trichiura. 40 patients were divided into 4 groups and received oxantel-pyrantel suspension at 15 or 20mg/kg once only or on 2 consecutive days. Another group of 20 patients was treated with 100mg of mebendazole twice a day for 3 days. Both drugs achieved a 100% cure rate for Ascaris infections. Against Trichuris infections, the average cure rate and egg reduction rate of oxantel-pyrantel treated groups was 87.5% and 92.3% respectively, and that for mebendazole was 65% and 89.1%. There were no side-effects. The results of the present study suggest that oxantel-pyrantel is more effective in the treatment of mixed infections of Ascaris and Trichuris, and was more acceptable to the patients, than mebendazole.


[Fluorometric method of determining urinary estrogens]. The authors describe a method for determination of estrogens in urine of nonpregnant women and men. The method includes enzymic hydrolysis of urine, gel filtration of Sefadex G25, extraction with organic solvents and modifies Kober reaction with spectrofluorometric determination. The technique of the method is not complex, the usage of reagents is small and is suitable for everyday work.


[Immunodepressive properties of diethyleneimine benzoquinone-containing polyvinylpyrrolidone complexes]. The authors examined the changes, which occurred in the weight of lymphoid organs (thymus, spleen, and lymph nodes) and titre of serum hemagglutinines against sheep erythrocytes in mice BAIB/c under the influence of treatment with diethyleniminbenzochinon and some of its complexes with polyvinylpirolidon (PVP). The ratio of the substances composing the complexes (in mg per 1000 mg of complex) was as followed: DEiBx- PVP complex NoI-340:660; DEiBx-PVP complex No2-200:800; DEiBx-PVP-Uracyl complex No3-250:500:250. There was a sharp reduction of the weight of lymphoid organs in mice, treated with DEiBx, singly or in the form of complexes NoI and No2 in comparison with the control nontreated mice or treated with complex No3. This effect was more manifested after treatment with DEiBx during the same regimen (0.8 mg/kg of body weight daily for 5 days). The ability of the treated animals to react to immunization with sheep erythrocytes practicaly was not impaired during the treatment with complexes No2 and No3 or the damage was slight (complex NoI) in contrast to the treatment with DEiBx.


[Antitumor activity of cytostatics on a newly transplanted tumor in mice, myosarcoma ISM]. The author examined the action of 14 known antitumor preparations on mice BAIB/c with newly transplanted tumour occurred after induction with tetrachlormethane. The tumour myosarcoma ISM showed high sensitivity to cyclophosphamide, administration of which caused complete inhibition of tumour growth and regression of tumours. A comparative high antitumour effect was found after usage of sarcolysine, brunemycine and mitomycine C (over 70% of inhibition). There was a moderately manifested inhibition of the tumour growth (around 50%) after administration of cytostatics degranol, purinetol, 5-fluorouracyl and ftorafur. The substances alexan, rubomycine and 1-(2-chlorethy)-3-cyclohexyl-1-nitrosourea were without effect on myosarcom ISM. The obtained data showed that then tumour well differentiated substances in accordance with their action. It is a prorer model for thorough investigation of antitumour substances.


[Changes in adrenocortical activity in grown rats following thymectomy]. The authors measured arterial blood pressure by direct and indirect method in 80 adult rats and examined: content of ascorbic acid and cholesterol and the activity of alkaline and acid phosphatase in adrenals after thymectomy. The indices were followed in dynamics on the 15, 30, 45, 60 and 90th day after thymectomy. The established changes, manifested by a reduced concentration of the ascorbic acid and cholesterol in the early period of the experiment and the increased phosphatase activity during the whole period were interpreted as a manifestation of elevated adrenal activity after thymectomy. Activation of the adrenal cortex preceded the hypertensive reaction.


[Effect of adepren on the rate of cerebral noradrenaline metabolism]. The authors examined the influence of the original Bulgarian antidepressant adepren on the metabolic rate of noradrenaline in the brain of rats. For this purpose they used an isotopic method for incorporation of C14 tyrosine. It was established that adepren lowered the metabolic rate of noradrenaline. The authors explained these changes by the elevated level of brain noradrenaline, found by them, which level inhibited the rate its synthesis by feed back mechanism.


[Effect of adepren on the cerebral concentration of serotonin]. Adepren is original Bulgarian antidepressant. The authors find that adepren elevates the level of brain serotonine both after single and multiple treatment of white rats. The authors interpret the elevated level of serotonine as a result of MAO inhibiting effect of the preparation. They connect the effect of adeprene on the level of serotonine with favourable action on the behaviour of depressed patients.


[Incorporation of glycine(14C) into liver proteins during low energy laser pulse irradiation]. The authors examined the action of irradiation with ruby lazer at lambda=6,948 A and level of energy 0.13 j/sm2. Liver of rats was irradiated through the surrounding tissues in five successive impulses. The skin in the region of action was stained with methylene blue. Changes in the incorporation of the label in the free amino-acids, in total cholesterol of liver and ribosomal protein as well as the proteins in the supernatant over ribosomes were examined. Glycine (14C) was identified by chromatographic was and autoradiographycaly. The relative radioactivity was determined by a scintillation radiometer. The data, estimated statistically, on the studies showed that 48 hours after lazer irradiation the incorporation of glycine was elevated over 12%. There were no apparent changes macroscopicaly and in the usual histologic preparations during the same period of time. Electronmicroscopic investigation revealed a certain alteration of the membrane structures, vacuolization at sites, but preserved ribosomal structures, accumulation of glycogen. The established changes were described as a manifestation of nonthermic effects of the type "striking wave" with successive increased course of reparative processes.


[Experimental study of the dynamics of alkaline phsophatase activity after a liver wound]. The investigation of alkaline phosphatase activity on 80 rabbits with an experimental model of liver wound showed the following results: 1. Alkaline phosphatase in blood serum was elevated considerably during the first postoperative days, but after the fifth day was close to the normal ranges. 2. Tissue alkaline phospatase sharply fell up to the third day. Its values began to raise after the 20th day and reached the normal level in the end of the experimental period (30th day). 3. Histochemical studies of liver wound showed a positive reaction for alkaline phosphatase in the cells of the inflammatory infiltrate during the first days. Increased phosphatase activity was demonstrated in fiber structures, epithelium of bile canals and capillary endothelium. The dynamics of alkaline phosphatase activity in blood serum is a reflection of the delicate biochemical and histochemical changes in the liver wound. The follow-up of serum alkaline phosphatase together with the clinical course of healing could be an useful index for evaluation of diet and working capacity of the patient.


[Effect of thymectomy on the functional activity of the thyroid gland in rats]. The authors examined the functional state of the thyroid gland of rats after thymectomy. The dynamics of incorporation of radioactivity I131 in the gland was examined on the 2,20 and 90th day after the operation. There was increased incorporation of the radioisotope in the thyroid giant at the early stages of the experimental period. A reduced incorporation and delayed excretion was observed in the distant periods. Changes in the activity of the thyroid gland were accepted as a manifestation of the existing functional link between the thymus and thyroid gland.


[Late morphologic changes in the myocardia of experimental animals following chronic wofatox poisoning]. The authors examined the morphologic changes in the myocardium of male white rats one and two months after chronic intoxication with the preparation BOFATOX, used in doses of 1/20 and 1/100 of LD50 for a period of two and four months. They observed circulatory and dystrophic changes during the first month, but after prolongation of repapatory period up to two months found definite pathologic changes, manifested by small cicatrixes, focal granuloma, vascular sclerosis and the presence of slightly manifested regenerative processes.


[The effects of phenylbutazone on the decrease of lithium clearance]. During the treatment of a manic depressive patient, the authors reported some lithium toxicity signs, as lithium carbonate (3 X 300 mg p.d.) and phenylbutazone suppository (3 X 250 mg/p.d.) were associated, this last medication being prescribed for a phlebitis. Lithiemia increased from .70 to 1,44 mEq/l., the lithiemia clearance falling from 10 ml to 5 ml/mn/1.73 m2) and the lithium tubular reabsorption percentage increasing from 85 to 94% (standard rates: 77.4 +/- 1.3%). In a second time, a rat experimentation corroborated these findings: phenylbutazone treatment (100 mg/kg/p.o. for five days) resulted in a lithium tubular reabsorption increase. It seems that the association of lithium carbonate with phenylbutazone should be avoided. The authors point out the risk of prescribing lithium and pyrazolic by-products as phenylbutazone, which are potentially nephrotoxic.


