Prediction of the effect of corticosteroid on idiopathic nephrotic syndrome based on a discriminant function.

For the purpose of discriminating between cases of nephrotic syndrome with and without corticosteroid effect, a linear discriminant function was applied in attempt to predict the effect of corticosteroid by the use of a computer. The parameters used were 15-min values of the PSP test, urinary protein, serum cholesterol, renal biospy findings, the number of red cells in the urinary sediment and immunoglobulin clearance ratio. The rate of correct prediction using the function with immunoglobulin clearance ratio was 87.0 %.


Cytochemical studies of acute tubular necrosis caused by simultaneous administration of dextran and kanamycin.

The increased nephrotoxicity of simultaneously administered kanamycin and low molecular weight dextran was studied in rats. The simultaneous administration of the two drugs showed an increase of nephrotoxicity, and caused pronounced vacuolation of the cytoplasm in the proximal tubular cells. The vacuoles were confirmed to be phagolysosomes by electron microscopic, histochemical and cell fractionation methods. The cell fractionation technique indicated that these phagolysosomes contained both kanamycin and dextran. The alteration of membrane was observed in the phagolysosomes, and these lysosomes of damaged renal tissue seemed to be more fragile than normal. The possible role played by lysosomes in the pathogenesis of acute tubular necrosis was discussed.


An approach to the diagnosis of overwhelming metabolic disease in early infancy.

Heritable metabolic disease is a significant cause of overwhelming illness in the very young infant. It appears that most patients with well recognized disorders are not being diagnosed, and it is our conviction that there are new, as yet unidentified, inborn errors of metabolism in this population of patients. We have attempted to develop a systematic approach to the seriously ill newborn as a candidate for an early diagnosis of metabolic disease. There are some clinical clues that suggest the presence of disordered metabolism. The laboratory can be useful in confirming initial clinical suspicions and in screening for the presence of abnormality. The complexity of laboratory evaluation increases as one proceeds to definitive diagnosis and modern organic analysis.


Contact urticaria due to polyethylene glycol.

Contact dermatitis developed in a patient from the use of Tinactin and Lotrimin solutions. Initially, the usual 'delayed' type of allergic contact dermatitis was suspected. However, covered patch tests gave negative results after forty-eight hours. 'Open' testing revealed an 'immediate' urticarial reaction to polyethylene glycol, which is used as a solvent in both antifungal agents. It should be emphasized that after a patient scratches or irritates an urticarial contact dermatitis, the resulting eruption closely resembles contact dermatitis of the usual delayed variety. Apparently, this is the first written report of such an 'immediate' reaction to polyethylene glycol. Although the modern, elegant antifungal agents with their complex vehicles are quite effective, one sometimes becomes nostalgic for the old-fashioned, inelegant but effective Whitfield's ointment (salicylic acid and benzoic acid) with its simple, nonsensitizing petrolatum base.


F-bodies as Y chromosome markers in mature human sperm heads: a quantitative approach.

It is generally accepted that at least some Y chromosomes in human mature sperm heads are represented in preparations by fluorescent F-bodies. From data consisting solely of F-body scorings and the visually estimated size of sperm heads from normal donors, a quantitative model is developed which permits simultaneous estimation of six parameters representing biological factors (the proportions of ploidy classes and of their sex-chromosome complements) and biassing factors (not all Y chromosomes represented by F-bodies, not all F-bodies representing Y chromosomes, and error in scoring ploidy from visual size). The analysis is statistically adequate and succeeds in predicting a variety of independently validated phenomena. The work may be regarded as a contribution to the integration of qualitative and quantitative evidence in the study of F-bodies. In all, 21,700 one-headed spermatozoa from 12 donors were scored. A mean of 54% spermatozoa lacking F-bodies was subject to a standard deviation between donors of 4.8, over and above binomial error. Analysis yielded the following estimates: 83.3% of diploid spermatozoa are XY, the remainder XX and YY in assumed equal number (this information assists analysis of the origin of embryonic triploidy); 2.4% of spermatozoa are diploid (this estimate does not compete in accuracy with direct estimates from DNA absorbance); only 83% of Y chromosomes are represented by F-bodies; 7% of haploid heads and 14% of diploids contain one or more "adventitious bodies" indistinguishable from true F-bodies. The visually scored head sizes "Small" and "Medium" correspond approximately with haploidy and diploidy; nearly all haploids are scored as Small, and 72% of the Medium are diploid. F-bodies are not thought at present to give a useful basis for estimating the presumably low incidence of sex-chromosome aneuploidy and nondisjunction. No such estimate has been attempted. The problem is overshadowed by not fully understood complicating factors of greater magnitude, which now appear to be a major subject of enquiry. Some implications and possible future developments are discussed.


Transient hypoxemia in firemen following inhalation of smoke.

Mild to moderately severe hypoxemia was documented in 19 of 21 mostly asymptomatic firemen who were exposed to dense smoke containing polyvinylchloride and other pulmonary irritants. The hypoxemia was transient, with nearly complete reversibility within 24 hours. Subsequent tests for pulmonary function one month later demonstrated that this transient hypoxemia was not related to previous underlying pulmonary disease. The potential for serious complications of inhalation of smoke, particularly smoke from burning plastics, is heightened by the frequent lack of symptoms associated with the type of exposure, despite the development of hemoglobinemia. Precautionary measures should include uninterrupted use of an effective breathing apparatus by firemen exposed to smoke and to noxious fumes and temporary oxygen supplementation, even in asymptomatic firemen, following exposure to dense smoke.


Prospective study of controlled oxygen therapy. Poor prognosis of patients with asynchronous breathing.

Thirty-two patients were evaluated within 24 hours of admission for 36 episodes of acute respiratory failure (arterial oxygen pressure less than or equal to 50 mm Hg). Clinical data, spirometric determinations, blood gas analysis, and synchronization of chest (rib cage) and abdominal (diaphragmatic) breathing movements were studied. All patients were initially treated with controlled oxygen therapy. In 25 episodes the patients recovered without intubation (successes). In nine episodes the patients required intubation and assisted ventilation; two of these patients died. Two patients died without intubation. The 25 successful episodes were compared with the 11 requiring intubation or associated with death (failures). The breathing pattern proved to be the best single factor for predicting success or failure (77 percent correct prediction). The breathing pattern plus the arterial carbon dioxide tension on admission was the best two-factor guide (86 percent correct prediction). Patients with asynchronous breathing  and severe hypercapnia are so unlikely to do well with a program of controlled oxygen therapy that preparations for intubation and assisted ventilation should be made on admission and such measures should be instituted at the first sign of deterioration.


Reversibility of small airway obstruction after therapy with salbutamol. Studies in asymptomatic asthmatic patients after inhalation of pressurized aerosol.

A group of 18 asymptomatic asthmatic patients and a control group of five healthy individuals were examined in order to evaluate the effect of inhalation of 400 microng of salbutamol on the small airways. All patients were free of symptoms for at least three days before the investigation. On the day of investigation, total lung resistance, static lung compliance, and dynamic compliance at a respiratory frequency of 60 breaths per minute (Cdyn60) were measured. While no change in Cdyn60 occurred in the control group, a statistically significant decrease in Cdyn60 was found before inhalation of salbutamol in all 18 asthmatic patients  (P less than 0.005), indicating obstruction of small airways. After inhalation of 400microng of salbutamol, a significant increase in Cdyn60 occurred (P less than 0.005), starting five minutes after inhalation and lasting over one hour, indicating an almost complete abolishment of the frequency dependence of lung compliance in these patients. The present findings indicate that sulbutamol aerosol has a potent bronchodilator effect on the large, as well as the small, airways in the early stage of recovery following an acute asthmatic attack.


Systolic time intervals before and after maximal exercise treadmill testing for evaluation of chest pain.

The change in systolic time intervals from before exercise to three to four minutes following a maximal-exercise treadmill test was measured to eveluate chest pain in 110 fasting supine subjects. Forty-six (85 percent) of 54 patients with chest pain and with abnormal findings on coronary arteriograms were found to have at least a 10-msec prolongation in the left ventricular ejection time index (LVETI), whereas only two (8 percent) of 25 subjects without heart disease and 5 (16 percent) of 31 subjects with chest pain but with normal findings on coronary arteriograms had 10 msec or more of prolongation of the LVETI after exercise. The change in the other systolic time intervals (total electromechanical systole, preejection phase [PEP], and PEP/LVET) were less reliable in detecting the presence or absence of coronary disease. We conclude that determination of LVETI before and after maximal-exercise treadmill testing is a clinically useful noninvasive disgnostic test for obstructive coronary disease in patients with chest pain.