[Comparative study of the pharmacological and clinical effects of clorimipramine and metaprimine (19560 R.P.)]. Although its pharmacology is virtually identical with that of the tricyclic antidepressants, metapramine (19560 R.P.), i.e. methyl-5 methylamino-10 dihydro-10, 11 dibenzo (b,f) azepine, differs biochemically from the tricyclics in that it markedly enhances the turnover of norepinephrine without notably inhibiting the re-uptake of this amine. Differences in the therapeutic effects of metapramine and clorimipramine have been investigated in a double-blind clinical test. The possible relationship between these differences and the biochemistry of both compounds is discussed in terms of the monoaminergic hypotheses.


[Depressive states: clinical symptoms and monoaminergic hypothesis]. Twenty somatic symptoms are listed, that are often met in depressive states but that are presently neglected by clinicians and by the various depression rating scales. Thanks to the data provided by animal pharmacology and clinical studies, an attempt to correlate the clinical studies with the biochemical results is proposed between those symptoms and eventual monoaminergic dysfunctions. This study leads to a clinical observation scale. In the future, the authors envisage a multifactorial analysis of the data obtained by the use of the scale. Symptomatic groupings could help establish a new classification for depressive states. They could also guide the choice of the medication according to the monoaminergic dysfunctions that are pointed out.


[Assertive training: techniques and clinical applications]. This paper successively examines the components of assertive behavior, its measurement instruments and the different techniques used to teach patients how to become more assertive. The therapeutic applications of assertive training are also summarized. The discussion emphasises the need for comparative studies with long term follow-ups and considers the problems of generalization outside the experimental setting. The use of anger is questioned because assertive training serves neither to eliminate nor exaggerate aggression but to control it. The authors conclude that a good assertive training technique should include simple and clearcut instuctions, behavior rehearsal and modeling.


ERCP, endoscopic papillotomy and gallstone removal by JFB2 Olympus and PFSB 1200 Machida. ERCP is now used as routine technique and has provided a useful tool for both diagnostic and therapeutic purposes in diseases of the biliary tract. Until now this examination has been performed throughout the world including Italy, using preferably an Olympus JF and JF B2 sideviewing duodenoscope. In addition to 727 ERCP and 55 papillotomies performed using this instrument we have also employed a convertible endoscope Machida PFSB 1200; this fiberscope, with which front and side views are possible, can be used in the study of the oesophagus, stomach, duodenum, cannulation of the papilla of Vater and papillotomy. They results obtained and advantages offered by this instrument will be discussed. Since this endoscope is not usually employed, at least in Europe, for these purposes, we considered it of interest to report on the 251 ERCP and 9 papillotomies including stone removal performed in our department with the Machida PFSB 1200.


Can Mirizzi syndrome be classified into acute and chronic form? An endoscopic retrograde cholangiography (ERC) study. Three cases of Mirizzi syndrome (partial mechanical obstruction of the common hepatic duct owing to compression by a stone impacted in the cystic duct or gallbladder neck, or due to the inflammatory reaction resulting from compression) are reported. The roentgen features at endoscopic retrograde cholangiography (ERC) are discussed. As there are two causes for obstruction, compression or chronic fibrosing reaction resulting from compression, two characteristic X-ray findings and two operating techniques, the authors contend that Mirizzi syndrome should be classified as acute or chronic.


Coloscopy: a necessary aid in the diagnosis of transient ischemic colitis. After a short review on endoscopic diagnosis of transient ischemic colitis, the author calls attention to the ischemic pathology of the colon emphasizing the importance of coloscopy as a necessary aid in the diagnosis of these diseases.


A laser-endoscope with direct beam coupling. An optical element for direct laser-beam coupling into the observation optic of a rigid endoscope was developed. Using this coupling element every suitable endoscope can be modified into a laser endoscope which can be used for laser surgery e.g. in ENT and urology. The requirements for the endoscope and the optical coupling element are discussed.


Diagnostic problems with gastrointestinal metastases in breast cancer. A case of a diffuse transmural infiltrating gastrointestinal metastasis of breast cancer in an eighty years old woman is reported. It is shown that endoscopy, along with biopsies can only provide a descriptive result.


Right pneumothorax following fiberoptic oesophageal dilatation. A case of spontaneous right pneumothorax following dilatation of an oesophageal stricture using the Eder-Puestow technique is reported.


Barium enema with subsequent perforation of the rectum following rectoscopic biopsy. Two case reports are presented in which a barium enema was carried out immediately following rectal biopsy. In both cases, perforation occurred. On the basis of these cases, the various possibilities of perforation are listed. The question of the time factor when both diagnostic procedures are to be carried out is discussed.


Bacteriological efficiency of a standardized cleansing and disinfection technique for duodenoscopes. Adequate cleansing and disinfection of the endoscopes is desirable to prevent bacteriaemia and septicemia following gastrointestinal endoscopy, especially endoscopic retrograde cholangiopancreatography and duodenoscopic sphincterotomy. A practical method, proved in our department over a period of 12 months, is described. As the result of this standardized cleansing and disinfection technique using the aldehyde derivative Gigasept (succine dialdehyde and 2,5-dimethoxytetrahydrofuran) in a 10% concentration as chemical disinfectant, sterile cultures from the biopsy channel were obtained in 75% of tested instruments. The remaining fiberscopes exhibited only a few bacteria left, resulting in a sufficient success of disinfection according to hygienic standards.


Experiences and problems in the disinfection of fibre endoscopes. The problem of the disinfection of fibre endoscopes is to achieve a good efficiency together with easy handling. There is not yet a disinfectant which shows a sufficient germicidal effect after a short time of contact with the fibre endoscope and which is harmless to the patient and medical staff. This paper deals with a two-stage disinfecting procedure in which the instrument undergoes a short intermediate disinfection using polyvidoneiodine (Betaisodona) between two investigations and a main disinfection at the end of a series of investigations using glutardialdehyde (Cidex). The measures lead to a sufficient reduction of the number of germs. The importance of the disinfection of all parts of the endoscopes, especially the channels and the accessories (water bottles etc.) is pointed out.


Upper gastrointestinal fiberoptic panendoscopy. A 4-year study in a district general hospital. Four years' experience of an upper gastrointestinal endoscopy service in a district general hospital is reviewed. The study comprises 500 prospective peroral endoscopic and radiographic investigations of 432 consecutive patients. The endoscopic diagnoses are compared with the results of conventional barium studies and the incidences of correct diagnoses with the two methods of investigation are estimated on the basis of the histological diagnoses on directed biopsy specimens. Endoscopy is more accurate than radiology in the examination of the stomach, especially in cases of radiologically distorted antrum and pyloric canal. We found fewer duodenal ulcers by means of combined panendoscopy than demonstrated by X-ray; the reason is discussed and the results of endoscopic biopsy and cytology in the diagnosis of gastric cancer are reported.


Chronic nonspecific duodenitis (bulbitis). "Bulbitis" was classified by fiberoptic endoscopy in: superficial, erosive and pseudopolypoid. Endoscopic diagnosis of "bulbitis" is reliable, as good agreement was obtained in 100 cases tabulated according to histological grading. Erosive "bulbitis" implies a severe histopathological compromise.


Porcine follitropin. Isolation and characterization of the native hormone and its alpha and beta subunits. The properties of porcine follitropin and its subunits which have not yet been characterized are presented. The porcine follitropin obtained has a biological potency of 81 times the National Institutes of Health Porcine Follitropin P-1 preparation. Its contamination by lutropin and thyrotropin amounted to 1 and 0.5 percent by weight respectively, as measured by radioimmunoassay. The alpha and beta subunits of porcine follitropin were obtained by incubation in an acidic urea solution followed by anion exchange chromatography. The amino acid composition of porcine follitropin alpha subunit was found to be identical to that of alpha chain of porcine lutropin and thyrotropin. These porcine alpha chains differ, nevertheless, markedly in their carbohydrate composition particularly with respect to their mannose and galactose contents. The amino-terminal residue of the follitropin alpha subunit is threonyl. The carboxy-terminal end of the alpha chain is of variable length. Cysteyl residue was detected at the aminoterminal end of the follitropin beta chain with glutamic acid at its carboxy-terminal end. Cross-contamination of the alpha and beta subunit preparations was measured by specific radioimmunoassay and amounted to 0.5 and 0.1 percent by weight respectively.


Porcine follitropin. The amino-acid sequence of the beta subunit. The amino acid sequence of the porcine beta subunit has been established by studies of peptides isolated after tryptic, thermolytic and staphylococcal protease treatments of the reduced and carboxymethylated chain. The primary structure of the amino-terminal region of the molecule has been solved by automatic sequencing of the reduced and tritium-labeled carboxymethylated subunit. The amino acid sequence of porcine follitropin beta subunit differs from that of its human counterpart by several amino acid replacements, deletion or addition of one or several residues. The porcine chain appears shorter at both its amino and carboxy-terminal ends. The chemical evolution of follitropin is briefly considered and compared to these of thyrotropin and lutropin.


Purification and some properties of L-glutamate decarboxylase from human brain. Glutamate decarboxylase (EC 4.1.1.15) from human brain has been purified 8000-fold with respect to the initial homogenate. The molecular weight of the native enzyme was found to be 140000 by electrophoresis on a polyacrylamide gradient gel slab. The presence of a single protein band (Mr 67000) on sodium dodecylsulphate/polyacrylamide gel and the existence of only one N-terminal amino acid suggest that the enzyme consists of two similar if not identical polypeptide chains. The Km of the enzyme at the optimum pH of 6.8 is about 1.3 x 10(-3) M for glutamate and 0.13 x 10(-6) M for pyridoxal phosphate. The analysis of the effects of various inhibitors of mouse brain glutamate decarboxylase on the human enzyme confirms the strong competitive inhibition caused by 3-mercaptopropionic acid (Ki = 2.7 x 10(-6) M) while the Ki values for allylglycine and chloride ion are 1.8 x 10(-2) M and 2.2 x 10(-2) M, respectively.


The amino-acid sequence of kangaroo pancreatic ribonuclease. Red kangaroo (Macropus rufus) ribonuclease was isolated from pancreatic tissue by affinity chromatography. The amino acid sequence was determined by automatic sequencing of overlapping large fragments and by analysis of shorter peptides obtained by digestion with a number of proteolytic enzymes. The polypeptide chain consists of 122 amino acid residues. Compared to other ribonucleases, the N-terminal residue and residue 114 are deleted. In other pancreatic ribonucleases position 114 is occupied by a cis proline residue in an external loop at the surface of the molecule. Other remarkable substitutions are the presence of a tyrosine residue at position 123 instead of a serine which forms a hydrogen bond with the pyrimidine ring of a nucleotide substrate, and a number of hydrophobichydrophilic interchanges in the sequence 51-55, which forms part of an alpha-helix in bovine ribonuclease and exhibits few substitutions in the placental mammals. Kangaroo ribonuclease contains no carbohydrate, although the enzyme possesses a recognition site for carbohydrate attachment in the sequence Asn-Val-Thr (62-64). The enzyme differs at about 35-40% of the positions from all other mammalian pancreatic ribonucleases sequenced to date, which is in agreement with the early divergence between the marsupials and the placental mammals. From fragmentary data a tentative sequence of red-necked wallaby (Macropus rufogriseus) pancreatic ribonuclease has been derived. Eight differences with the kangaroo sequence were found.


Electron-microscopic demonstration of terminal and internal initiation sites for cDNA synthesis on vitellogenin mRNA. cDNA synthesized on purified vitellogenin mRNA from Xenopus liver was hybridized to the template in formamide/urea at 22 degrees C to avoid degradation of the RNA. The hybrids formed were visualized by spreading for electron microscopy. Contour length measurements proved that most of the RNA molecules in the hybrids were still intact showing the expected molecular weight of 2.3 x 10(6). The hybridized cDNA corresponded on the average to 12% of the RNA length. In about 80% of the molecules the cDNA was located at one end. Since cDNA synthesis was primed by oligo(dT), the terminal duplex region marks the 3' end of the vitellogenin mRNA molecule. Internal duplex regions were mainly located at a specific position starting about 2800 nucleotides from the 3' end. Since the cDNA hybridizing at the internal position could specifically be synthesized on a vitellogenin RNA fragment isolated on poly(U)-Sepharose as an oligo(A)-containing RNA, we conclude that cDNA synthesis is not only initiated by the poly(A) of the 3' end, but also by a specific internal sequence.


On the activity of RNA polymerase B in lysates from Ehrlich ascites cells. Transcription by endogenous RNA polymerase B in lysates of Ehrlich ascites cells was investigated. The enzyme exhibits two salt optima at 0.025 M and at 0.3 M (NH4)2SO4 respectively. Preincubation of the cells with the nucleoside analogue 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole results in an inactivation of the polymerase molecules active under condition of low salt. This indicates two functional states of the enzyme in vivo. Initiations of RNA chains by polymerase B do not occur in vitro as judged by the incorporation of [beta-32P]GTP. Thus the two functional states seem to be both elongating polymerase molecules. Polymerase B does not occur in the lysates in a state ready to initiate on an exogenous template, in contrast to polymerase A and C which do occur in free form. Pretreatment with dichlororibofuranosylbenzimidazole in vivo does not result in an accumulation of free polymerase B.


A 1H nuclear-magnetic-resonance study of the conformation and the molecular dynamics of the glycoprotein cow-colostrum trypsin inhibitor. The glycoprotein cow colostrum trypsin inhibitor was investigated by high resolution 1H nuclear magnetic resonance (NMR) at 360 MHz and, on the basis of the NMR data, compared with the basic pancreatic trypsin inhibitor (Kunitz) from bovine tissue. Detailed studies of the chemical shifts and the exchange kinetics of the labile protons indicated extensive homologies between the spatial structures of the polypeptide chains in the two compounds. This was further corroborated by comparison of the NMR spectral features and the dynamic properties of the aromatic amino acid residues in the two inhibitors. It thus appears that the covalently attached carbohydrate moiety in the colostrum inhibitor has only very limited effects on the spatial structure of the protein part of the molecule. On the other hand, as evidenced by the NMR line widths, the carbohydrate attachment causes a pronounced restriction of the overall mobility of the molecule, indicating a sizeable increase of the average radius of gyration as compared to the basic pancreatic trypsin inhibitor. Possible spatial arrangements of the globular polypeptide and the carbohydrate moieties in the colostrum inhibitor, which would be compatible with the experimental observations, are discussed.


DD-Carboxypeptidase activity of membrane fragments of Mycobacterium smegmatis. Enzymatic properties and sensitivity to beta-lactam antibiotics. A DD-carboxypeptidase activity is present in membrane fragments of Mycobacterium smegmatis. Kinetic parameters of the enzymatic activity have been studied using UDP-N-glycolylmuramyl-L-alanyl-gamma-D-glutamyl-meso-2,2'-diaminopimelyl-D-[14C]alanyl-D-[14C]alanine as substrate. The DD-carboxypeptidase can be solubilized by Triton X-100 and Genapol X-100. It is inhibited by beta-lactam antibiotics although intact cells of M. smegmatis are insensitive to that kind of antibiotics. Inhibition by penicillin G is slowly reversible. By storage, at -20degrees C, kinetic parameters and sensitivity to penicillin G vary non-concomittantly, suggesting a penicillin binding site different from the substrate binding site.


L-2-hydroxytetradecanoic acid as a constituent of Salmonella lipopolysaccharides (lipid A). L-2-Hydroxytetradecanoic acid was recognized as a characteristic, although minor, constituent of the lipid A component of Salmonella lipopolysaccharides. The 2-hydroxy fatty acid was present in lipid A as an ester, probably bound to the hydroxyl group of some D-3-hydroxytetradecanoic acid residues. A survey of enterobacterial lipopolysaccharides showed that L-2-hydroxytetradecanoid acid was also present in Klebsiella and Serratia strains. It was absent, however, from lipopolysaccharides of other genera of the family including Escherichia, Shigella, Proteus, Enterobacter and Yersinia. This restricted distribution of the 2-hydroxy acid may be of significance for taxonomic studies of bacterial genera.


The interaction of human hemoglobin with erythrosin. Comparison of hemoglobins with variously liganded heme groups. The interactions of erythrosin with deoxyhemoglobin, oxyhemoglobin, carbonmonoxyhemoglobin, methemoglobin, cyanomethemoglobin and hemoglobin alpha and beta chains have been studied by using the equilibrium dialysis, the difference and circular dichroic (CD) spectra and stopped-flow method. The values of equilibrium and kinetic parameters, as well as CD characteristics, show that in addition to a number of weak binding sites hemoglobin contain four, relatively strong binding sites, one per chain. The properties of the strong binding sites depend on the ligand of the heme group and the charge of the heme group is not directly responsible for this fact. Consequently the properties of deoxyhemoglobin and methemoglobin, differing from the mutually close properties of the other derivatives, confirm that the state of the heme group affects the conformation of hemoglobin molecules in solution. These results are in a good agreement with the classification established on the heme iron spin state.