Evaluation of electrocardiogram in emergency room as a decision-making tool.

The contribution of the electrocardiogram to the clinical judgment used by the physician in the emergency room to determine the necessity for hospitalizing patients was evaluated. Thirty-five percent of all 1,578 patients with presumed myocardial infarction referred to the Chaim Sheba Medical Center, Tel Hashomer, Israel, for a one-year period had subsequently diagnosed myocardial infarctions. The ECG in the emergency room detected only 65 percent of these. The physician's clinical judgment was impressive in his decision to admit to the hospital almost all of the remaining 35 percent, while not admitting very many of the patients who did not have subsequently diagnosed myocardial infarctions. When the myocardial infarction was not evident on the ECG and the abnormalities on the tracings were identical for patients with subsequent myocardial infarctions and those without, again the physician made the right choice more often than the wrong. The follow-up ECG also attested to the good judgment of the physician in the emergency room. Of the emergency room ECGs of patients without subsequent myocardial infarctions who were admitted to the hospital, 17 percent showed myocardial infarction by follow-up, while this happened to only 2 percent of those denied admission.


Squamous cell carcinoma of the lung. Clinicopathologic study.

This study was undertaken to investigate the diagnostic, therapeutic, and prognostic features of squamous cell carcinoma of the lung. The overall five-year survival rate for 734 patients was 5 percent, with a median survival of 5.9 months. Surgical excision for early-stage disease was particularly effective therapy. In 151 of 201 patients having surgical excision, the resections were deemed curative. Other modes of therapy proved ineffective, although a combination of radiation and chemotherapy provided cure in one of 39 patients; that patient is alive today after 11 years and three months.


Better visualization of the asymmetric lesion in coronary arteriography utilizing cranial and caudal angulated projections.

For optimum accuracy, coronary arterial lesions should be visualized as perpendicularly and circumferentially as possible to the course of the affected segments. In the presence of left ventricular enlargement or a heart lying transversely within the chest, the proximal left coronary artery and its two major branches, as well as the distal right coronary artery, show foreshortening or overlap in the standard transverse oblique projections, leading to serious underestimation of the degree of disease present. If the lesions are also asymmetric, then the underestimation will be further enhanced unless the vessel is viewed with added transverse axial projections obtained when an image-intensifier system mounted with a C-arm or U-arm is used.


Disseminated coccidioidomycosis with pericarditis. Successful treatment with amphotericin B.

Pericarditis with effusion can occur as a complication of disseminated coccidioidomycosis. Information on management of this condition is very scanty in the medical literature. One case is described in detail. Early diagnosis and appropriate therapy with amphotericin B have been emphasized as keys to success in treating this condition.


Tricuspid atresia. A review of 68 cases.

Sixty-eight patients with tricuspid atresia were seen at Indiana University during the past 30 years. Long term survivors treated without operation emerged from our review. In these, there was a combination of tricuspid atresia and transposition of the great vessels.


Coincidence of sarcoidosis and amyloidosis.

Amyloidosis was diagnosed in a patient with sarcoidosis. There was no evidence of any other disease known to be associated with amyloidosis. The joint occurrence of amyloidosis and sarcoidosis appears to be extremely rare, and to our knowledge, this is the second such patient to be reported. Whether the association of the two diseases in this patient represents a causal relationship remains an open question.


Massive hemopericardium in a patient with postmyocardial infarction syndrome.

A 44-year-old man sustained a transmural inferolateral myocardial infarction and began to show signs of postmyocardial infarction syndrome (Dressler's syndrome) one week after infarction. Anticoagulant therapy had been initiated for suspected pulmonary thromboembolism. Administration of steroids did not improve the patient's clinical condition or the results of laboratory investigations. A massive pericardial effusion was diagnosed clinically, and this diagnosis was confirmed by a pericardial scan using 99m technetium. Subsequently, 1,800 ml of bloody fluid was removed from the pericardial cavity, and following the pericardiocentesis, the patient became asymptomtic. This case reemphasizes the hazards of anticoagulant therapy in patients with the postmyocardial infarction syndrome.


Exit block of artificial pacemaker induced by carotid sinus massage.

Failure of the pacemaker is a common complication of pacemaker therapy. Identification of the disorder responsible for the failure to pace is often difficult. An increase in myocardial threshold can result in nonconduction of the artificial impulse, particularly near the end of the life of the battery, when the output of current has started to decline. This report demonstrates such an increase in myocardial resistance which was apparent only upon massage of the carotid sinus.


Early detection of chronic obstructive pulmonary disease using radionuclide lung-imaging procedures.

One hundred subjects answered a respiratory questionnaire and underwent a physical examination, tests of pulmonary function, and three radionuclide lung-imaging procedures. The results of the radionuclide procedures were compared with each other and with pulmonary function tests and other diagnostic findings to determine their relative sensitivity for detecting evidence of early obstructive airway disease. Perfusion lung imaging was less sensitive than most of the other diagnostic tests evaluated. The aerosol and xenon lung-imaging procedures revealed abnormalities with approximately the same frequency as each other, but more often than any one group of pulmonary function tests, including spirometric data, maximal expiratory flow-volume curves, alveolararterial oxygen gradient, or indices derived from single-breath nitrogen washout. We concluded that xenon and aerosol lung-imaging studies are sensitive and useful screening procedures for detecting evidence of early localized obstructive airway disease and for locating regional abnormalities in the airways of patients with respiratory disease.


High reversion of atrial flutter to sinus rhythm after atrial pacing in patients with pulmonary disease.

The effect of atrial pacing on atrial flutter was evaluated in 36 consecutive episodes in 33 patients. Seventeen episodes occurred in a pulmonary setting, 14 of these in patients with chronic pulmonary disease. Twenty-four (67 percent) of the 36 episodes converted to sinus rhythm within one minute after atrial pacing. In nine (25 percent) of the 36 episodes, atrial fibrillation developed after atrial pacing. Atrial flutter was not affected by atrial pacing in three (8 percent) of the 36 episodes.n 12 (86 percent) of the 14 patients with chronic pulmonary disease and in 14 (82 percent) of the 17 patients in whom a pulmonary setting was responsible for atrial flutter, atrial pacing caused conversion to sinus rhythm. Atrial pacing may be the treatment of choice for atrial flutter in patients with pulmonary disease because of its excellent rate of success in this subgroup whose risk of cardioversion is increased by poor anesthetic tolerance and hypoxia.


Methemoglobinemia induced by a topical anesthetic spray (cetacaine).

In two seriously ill patients, cyanosis developed shortly after a topical anesthetic spray (Cetacaine) was used. In both cases the presence of methemoglobinemia was suggested by a discrepancy between the arterial oxygen tension and the oxygen saturation of hemoglobin, as measured spectrophotometrically. The characteristic responses of the spectrophotometric oximeter to blood containing different concentrations of methemoglobin are described. Physicians administering this topical anesthetic spray (Cetacaine) should be aware of the possible development of methemoglobinemia.


Beta-adrenergic blockade as adjunctive oral therapy in patients with chronic atrial fibrillation.

In many patients with chronic atrial fibrillation, it is difficult to prevent an excessive ventricular rate under stress, even with high levels of digoxin in the blood. The effect of adding beta-adrenergic blockade with practolol to digoxin on the heart rate at rest and during low-grade controlled exercise was investigated in 28 patients with chronic atrial fibrillation and in ten normal control subjects who were receiving maintenance dosages (0.25 to 0.75 mg) of digoxin. In atrial fibrillation, therapy with practolol decreased the mean heart rate at rest from 99.8 beats per minute to 77.5 beats per minute (23 percent reduction; P less than 0.01) and during mild exercise from 148.9 beats per minute to 105.4 beats per minute (29 percent) reduction (P less than 0.001). Fifteen patients had clinically significant heart failure; therapy with practolol did not worsen it. Reversible side effects were detected in two patients. When therapy with digoxin is not sufficient to control atrial fibrillation, the addition of a beta-adrenergic blocking agent is recommended as adjunctive treatment in selected patients.


The antiarrhythmic efficacy of intravenous therapy with disopyramide phosphate.