The structure of carbohydrate chains of blood-group substance. Isolation and elucidation of the structure of higher oligosaccharides from blood-group substance H. Twenty individual higher reduced oligosaccharides, having from seven to eleven monosaccharide units, were isolated after sodium borohydride degradation of blood-group substance H from pig stomach linings. Anion-exchange high-pressure liquid chromatography appears to be a very convenient and effective method for this kind of higher oligosaccharide mixtures separation. The oligosaccharide structures were determined by means of periodate oxidation, methylation analysis, partial acid and enzymic hydrolysis. It has been found that all the oligosaccharides investigated can be divided into four series. The oligosaccharides belonging to each series have the common oligosaccharide fragment to which terminal L-fucose and/or N-acetyl-D-glucosamine residues are attached. Comparison of all the oligosaccharide structures, including tri, penta and hexasaccharides described earlier, shows that the lower oligosaccharides represent the structural element of the higher oligosaccharides.


Biosynthesis of thromboxane B2 and 12-L-hydroxy-5,8,10-heptadecatrienoic acid in human platelets. Evidence for a common enzymatic pathway. Human platelet microsomes convert prostaglandin H2 to thromboxane B2 and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (12OH-17:3) in approximately equimolar amounts. The synthesizing activities of both products appear to go in parallel, both activities gradually decline upon storage and are equally destroyed by heat inactivation. Furthermore imidazole, a potent inhibitor of thromboxane synthetase activity, is an equally effective inhibitor of 12OH-17:3 formation in platelets. These results suggest that both thromboxane B2 and 120H-17:3 are derived from a common intermediate. We propose two alternative pathways for the conversion of prostaglandin H2 to thromboxane A2 and 12OH-17:3 in human platelets. The first pathway depicts thromboxane A2 as the common intermediate for the formation of both thromboxane B2 and 12OH-17:3. In the second pathway, prostaglanding H2 is converted to an activated intermediate which is converted to either thromboxane A2 or 12OH-17:3.


Translational regulation of expression of the brome-mosaic-virus RNA genome in vitro. Total brome mosaic virus (BMV) RNA, comprising four mRNA molecules, was translated in the wheat germ system. It was shown that at a low ratio of total BMV RNA to cell-free extract all four BMV genes were expressed. At a high excess of total BMV RNA over the cell-free extract, the only BMV gene translated was the coat protein cistron (RNA 4). The effect was due to diminished initiation of synthesis of non-coat proteins in the presence of a high excess of template over 23 000 X g extract. This leads to exclusion from the translational machinery of all but coat protein genes. The effect is responsible for regulation of expression of BMV genes in vitro and can be of importance for enhancement of coat protein synthesis as expected in the late phase of virus development in vivo.


The effect of fatty acids on the regulation of pyruvate dehydrogenase in perfused rat liver. The effect of fatty acids on the rate of pyruvate decarboxylation was studied in perfused livers from fed rats. The production of 14CO2 from infused [1-14C]pyruvate was employed as a monitor of the flux through the pyruvate dehydrogenase reaction. A correction for other decarboxylation reactions was made using kinetic analyses. Fatty acid (octanoate or oleate) infusion caused a stimulation of pyruvate decarboxylation at pyruvate concentrations in the perfusate below 1 mM (up to 3-fold at 0.05 mM pyruvate) but decreased the rate to one-third of control rates at pyruvate concentrations near 5 mM. These effects were half-maximal at fatty acid concentrations below 0.1 mM. Infusion of 3-hydroxybutyrate also caused a marked stimulation of pyruvate decarboxylation at low pyruvate concentrations. The data suggest that the mechanism by which fatty acids stimulate the flux through the pyruvate dehydrogenase reaction in perfused liver at low (limiting) pyruvate concentrations involves an acceleration of pyruvate transport into the mitochondrial compartment due to an exchange with acetoacetate. Furthermore, it is proposed that a relationship exists between ketogenesis and the regulation of pyruvate oxidation at pyruvate concentrations approximating conditions in vivo.


Incorporation and asymmetric orientation of glycophorin in reconstituted protein-containing vesicles. Glycophorin can be incorporated in lipid vesicles without the use of detergents [MacDonald, R.J. and MacDonald, R.C. (1975) J. Biol. Chem. 250, 9206-9214]. In this paper it has been shown that the protein spans the lipid bilayer in these vesicles. In addition it has been shown that the protein is oriented in an asymmetric way with 75-80% of its sugar residues directed to the outside of the vesicles. Freeze-fracturing electron microscopy suggests that the protein is present in a slightly aggregated form. Sonication of these recombinants leads to the formation of small glycophorin-containing vesicles, in which almost all sugar residues are directed to the outside.


Absence status in the adult. New results including computerized transverse axial tomography. 7 adult cases with petit mal status are described; most of these patients had clinical recurrences of petit mal seizures after time intervals ranging from 15 to 50 years. Electroencephalography (EEG) and computerized transverse axial tomography (CT) findings are described and correlated. All CT studies showed frontal lobe abnormalities. When speaking of absence status in the adult, it is useful to distinguish between such an event within the course of primary generalized epilepsy and its reactivation after a very long seizure-free period at an older age. Such reactivations occur preferentially in women. CT supplies more structural information on the living brain and thus we could identify a dysplastic configuration of the skull and hemispheres in a 28-year-old patient and frontocortical and moderate subcortical lesions in the older age-group. The role of the frontal lobe in releasing spike-and-wave discharges of different degrees of generalization appears to be a new aspect worthy of further investigation.


Smell and taste acuity in epileptic syndromes. Taste and smell acuity were determined in 50 normal subjects and 48 epileptic patients by means of Henkin's method. Smell detection thresholds are greatly reduced in epileptic patients, mainly those suffering from partial seizures with complex symptomatology. Epileptic patients show also a reduced threshold for sweet and bitter taste. Age, sex and antiepileptic drugs do not affect taste and smell acuity. The significance of these findings in the pathogenesis of epileptic seizures is discussed.


Infantile spinal muscular atrophy. Unusual fiber typing and distribution in a muscle biopsy. A right gastrocnemius muscle biopsy of a 13-month-old floppy male infant, which appeared at a more advanced age to suffer from an infantile spinal muscular atrophy, showed unusual histochemical changes: the chequer-board distribution was replaced by three groups of muscle fibers with a same mean narrow diameter of 12.5 micrometer. The smallest groups could easily be recognized as type I and type IIB fibers, while the largest group, involving more than 75% of the whole biopsy, revealed an intermediate hybrid fiber population, which would be classified as type I, if based on their phosphorylase and myofibrillar ATPase activities alone. The pathogenesis of this unusual finding is discussed.


Morel's laminar sclerosis.

Morel's laminar sclerosis. A 49-year-old alcoholic woman was admitted for convulsions. She died after a 4-week clinical course characterized by a persistent coma with diffuse muscular hypertonia. Post-mortem examination of the brain demonstrated a spongy degeneration and gliosis of the cerebral cortex, limited to the 3rd and the 4th layers. No other pathological lesion of the central nervous system could be objectivated. This is the first reported case in which Morel's laminar sclerosis was the only manifestation of 'alcoholic encephalopathy'. Morel's syndrome should be considered as a pathological entity separate from the Marchiafava-Bignami disease.


The sausage-string phenomenon in acutely induced hypertension--arguments against the vasospasm theory in the pathogenesis of acute hypertensive encephalopathy. Pial microcirculation was observed in cats during acutely induced blood pressure increase using the window technique. Measurements of arteriolar diameter changes in situations of preserved and altered cerebrovascular autoregulation were made, when diffuse vasoconstriction and sausage-like dilation, respectively, occurred. Comparison of percentage changes of narrow segments between sausage-like dilated arterioles and diffusely constricted (= autoregulating) vessels gave evidence that a failure of autoregulation in this situation is not associated with vasospasm but with dilation. Individual narrow segments did not constrict more--but on an average even rather less--than diffusely constricted vessels. Evans blue extravasation occurred only with dilation, never with vascular constriction. From these data it is concluded that extravasation due to acute blood pressure increase is not of ischemic nature, but a consequence of high filtration pressure due to arteriolar and venous congestion.


5-Hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid below partial and complete spinal subarachnoid block. Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were investigated by lumbar cerebrospinal fluid (CSF) of 21 patients with partial and total spinal subarachnoid block. HVA levels in CSF below a complete block were significantly lower and 5-HIAA levels were signigicantly higher than controls. Below a partial block, HVA levels were normal; 5-HIAA levels were higher than in patients with complete block. Possible explanations for these findings are discussed.