Disopyramide phosphate was administered intravenously to 57 patients with 60 episodes of arrhythmia (21 supraventricular and 39 ventricular) as a 2 mg/kg bolus. Conversion to sinus rhythm was achieved in three (38 percent) of eight patients with atrial flutter, two (20 percent) of ten patients with atrial fibrillation, one (33 percent) of three patients with paroxysmal atrial tachycardia, and two (50 percent) of four patients with sustained ventricular tachycardia. In nine (75 percent) of 12 patients with nonsustained ventricular tachycardia, suppression of the arrhythmia was accomplished following the intravenous bolus of disopyramide. In 18 (78 percent) of 23 patients with frequent ventricular premature contractions, greater than 50 percent suppression of the ventricular premature contractions was achieved. These effects were satisfactorily maintained in six (86 percent) of seven patients with nonsustained ventricular tachycardia and in 14 (88 percent) of 16 patients with frequent ventricular premature contractions in whom therapy with disopyramide phosphate was continued as a 20 mg/hour intravenous drip infusion for up to 24 hours. Side effects were observed in only eight patients (14 percent) and were primarily anticholinergic in nature. Transient hypotension, not necessitating treatment with pressor agents, was observed in three patients (5 percent), in two of whom discontinuance of therapy with disopyramide was deemed necessary. Intravenous therapy with disopyramide in the dosage regimen employed appears to be moderately effective against supraventricular arrhythmia and particularly effective against ventricular arrhythmia with minimal toxicity. It appears to be a suitable alternative to intravenous therapy with lidocaine and has the additional advantage of availability for oral administration.


Second-degree atrioventricular block in the His-Purkinje system following acute myocardial infarction. Clinical observations on its evolution.

The evolution of second-degree atrioventricular block in the His-Purkinje system was studied in four patients with acute myocardial infarction, utilizing continuous electrocardiographic monitoring and serial His bundle recordings. Three patients had anterior wall infarction; all developed acute right bundle-branch block and two also showed a left anterior hemiblock one to four hours prior to onset of second-degree atrioventricular block. The fourth patient had an old anteroseptal infarction and chronic right bundle-branch block and left anterior hemiblock; he developed second-degree atrioventricular block following an acute lateroposterior infarction. His bundle electrograms were obtained during the insertion of a temporary ventricular pacemaker within the first 24 hours of onset of chest pain. A second His bundle electrogram was obtained during removal of the temporary paceemaker 7 to 14 days after the first recording. In all cases the block was localized in the His-Purkinje system. In three patients the first His bundle recording showed second-degree atrioventricular block with minimal increment of delay in conduction (3 to 10 msec) prior to the blocked beat (equivalent of Mobitz type 2 block). The second His bundle electrogram showed the development of significant increment of delay in conduction (35 to 210 msec) prior to block (equivalent of Wenckebach conduction). The fourth patient illustrated the reverse order of the observations seen in the other three. Three patients showed resumption of 1:1 atrioventricular conduction; however, when one patient was challenged with rapid atrial pacing, he developed repetitive block in the His-Purkinje system.


The induction of ventricular arrhythmias in acute myocardial ischemia by atrial pacing with long-short cycle sequences.

Recent studies emphasize the importance of heart rate in the genesis of ventricular arrhythmias during myocardial ischemia. The role of alterations in rhythm has not previously been systematically investigated. In 20 dogs subjected to acute myocardial ischemia and crushing of the sinus node, standard electrocardiographic leads were recorded, as well as His bundle and epicardial electrograms from the normal and ischemic areas. Abrupt pauses in regular atrial pacing did not cause arrhythmias prior to the onset of ischemia; however, during ischemia, atrial pacing with intermittent abrupt pauses resulted in the induction of ventricular arrhythmias beginning after the second conducted beat following each pause (ventricular premature beats, 20/20; ventricular tachycardia, 19/20; and ventricular fibrillation, 8/20). Onset of the arrhythmia was associated with increased delay in activation of ischemic epicardium and fractionation of the electrogram potential of the second conducted impulse. Typical Gouaux-Ashman phenomenon was an incidental observation. Unlike the Gouaux-Ashman phenomenon, which is restricted to the His-Purkinje system, the phenomenon we observed orginated within ischemic myocardium. In vitro studies indicate that the underlying mechanism may be related to postrepolarization refractoriness induced by ischemia.


Positive radionuclide myocardial infarction pattern after ventricular fibrillation and direct current countershock.

A patient is presented in whom direct current counter-shock was applied for primary ventricular fibrillation. He recovered uneventfully and no evidence was found of a myocardial infarction; however, a positive 99m technetium stannous diphosphate scan obtained four days after the defibrillation showed positive findings. This positive scintigram was most probably due to myocardial or skeletal muscular damage consequent to counter-schock, but myocardial necrosis induced by ventricular fibrillation may be another cause. This case demonstrates again that a transmural or subendocardial infarction is not the only circumstance under which an abnormal scintigram can be obtained.


Value of perfusion lung scans in selection of patients for vena cava interruption.

Sixty-seven patients with pulmonary embolic disease (diagnosed clinically and with perfusion lung scans) were studied. In 48 of them, the scans were interpreted as positive for pulmonary emboli and in 19, as questionable. All 67 patients underwent pulmonary arteriography. The pulmonary arteriogram showed no evidence of pulmonary embolus in 11 of the 48 patients with positive findings on lung scan and no evidence in 12 of the 19 patients with questionable lung scan. Because of the high false-positive rate of the perfusion lung scan, we strongly recommend angiographic confirmation of pulmonary embolism when interruption of inferior vena cava is contemplated for the prevention of recurrence of pulmonary embolism.


Psychiatric hospitalization. II. Effect of social class and delivery systems.

The effects of social class and delivery system on admission and behavioral variables, diagnosis, treatment, and length of hospitalization were studied by comparing patients admitted over a one-year period to the psychiatric services of a public and a private general hospital, staffed by the same Department of Psychiatry. Patients were of similar age and sex and were matched by social class. Crisis-precipitated admissions and affective-disorder diagnoses varied with social class irrespective of treatment facility. Patients diagnosed as schizophrenic were more common in the upper classes at the private facility and the lower classes at the public facility. Somatic treatments and length of hospitalization also varied according to social class as well as delivery system. The results of this study imply that economic differences between public and private delivery systems operate to select patients for admission and affect expeditiousness of treatment, perhaps to the detriment of patients in both systems.


Carotid-vertebral artery blood transit time in health and in neurological patients: a preliminary study by a non-invasive impedance method.

Thirty-one healthy subjects and nineteen neurological patients covering a range of chronic neurological and neurovascular syndromes were examined by an electrical impedance method. Two estimates of carotid-vertebral artery transit times were measured: one time taken between the Q wave of the EKG to the commencement of the next succeeding impedance pulse-volume wave (CT1), and the other, this estimate together with the time to maximum point of the impedance wave (CT2). Results indicated prolonged circulation times for the patients as compared with the controls without relevance to age in the case of CT1, although transit times did increase with age for CT2. It is suggested that this impedance technique may be valuable in the initial screening of transient cerebral ischaemia.


Hallucinations as a conversion reaction.

This clinical report describes a patient who experienced complex visual and auditory hallucinations as a conversion reaction. The evidence suggests that hallucinations as a conversion reaction are qualitatively different from other types of hallucinations.


[Human lymphocytes examined by freeze-fracture technique (author's transl)].

Preliminary results of visualising lymphocytes by freeze-fracture are presented. It is a simple yet informative method. Because of the rapid cell manipulation without fixation (freezing of the cells with a temperature gradient of 1000 degrees C/s artefacts are highly unlikely, The method makes it possible to view the interior of the cell.


[Treatment of intrahepatic cholesterol stones by chenodeoxycholic acid (author's transl)].

Intrahepatic gallstones were demonstrated by operative cholangiography in two men, aged 34 and 46 years, respectively. The cholesterol stones were dissolved in both patients within eight and two months, respectively, by retrograde instillation of chendeoxycholic acid via a T-drain. Additional endoscopic papillotomy was performed because of a papillary stenosis in one instance, and extrahepatic occlusion during treatment in the other. During treatment there was a rise of transaminases of 5-fold levels, of gamma-glutamyl transferase up to 10-fold of normal. Since chenodeoxycholic-acid instillations both patients have been receiving the drug orally to prevent recurrence of gallstones. So far all biochemical values are within the normal range, the patients are without symptoms and have a normal exercise tolerance.


[Endoscopic and histological changes at the Z-line (author's transl)].

The Z-line, the transitional zone from oesophageal to gastric mucosa, is a clearly defined point of reference. Selective forceps biopsies were obtained from the Z-line, just below it from the cardia and 1-3 cm above it from the oesophagus, in 79 patients with an age average of 47 1/2 years. A comparison was made between endoscopic and histological findings, on the one hand, and symptoms on the other. Moderately severe inflammatory changes correlated positively with only minor endoscopic changes of the Z-line: patients of this group had significantly more symptoms of reflux than those with a normal line. Exact endoscopy, complemented by histological examination, can discover reflux oesphagitis in its early stages, although endoscopically and histologically the delineation from normal is difficult.