Effect of cimetidine, histamine H2 receptor antagonist, in the prevention of experimental stress ulcer in the rat. The protective effect of cimetidine on gastric mucosal lesions in the rat was investigated. Through prophylactic administration of 3x 25 7g/kh body weight for 24 just prior to the test period, the incidence rate of lesions, as well as upper gastro-intestinal haemorrhage was highly significantly reduced.


Distribution and metabolism of gastrin. An experimental study of the  fate of 123 I-gastrin in the rat as studied by external detection with a gamma camera. In anesthetized rats, the activity distribution of intravenously administered synthetic human gastrin I, labelled with 123 I, was recorded externally by a gamma camera. In intact rats activity was found to accumulate in the kidneys and later in the stomach. After bilateral nephrectomy, the gastric apperance of activity was delayed. In both cases, the gastric activity is considered to emanate not from intact 123 I-gastrin but from free iodide, split off during gastrin degradation. The renal accumulation of gastrin in intact animals as well as the delayed gastric uptade of iodide in nephrectomized animals support the hypothesis that the kidneys are important organs for gastrin metabolism.


Comparative study of two models for experimental cirrhosis in the dog. Two canine models of cirrhosis induced by administration of dimethyl-nitrosamine (DMNA) alone or in combination with hepatic vein ligation, were studied. The criteria used for development of cirrhosis were not only the appearance of portal hypertension, ascites, biochemical disorders or retention of BSP but also the formation of histological lesions such as sclerotic transformation of the liver lobules together with nodular regeneration. According to these criteria, the experimental protocol consisting in hepatic vein ligation and prolonged administration of DMNA was successful in inducing in animals liver cirrhosis similar to human conditions.


Gastric acid secretion after chronic administration of the anti-secretory agent salbutamol in the dog. Salbutamol is known to be a potent inhibitor of pentagastrin stimulated gastric acid secretion in both man and dog. This study describes the results, in both acute and chronic experiments in the dog, of salbutamol administration on gastric acid output and plasma gastrin concentration in response to a standard food stimulus. In the acute experiments, salbutamol in fusion reduced both gastric acid output and peak plasma gastrin concentration.  In contrast, during chronic oral administration, salbutanmol caused a significant increase in the acid secretory response to the food stimulus; 2 weeks after the drug was stopped acid output has returned to control values. Only small changes in plasma gastrin concentration were found in the chronic study and these changes could not explain the increase in acid output.


Colonic anastomosis healing. The effect of topical povidone-iodine. The effect of povidone-iodine (0.1% available iodine) irrigation on colonic anastomosis healing was investigated in 196 Sprague-Dawley rats. Each end of the divided colon was irrigated with 5 ml of povidone-iodine solution or with an equal volume of normal saline before anastomosis and again after the anastomosis had been completed. Healing was assessed at 2, 4, 6, 8, 10, and 14 days after operation: macroscopically, mechanically, histologically and angiigraphically. Povidone-iodine irrigation did not impair healing in any way.


Urinary lithiasis in children. A review of 155 cases. 155 children presenting with lithiasis have been studied. The study confirms other recent analyses: (1) Urinary lithiasis in the child is far more frequent than was previously thought. It is not always easy to diagnose because of the limited opacity of the calculi. (2) Its secondary nature is shown in 25% of the cases. (3) Its cause is still debated in spite of the evident part played by Proteus infection. (4) The prognosis is generally favourable.


Progestogens in prostatic cancer.

Progestogens in prostatic cancer. A series of 20 patients with a histological diagnosis of prostatic cancer were treated with high doses of MAP (6alpha-methyl-17alpha-hydroxyprogesterone acetate). No response was noted in 9 patients with prostatic cancer in relapse. Objective and/or subjective response was noted in 6 of 11 patients who were untreated at the time of diagnosis.


Operative treatment of vesicoureteric reflux in duplicated ureters. Over a 10-year period 321 children underwent 490 antireflux operations. 21 duplicated vesicoureteric reflux was observed in 18 patients. The follow-up and the comparison with other authors results in 334 patients indicate that the submucosal inlay of the duplicated ureters is a particularly suitable operation. The Politano-Leadbetter and the Lich-Grégoir techniques yield good results.


Transitional cell tumours of the urinary bladder. The histological grade (WHO) and the clinical stage (UICC). Correlation of histological grade (WHO) with clinical stage (UICC) of transitional epithelial tumours of the bladder has been evaluated in 130 patients. A moderate statistically highly significant positive correlation was established (Pearson's r 0.37--0.75 and eta correlation ratio coefficient 0.49--0.81 in various subsets of the material). Transurethral biopsies gave on average 0.53 lower histological grade than open operative biopsies of the same tumours. The data show that the information contained in histological grade and clinical stage is parallel and support the idea that histological diagnosis of transitional cell carcinoma is possible also in the absence of histological evidence of invasion.


Posterior urethral valves in infants--a therapeutic approach. Posterior urethral valves were treated in 9 children by rupture with a Foley catheter. The interest and advantages of this simple method are underlined especially in newborns where the infant resectoscope can be traumatic and difficult to use.


Transurethral bladder neck operation in neurogenic bladder. 86 adults with bladder outlet obstruction and neurogenic bladder underwent bladder neck resection or incision to establish effective vesical emptying or damping of detrusor reflex activity. Follow-up examinations revealed a good effect on flow, reflux and hydronephrosis, infection rate and symptoms such as frequency, dysuria, nocturia and urgency. Since 1974, bladder neck incision is preferred; resection remains for selected cases only.


Pacemaker localization in the renal pelvis of the unicalyceal kidney. In vitro study in the rabbit. To determine the precise localization of the pacemaker in the renal pelvis of the unicalyceal rabbit kidney, the spontaneous activity of muscle strip preparations was investigated in vitro. (1) The highest frequency of spontaneous contractions was found in the most intrarenal part of the renal pelvis. (2) The frequency diminished from the most intrarenal parts to the pyeloureteral junction. (3) No spontaneous activity was observed in ureter preparations; even adrenaline, noradrenaline, acetylcholine and oxytocin did not start any contraction. In the pyeloureteral system the cells with the highest spontaneous frequency will act as a pacemaker. Cells with a less frequent activity can only work as secondary or latent pacemakers.


Ultrastructural changes of the intestinal wall after transileal cutaneous ureterostomy in men. A preliminary study. (With 1 color plate). Pre- and postoperative specimens of ileal loops used in transileal ureteroplasty have been taken and ultrastructural modifications concerning the intestinal mucosa with special attention to the epithelial cells are described. The enterocytes undergo significant modifications because of the operation (i.e. collapse of striated border and entrancement of lysosomal inclusions). Contact with the urine brings about osmotic changes of the intestinal epithelium as well as irritation of the capillar endothelium. But most structural modifications observed histologically or by electron microscopy seem to be reversible. 6 months after the operation the histological structure of the ileum in contact with urine again becomes morphologically normal.


Quantitative element investigations in urine, serum, kidney and muscle tissue of calcium oxalate stone patients. Concentration and excretion in 24-hour urine, as well as serum concentrations of Na, K, Mg, Ca, Cl, P, uric acid and citrate were investigated in 209 calcium oxalate stone patients and 42 stone-free patients. Especially the concentration values of the urine components, except for uric acid and citrate, were found to be significantly lower for calcium oxalate stone patients. 21% of the stone patients showed hypercalciuria; hypercalciuria combined with hyperuricuria was found in only 7.1% of the cases and a solitary hyperuricuria in only 17%. As for kidney cortex, kidney papilla and muscle tissue in 10 calcium oxalate stone patients and 10 stone-free patients, the concentrations of Na, K, Ca, Mg as well as some trace elements were determined quantitatively by means of neutron activation analysis. Statistic analysis yielded a significantly lower sodium content of the kidney cortex within the stone-carrying group. Mean values of the calcium concentration in stone patients were lower for papilla and muscle tissue than in the control group. For magnesium no clear differences were found. The iron content in the papilla and muslce tissue of stone patients was significantly lower.


Percutaneous embolic occlusion of an acquired bleeding intrarenal aneurysm. A diabetic patient presenting with an acquired bleeding aneurysm secondary to a nephrostomy for papillary necrosis was sucessfully treated by super-selective embolic occlusion of the artery supplying the aneurysm.


Spontaneous renal arteriovenous fistula and arterial hypertension--conservative treatment and healing. A case is reported of idiopathic renal arteriovenous fistula in a young adult suffering from arterial hypertension. It was treated by conservative surgery with endo-aneurysmorrhaphy and extrasinusal clamping of the artery supplying the fistula. The post-operative course was uneventful. Arterial pressure returned to normal after 30 months. Diagnosis, therapy and the relationship between hypertension and fistula are discussed.


Destructive sterile vesicoureteral reflux observed over a 12-year period. The evolution over a 12-year follow-up period from only slightly damaged kidneys to end-stage renal disease due to sterile ureteral reflux is reported.


Vulvar fusion-unusual cause of urinary obstruction. A case of urinary obstruction caused by vulvar fusion in an adult is reported. Anterograde micturition-urethrocystography revealed reflux of urine in the vagina and cavum uteri. Treatment consisted of sharp separation of the labia. Ointment dressing was applied to prevent reagglutination. After 1 year the patient has no urological complaints.


Total replacement of the ureter by a segment of the sigmoid colon in the treatment of giant hydronephrosis: calyco-sigmoido-cystostomy. Two cases of giant hydronephrosis of a solitary kidney are reported. In both of them correctly performed pyelo-ureteroplasties had not assured satisfactory emptying of the pyelocalyceal system. Its dilatation and infection had not disappeared. In order to liquidate the nephrostomy, the ureters were replaced by a sigmoidal loop (calyco-sigmoido-cystostomy) with favorable results assessed 24 and 19 months after operation. The use of an isolated sigmoid segment for replacement of the ureter is discussed.


Steady state serum concentrations and renal clearance of digoxin in neonates, infants and children. Steady state serum concentrations of digoxin were determined repeatedly in 34 infants with congenital heart disease. Simultaneous measurements of renal clearances of digoxin, creatinine and urea were obtained in 29 of the subjects. Serum digoxin concentrations were markedly higher in children under the age of 3 months than in those over this age, despite equal weight--adjusted 24 h doses. This finding was explained by a very rapid increase in renal digoxin clearance in the first 3 months--32 +/- 7 ml/min/1.73m2 at 1 week to 65.6 +/- 30 at 3 months. The subsequent increase in digoxin clearance was much slower, e. g. to 87.7 +/- 43 ml/min/1.73m2 at 12 months. Renal clearance of digoxin was equally well correlated with creatinine clearance (r = 0.87) as with urea clearance (r = 0.83), but it exceeded that of creatinine in all age groups. The findings indicate that both glomerular and tubular function is involved in the renal elimination of digoxin in young children, and that development of renal elimination of the drug parallels that of the maturation of renal function in the early months of life. The neonate and infant with congestive heart failure display impaired ability to eliminate digoxin. The impairment lessens rapidly with the development of renal function over the first 3 months of life. Diminished doses of digoxin should be advocated in this age group if therapeutic serum concentrations of the drug are to be maintained and toxicity avoided.


Pharmacokinetics of bendroflumenthiazide in hypertensive patients. After four weeks on placebo treatment, 8 hypertensive patients (WHO stage I) were treated for 2 weeks with bendroflumethiazide (bft) 2.5 mg and KCl 1.5 g daily. Subsequently they received bft 5 mg and KCl 1.5 g daily for a further fortnight. At the end of each period of treatment blood pressure was recorded and blood samples and urine were collected for analysis of bft by GLC. Before taking the daily dose of bft, no trace of the drug was found in plasma. Peak levels of bft were seen after 2.3 h and averaged 23 and 50 ng . ml-1 after 2.5 and 5 mg, respectively. After bft 2.5 mg the plasma level was too low for kinetic analysis. The plasma half-life after 5 mg averaged 4.1 h. The mean apparent volume of distribution was 1.18 1 . kg-1. Non-renal clearance averaged 200 ml . min-1. The renal clearance of bft was significantly lower (p less than 0.05) after 5 mg (48 ml . min-1) than after 2.5 mg bft (93 ml . min-1), although the creatinine clearance remained unchanged. No correlation was found between the plasma level of bft and its effect on blood pressure.


Gastrointestinal absorption of hydrochlorothiazide enhanced by concomitant intake of food. Hydrochlorothiazide (hct) 75 mg was administered orally to eight healthy volunteers without (Study I) or together with a standaridized meal (Study II), and plasma and urine concentrations of hct were analyzed by GLC. The plasma levels of hct were higher initially when the tablets were taken on an empty stomach, but after 5 h they were higher in Study II. There was no difference between the two studies in the area under plasma concentration time curves. The urinary recovery of hct totalled 55.6 +/- 4.9 mg when the drug was given with food and 47.4 +/- 6.0 when it was taken on an empty stomach. The difference is significant (p less than 0.01). As the urinary recovery represents the uptake of hct, it appears that the gastrointestinal absorption of hct is enhanced when the drug is given with food.


Placental transfer of chlorthalidone and its elimination in maternal milk. A gas chromatographic method has been used to determine chlorthalidone in amniotic fluid, maternal and foetal blood at delivery, and in maternal milk and blood three days after delivery, following the administration of chlorthalidone to nine pregnant women suffering from toxaemia of pregnancy. Placental transfer of chlorthalidone and elimination in maternal milk have been shown and the implications of these factors are discussed. An explanation has been proposed for our observations that foetal blood levels of the drug are about 15% of those in maternal blood.


Effect of aminoglycosides on proximal tubular membranes of the human kidney. The effect of the aminoglycosides amikacin, gentamicin, netilmicin sisomicin and tobramycin on the proximal tubule of the human kidney was investigated in 78 healthy subjects. Fifteen adults were each given gentamicin, sisomicin or tobramycin 3 mg/kg bodyweight, 10 subjects received netilmicin 3 mg/kg or amikacin 15 mg/kg additionally seven subjects amikacin 10 mg and six subjects netilmicin 6 mg on three consecutive days. The principal enzyme of the brush border membrane of the proximal tubule, alanine aminopeptidase (AAP), was determined enzymatically and immunologically in 24-hour urines. The effects of the various aminoglycosides on the membranes were different. Less of membrane AAP was greatest after amikacin and was least after tobramycin. There was no difference between gentamicin, netilmicin, and sisomicin, which had an effect intermediate between the other two compounds. The elimination of AAP occurred at intervals which might possibly have been caused by impairment of cell cycles.


The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. I. Lignocaine. The pharmacokinetics and metabolism of lignocaine in premature neonates was studied after subcutaneous administration. The collection of serial urine together with a limited number of blood samples from neonates enabled simultaneous computer fitting of data to a pharmacokinetic model. The disposition kinetics of lignocaine in four neonates were compared with similar data reported for adults. Neonates had prolonged t1/2 (neonate mean: 3.16 h; adult mean: 1.80 h), and an increased total volume of distribution (neonate mean: 2.75 l/kg; adult mean: 1.11 l/kg) compared with adults. Total plasma clearance (Cltp) normalised on body weight showed no significant difference between neonates (mean: 0.610 l/h/kg) and adults (mean: 0.550 l/h/kg). The urinary excretion of lignocaine and several of its metabolites was studied in 8 neonates and 11 adults. Neonates were shown to excrete much more unchanged lignocaine (mean: 19.67%) compared with adults (mean: 4.27%) and the proportion of the dose excreted as 4-hydroxyxylidine is considerably reduced in neonates (neonate mean: 8.89%; adult mean: 63.78%). The use of the two pharmacokinetic parameters, t1/2 and Cltp, as indices of drug elimination ability are discussed.


Studies on the pharmacokinetics and pharmacodynamics of atenolol in man. The non-stimulant cardioselective beta adrenocepter antagonist atenolol has been studied in volunteers in order to define its pharmacokinetic characteristics. Atenolol (100 and 200 mg orally) is rapidly absorbed, reductions in heart rate and systolic pressure being observed in 30 min. The effect persists for up to 8 h. Over 85% of an intravenous dose is excreted in urine within 24 h but only 50% of an oral dose. The bioavailability of approximately 50% is due to reduced absorption. Peak blood levels are observed at 2-4 h and the half life of atenolol given orally is 5-6 h. Atenolol reduces the cardiac response to standing and head-up tilt. It does not reduce circulating levels of renin but slightly impairs the renin response to tilt. Atenolol both orally and intravenously reduces supine diastolic pressure about four hours after administration, the effect persisting for up to 24 h.


Effect of adrenergic beta receptor blockade on ethanol elimination and on ethanol-induced changes in carbohydrate and lipid metabolism in man. The effect of adrenergic beta receptor blockade on the elimination rate of ethanol was studied in seven healthy young men. The studies were performed before and after 14 days of propranolol 240 mg/day: the ethanol was given per-orally--0.8 mg/kg b.w. The blood concentration of ethanol, glucose, lactate and glycerol, and the plasma concentration of free fatty acids and triglycerides were followed in samples from the superior vena cava taken every 20 min for four hours. The splanchnic hepatic blood flow was estimated with a single i.v. injection of indocyanine green. The absorption rate, absorption fraction and elimination rate of ethanol were not changed by propranolol. The splanchnic hepatic blood flow was significantly reduced (mean 19 per cent) during beta receptor blockade. The ethanol-induced change in the concentration of glucose, lactate and free fatty acids was affected by propranolol, the time-concentration curves for glucose and lactate being significantly elevated and that for free fatty acids being significantly reduced. The time-concentration curves for glycerol and triglycerides did not differ in the two studies.