[A multi-centre study of reproterol, a bronchodilator (author's transl)].

Reproterol (Bronchospasmin), a monomolecular combination of catecholamine and theophylline, was tested in 81 patients with bronchial asthma or chronic obstructive bronchitis after a single oral dose, and compared with orciprenaline by intra-individual cross-over test. Five pulmonary-function laboratories cooperated in the study. A statistically significant bronchodilator effect, as measured by airway resistance and volume-corrected resistance, was obtained with 20 mg reproterol, having its onset after about 30 minutes, reaching its peak after 2-3 hours, and lasting for at least 4 hours. Comparing the area under the time-effect curves, the total effect was greater than that after 20 mg orciprenaline, pO2 rose higher after reproterol than after orciprenaline, but only by a few mm Hg. Neither heart rate nor blood pressure changed significantly after reproterol.


[Causes and treatment of jaundice associated with inflammatory pancreatic disease (author's transl)].

Jaundice or biliary stasis occurred in 32 of 82 patients with acute and 58 of 152 patients with chronic pancreatitis. A biliary cause was present in only 12 patients with acute and 19 with chronic pancreatitis. In the case of mild acute pancreatitis the cause of the jaundice lay in oedema of the head of the pancreas, while in the severe forms there was necrosis of the head. In chronic pancreatitis the jaundice is caused by tube-like, long stenosis of the choledochal duct or its compression by a cyst within the head of the pancreas. In acute pancreatitis treatment depends on the severity of the inflammation; in the biliary form the biliary tracts are attended to. In chronic pancreatitis resection of the head of the pancreas is preferred, biliodigestive anastomosis being practised if there is likely to be poor cooperation by the patient.


The metabolism of trans-cyclohexan-1,2-diol by an Acinetobacter species.

1. Acinetobacter TD63 was one of some thirty organisms isolated by elective culture with trans-cyclohexan-1,2-diol as sole source of carbon. The great majority of these isolates displayed the same growth spectrum as Nocardia globerula CL1 and Acinetobacter NCIB 9871 being capable of utilizing trans-cyclohexan-1,2-diol, 2-hydroxycyclohexan-1-one, cyclohexanol, cyclohexanone,1-oxa-2oxocycloheptane and adipate and were assumed to use well described metabolic pathways. 2. Acinetobacter TD63 was distinctive in being incapable of growth with cyclohexanol, cyclohexanone or 1-oxa-2-oxocycloheptane and because of this it was hoped that it would display an alternative pathway for the oxidation of trans-cyclohexan-1,2-diol. 3. Studies with cell extracts have shown the presence of inducible dehydrogenase for the conversion of trans-cyclohexan-1,2-diol to 2-hydroxycyclohexan-1-one and cyclohexan-1,2-dione and of 6-oxohexanoate to adipate. These enzymes are linked into a metabolic sequence by the action of a monooxygenase of broad specificity but efficiently capable of converting 2-hydroxy-cyclohexan-1-one into the lactone 1-oxa-2-oxo-7-hydroxycycloheptane that spontaneously rearranges to yield 6-oxohexanoate. 4. An enzyme capable of attacking cyclohexan-1,2-dione (mono-enol) in the absence of an electron donor or oxygen has also been detected. Evidence has been presented indicating that this enzyme catalyses a keto-enol tautomerization between cyclohexan-1,2-dione (mono-enol) and cyclohexan-1,2-dione (mono-hydrate) and is not involved in the pathway of ring cleavage. 5. The failure of Acinetobacter TD63 to grow with cyclohexanol, cyclohexanone or 1-oxa-2-oxocycloheptane is due not to this organism possessing a distinctive metabolic sequence but to a narrow inducer specificity coupled with an inability to form a lactone hydrolase enabling it to cleave the stable 1-oxa-2-oxocycloheptane which is an intermediate in the established pathway of cyclohexanol and cyclohexanone oxidation.


RNA methylation and control of eukaryotic RNA biosynthesis. Effects of cycloleucine, a specific inhibitor of methylation, on ribosomal RNA maturation.