Pharmacokinetics and side-effects of clonidine. A single oral dose of clonidine 300 microgram was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17 +/- 0.12 ng/ml at about 2 h: the absorption half-life was 0.6 +/- 0.2 h. Elimination followed first order kinetics with a half-life of 7.7 +/- 2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p less than 0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 microgram t.i.d.) for one week a steady state serum level of 0.30-0.35 ng/ml was achieved. One 75 microgram tablet of clonidine raised the serum level to about 0.69 +/- 0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5 +/- 1.5 h. The urinary excretion of unchanged clonidine was found to be about one third of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.


Correlations between the genetic control of natural and oxazolone-induced antibody production. Nonimmune sera of inbred and H-2 congenic mouse strains contain natural antibodies of the IgM type reacting with 4-(ethoxymethylene)-2-phenyloxazolin-5-one (oxazolone). The genetic regulation of the level of natural and induced antibodies to oxazolone was compared. High natural antibody-producing ability was inherited recessively, while high oxazolone-induced IgM antibody formation was dominant in F1 animals. Studies on nude mice demonstrated that T cells do not affect the natural antibody level, but were required for induced antibody production. Breeding studies and linkage analysis revealed multigenic control and a significant role of allotype-linked genes in both cases. Furthermore, the influence of H-2 linked genes on induced primary IgM antibody production was demonstrated.


Eosinophil-dependent cytotoxicity in rat schistosomiasis. Involvement of IgG2a antibody and role of mast cells. Using Schistoma mansoni schistosomula collected in vitro and sensitized with 42-day-infected rat serum, normal rat peritoneal cells enriched in eosinophils were proven to subsequently adhere to and kill the schistosomula within 24 to 48 h. The cell-dependent, heat-stable antibody in infected rat serum reached a peak between 30 and 42 days after infection. Inhibition experiments with aggregated immunoglobulins indicated the role of IgG2a antibody in the adherence of eosinophils to sensitized schistosomula. The immune absorption technique showed that IgG2a antibody was involved in the mechanism of cytotoxicity of effector to target cells, whereas the role of IgE antibody could be excluded. Ultrastructural studies revealed the constant presence of eosinophils and mast cells in contact with schistosomula. The use of purified cell populations showed that the cytotoxic effect of the original cell population was significantly decreased after depletion of mast cells and partially restored after addition of mast cells. These observations, together with those concerning the role of IgE immune complexes in macrophage cytotoxicity, suggest the possible participation of anaphylactic antibodies in immunity to schistosomes in the rat.


Localization of antigenic activity and immunogenic capacity in different conformational domains of procollagen peptide. The antibody response to the amino-terminal CNBr peptide of sheep procollagen which consists of a globular and a collagenous segment, was studied in inbred strains of mice. The determinants reacting with antibody could be localized in the globular domain and were lost by reduction of disulfide bridges. The ability to induce an antibody response required the collagen-like sequences and was independent of the triple-helical conformation of this segment. The data were interpreted as indicating a different conformation dependence of hapten and carrier determinants.


Peturbation of lymphocyte response to concanavalin A by exogenous cholesterol and lecithin. Incubation of lymphocytes with lecithin liposomes enriched with cholesterol, elevated the cholesterol level of the cells relative to phospholipids. Treatment of lymphocytes with pure lecithin liposomes resulted in the converse effect. Both these treatments resulted in suppression of the induction phase of the response to concanavalin A and were practically reversible. It is suggested that these changes induce modulations of the fluidity of the lymphocyte membrane which may also take place in vivo by serum lipoproteins. Based on this study, the possible effects of lipids on lymphocyte activation are discussed.


A new technique for selective cannulation of the sino-atrial node artery. The electrical activity of the sino-atrial node was studied after the selective cannulation of its artery in the intact open-chest dog. After tetrodotoxin infusion and despite cardiac arrest, a slow rhythmic activity was recorded from the sinus epicardial electrode.


Blockade of neuronal tryptamine receptors by metoclopramide. Metoclopramide (0.13, 0.51, 2.0 and 8.1 X 10(-6) M) caused parallel, rightward, shifts in the dose response curves to 5-HT on the isolated rabbit heart. A significant straight line relationship was found between log (5-HT dr--1) and log [metoclopramide] (molar) with a slope of 1.08 +/- 0.13 and giving a pA2 value of 7.20. Metoclopramide did not significantly alter responses to noradrenaline and was 575 times less effective as an inhibitor of DMPP than of 5-HT. The results indicate that metoclopramide is a potent, surmountable and selective antagonist of tryptamine receptors on rabbit cardiac sympathetic nerves.


Analgesia by enkephalins injected into the nucleus reticularis gigantocellularis of rat medulla oblongata. Methionine-enkephalin (0.2--20 microgram/rat) and leucine-enkephalin (1--20 microgram/rat) produced a dose-related and naloxone-antagonizable analgesia in the tail-pinch test, when microinjected into the nucleus reticularis gigantocellularis (NRGC) and nucleus reticularis paragigantocellularis (NRPG) of the medulla oblongata of the rat. The median analgesic doses were 1.4 and 4.8 microgram/rat for methionine- leucine-enkephalin, respectively. The possibility that the endogenous enkephalins play a part as pain control substances or modulators in the NRGC and NRPG was discussed.


Comparative pharmacology of the optical isomers of ketamine in mice. Relative pharmacological potencies of the optical isomers of ketamine have been estimated in ICR mice. The (+)-isomer was 3X more potent than (-)-ketamine as an analgesic using the phenylquinone writhing test, only 1.5X more potent in terms of hypnotic activity and 1.8X more potent in causing locomotor stimulation. At equianalgesic doses (+)-ketamine caused less stimulation of locomotor activity than the (-)-isomer. These potency differences did not appear to be due to differences in biodisposition although stereoselective metabolism was demonstrated in vivo. Analgesia induced by ketamine was reversed by 10 mg/kg of naloxone.


Dual mechanism of the stimulant action of N,N-dimethyl-5-hydroxy-tryptamine (bufotenine) on cardiac sympathetic nerves. The indirect sympathomimetic effects of N,N-dimethyl-5-hydroxytryptamine (bufotenine) have been analysed on the rabbit heart perfused in vitro by the Langendorff technique. Comparisons have been made with the effects of 5-hydroxytryptamine (5-HT), which activates tryptamine receptors, and dimethylphenylpiperazinium (DMPP), which stimulates nicotine receptors. Bufotenine, 5-HT and DMPP stimulated the rate and force of cardiac contraction but whereas all were powerful stimulants of cardiac rate, bufotenine and DMPP were much stronger stimulants of atrial and particularly ventricular tension than 5-HT. Responses to 5-HT were markedly reduced by perfusion of hearts with an excess of 5-HT, and those to DMPP, during perfusion with hexamethonium. A combination of 5-HT with hexamethonium was necessary to abolish the effects of bufotenine. The data suggest a dual mechanism of stimulant action of bufotenine on the cardiac sympathetic nerves of the rabbit heart involving activation of receptors sensitive to 5-HT and nicotine receptors.


Lack of effect of fever on antipyrine oxidation in the rat. The pharmacokinetics of 14C-antipyrine were studied in rats with fever induced by intracerebroventricular injections of prostaglandin E1. The rats were used as their own controls with at least 5 days between the control and the fever period. The effect of temperature on rates of antipyrine metabolism (oxidation followed by conjugation) and paracetamol metabolism (conjugation) was also tested in suspensions of isolated liver cells. Fever increased the biological half-life of antipyrine to 147% of control values (P less than 0.01) and the apparent volume of distribution to 113% of control values (P less than 0.05). In individual rats the increase in biological half-life was most counterbalanced by the increase in apparent volume of distribution, resulting in non-significant changes in the metabolic clearance of the drug. The half-life of antipyrine elimination in suspensions of isolated liver cells was not changed by increasing the temperature from 29 to 39 degrees C. The half-life of paracetamol elimination in suspensions of isolated liver cells decreased, however, when the temperature was increased from 29 to 39 degrees C. The results suggest that antipyrine oxidation was not influenced by temperature changes in the range of moderate fever and that temperature changes affected different types of metabolic reactions differently.


Pharmacological and biochemical properties of isomeric yohimbine alkaloids. The stereochemical and pharmacological properties of yohimbine and some of its isomers are briefly reviewed. Several pharmacological and physical properties of a selection of the isomers have been determined with a view to elucidating which might be important in the elaboration of the known behavioral effects produced by them. Activity is not dependent upon lipid solubility or on the ease of access to the central nervous system. The isomers are weak inhibitors of rat-brain acetylcholinesterase and weak antagonists at muscarinic cholinergic receptors. In the rat brain in vitro they do not possess significant monoamine oxidase-inhibiting properties nor do they inhibit the uptake of serotonin. They are relatively potent antagonists of 5HT on the rat isolated fundus preparation and their potency in this preparation may be related to their ability to produce behavioral and cardiovascular effects in man and dogs.


Effects of an aminosteroid, ORG 6001, on various membrane phenomena of non-myelinated nerve fibres of the rat. The aminosteroid ORG 6001 (3 alpha-amino-5 alpha-androstan-2 beta-ol-17-one hydrochloride) was shown to be a compound with a rather strong local anaesthetic action. Compound action potentials evoked in non-myelinated nerve fibres of the desheathed rat vagus with the single sucrose gap method showed, in presence of this drug, a decrease in amplitude and increase in conduction time comparable with the effect of lidocaine. Since the total membrane resistance represented by the amplitude of the electrotonic potential was not affected by ORG 6001, it is likely that ORG 6001 reduces the transient increase in sodium conductance during the action potential, a mechanism also postulated for lidocaine. This is confirmed by the decrease of the post-tetanic hyperpolarization in the presence of both ORG 6001 and lidocaine. Since neither sodium pump activity nor the Na/K coupling ratio was affected by ORG 6001, the increase of the potassium-activated response was explained by an increased sodium permeability during rest. The local anaesthetic action of these drugs was even seen with a concentration (20--40 micron) sufficient to produce antiarrhythmic effects in vivo in man if the nerve was stimulated frequently (1--4 c.p.s.).


Inhibition by d,l-methadone of RNA and protein synthesis in neonatal mice: antagonism by naloxone or naltrexone. Neonatal mice were injected once daily with d,l-methadone in a dosage of 2 mg/kg. The remaining half of the litter was injected with saline. After one week the incorporation of labeled uridine and labeled leucine was significantly (P less than 0.05) reduced in skeletal muscle. Longer treatment with methadone impaired RNA and protein synthesis in liver, heart, skeletal muscle and brain. The percentage reduction RNA was log-dose related. When methadone was discontinued for 1 week following 4 weeks of treatment, incorporation of precursors into RNA and protein was found to be normal. A specific opioid effect is suggested by the finding that naltrexone or in part, naloxone, given concomitantly with with the methadone prevents development of the biochemical lesion.


Genetical differences in sensitivity to tremorine and oxotremorine in mice. Male mice from 14 strains were injected i.p. with tremorine (3.0 mg/kg) or oxotremorine (0.15 or 0.1 mg/kg). Large inter-strain differences in the degree and duration of the subsequent hypothermia were noted. 2 strains, BALB/c and Simpson, were particularly sensitive to the hypothermic effect of oxotremorine. The offspring from a cross between BALB/c and Simpson were less sensitive than the parental strains, suggesting genetic complementation. A set of 7 recombinant inbred (RI) lines derived from strains C57BL and BALB/c were tested with oxotremorine. 5 RI lines resembled strain C57BL in their response and 2 RI lines resembled strain BALB/c. It was concluded that strains C57BL and BALB/c differ at a gene which has a major effect on the response to oxotremorine.


Direct evidence for ATP release from non-adrenergic, non-cholinergic ("purinergic") nerves in the guinea-pig taenia coli and bladder. Demonstration of release of ATP from smooth muscle preparations during stimulation of purinergic nerves is complicated by the difficulty in showing whether it comes from nerve or muscle. ATP released during relaxation of the guinea-pig taenia coli and contraction of bladder strips in response to purinergic nerve stimulation was measured in the superfusate using the luciferin-luciferase ATP assay method. The amount of ATP increased 2-6 fold during isometric responses to purinergic nerve stimulation. This release was blocked by tetrodotoxin but not by adrenergic nerve destruction with 6-hydroxydopamine. No significant release of ATP was detected during comparable responses elicited by direct muscle stimulation. These results provide further support for the purinergic nerve hypothesis.


Pharmacologic characterization of isolated canine bronchial smooth muscle. The response of isolated canine bronchial smooth muscle to several agonists was investigated. Carbachol, serotonin, histamine and acetylcholine, in that order of potency, elicited a concentration-related contraction of bronchial smooth muscle. The maximal contractions produced by histamine and serotonin were somewhat less than those obtained with carbachol. Prostaglandin F2alpha and bradykinin failed to cause contraction. Bronchial smooth muscle strips in which a tone was induced with submaximal concentrations of carbachol underwent a concentration-related relaxation when exposed to prostaglandin E2,(+/-)-isoprenaline and (--)-norepinephrine, in that order of potency. Bradykinin, in three of four experiments, failed to relax the tissue.


Effects of baclofen and gamma-hydroxybutyrate on rat striatal and mesolimbic 5-HT metabolism. The effects of D, L-baclofen and gamma-hydroxybutyric acid (GHBA) on endogenous 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the rat striatum and the mesolimbic area were investigated and compared with their effects on dopamine (DA) concentrations in the same regions. Both baclofen (5-50 mg/kg i.p.) and GHBA (300--1500 mg/kg i.p.) led to dose-dependent increases in the striatal levels of 5-HT and 5-HIAA by up to 200%. Maximal effects of both drugs occurred about 3 h after treatment. Normalization was reached 6 h after GHBA and 16 h after baclofen. The effect of GHBA in the mesolimbic area was qualitatively similar to, but weaker than, its effect in the striatum. Baclofen had little or no effect in the mesolimbic area, the cortex or the brain stem. The two drugs affected striatal 5-HT and DA metabolism similarly. Their effects on the latter are thought to be due to cessation of impulse flow. The effects on striatal 5-HT may be related to more complex phenomena.


Drug-cue conditioning to external stimulus conditions. Rats were trained to discriminate 0.04 mg/kg fentanyl from saline in a 2-lever procedure, and to discriminate 10 mg/kg pentobarbital from saline in a maze procedure. Stimulus generalization experiments in rats trained in this double discrimination indicate that the internal cues produced by these training drugs can be conditioned to the external stimulus conditions associated with the different discrimination procedures.


Excitation of autonomic nerves by 4-aminopyridine in the isolated, blood-perfused sino-atrial node preparation of the dog. 4-Aminopyridine injected into the sinus node artery produced a long-lasting decrease in sinus rate preceded by a transient increase. With a large dose, a long-lasting increase in sinus rate was superimposed on the long-lasting decrease phase. The long-lasting decrease and increase in sinus rate were abolished by 1-hyoscyamine and propranolol respectively, and both were reduced by tetrodotoxin. These results can be interpreted as being due to excitation of autonomic nerves by 4-aminopyridine.


The myorelaxant effect of theophylline on smooth muscle cells of the afferent arterioles and glomerular tuft. Theophylline, infused i.v. into rats increased the diameter of the glomerular afferent arterioles by 35.78%; when added to a suspension of isolated glomeruli, it increased the diameter of the capillary tuft within the glomerulus by 25-30%. These variations in diameter can be explained by the myorelaxant effect of theophylline on the smooth contractile fibers present in the arteriolar cells and in certain glomerular cells, such as the mesangial cells. These observations explain, in part, the marked changes in glomerular hemodynamics caused by the injection of theophylline.


Vascular and myocardial effects of mecinarone. The effects of mecinarone on the contractions induced by noradrenaline, potassium and calcium were studied with the isolated aorta and central artery of the rabbit ear. In our experimental conditions mecinarone was found to act as a competitive antagonist of calcium. It preferentially inhibited the noradrenaline-evoked contraction induced in the rabbit ear artery and had a smaller effect on the extracellular calcium-induced contraction of depolarized arterial smooth muscle. In the isolated guinea pig heart, mecinarone produced a reversible decrease in the rate of rise of the ascendant phase of the action potential without significantly changing the resting potential. In hearts inactivated by depolarisation, mecinarone inhibited the contractions restored by isoproterenol without suppressing the calcium action potential. These results suggest that the mode of action of mecinarone is different from that of verapamil or nifedipine but is comparable to that of chlorpromazine, although mecinarone has no sedative effect.