The role of RNA methylation in the control of ribosome production in mammalian cells has been reinvestigated through a study of the effects in vivo of cycloleucine, a specific and reversible inhibitor of nucleic acid methylations. No close coupling is observed between methylation and transcription. During an extensive blocking of methylation, the synthesis of preribosomal 45-S RNA continues, although at a slightly reduced rate. Transcription and methylation can be temporarily uncoupled in vivo without impairing significantly the efficiency of the subsequent maturation of the transcript which takes place when the methylation is resumed. At the post-transcriptional level, two main observations are made. First, the cleavage pattern of ribosomal RNA is not qualitatively modified by the drug treatment. Preribosomal 45-S RNA which is synthesized during an extensive blocking of methylations (95%) is cleaved in vivo in a stepwise fashion into molecules resembling the species of the normal processing. Undermethylation does not result in the appearance of new size products and no extensive or rapid degredation of rRNA precursors can be detected. Second, the global efficiency of the process of ribosomal RNA maturation is severely affected, in quantitative terms; the undermethylation partially inhibits several stages in the maturation pathway and does not block selectively at a definite step of processing, as previously reported by others. Two main modifications are observed. (a) In the nucleus, the life times of the various undermethylated intermediates of ribosomal RNA maturation are markedly increased and a significant accumulation of these forms is detected by long-term labelling studies. (b) The rate of appearance of ribosomal 28-S RNA into the cytoplasm is severely affected (85-90% inhibition), in much higher proportions than the formation of its immediate precursor, nuclear 28-S RNA, thus suggesting a particular sensitivity to a lack of methylation of the last stage of preribosome maturation (possibly the release to cytoplasm). Finally, if a normal level of methylation does not appear to be stringently required for the completion of ribosomal RNA maturation, our results indicate that the degree of RNA methylation can modulate the general efficiency of the maturation processess.


Chemical and pharmacological characterization of toxic polypeptides from the venom of Bungarus caeruleus.

Five toxic fractions have been purified to homogeneity from the venom of Bungarus ceruleus by chromatography on CM-Sephadex, QAE-Sephadex and Bio-Rex 70 followed by filtration on Sephadex G-50 and Biogel P-30. One of them blocks synaptic transmission at the pre-synaptic level and is identified as a beta-bungarotoxin similar to that described by Lee from the venom of B. multicinctus. Three other ones are short-chain (type I) alpha-toxins which block the response of the isolated electroplaque from Electrophours electricus to bath-applied carbamylcholine. These basic polypeptides of 61-62 amino acids contain four disulfide bridges. A postsynaptically acting toxin, different from the alpha-toxins, has also been purified from the same venom. This ceruleotoxin is acidic and made up of several subunits.


Ceruleotoxin: a possible marker of the cholinergic ionophore.

Ceruleotoxin, a toxin component of Bungarus caeuleus venom, blocks in vivo the depolarisation caused by carbamylcholine on the isolated electroplaque from Electrophorus electricus and in vitro in increase of 22Na+ and 42K+ efflux caused by cholinergie agonists on excitable receptor-rich microsacs prepared from Torpedo marmorata electric organ. However, at variance with the typical alpha-toxins, ceruleotoxin does not interfere with the binding of [3H]acetylcholine and of alpha-[3H]toxin to the cholinergic receptor site. Ceruleotoxin also slightly modifies 35SO 2 4-and [14C]glucose efflux. Some of its effects on the postsynaptic membrane may be related to the presence of a phospholipase activity present in the preparation and are discussed in those terms. It is proposed that ceruleotoxin selectively blocks the electrogenic action of acetylcholine on the postsynaptic membrane without binding to the cholinergic receptor site, and might serve as an useful tool to characterise the ion translocating device, the ionophore, associated with the cholinergic receptor site.


Changes in the sequence diversity of polyadenylated cytoplasmic RNA during testis differentiation in rainbow trout (Salmo gairdnerii).

We have compared the sequence diversity of polyadenylated cytoplasmic RNA derived from naturally maturing trout testis at three different stages of spermatogenesis, by performing hybridization experiments between cDNA synthesized on a template of polyadenylated RNA and a vast excess of polyadenylated RNA. Polyadenylated RNA from early testis has a base sequence complexity of 7.2x10(9) daltons. As testis maturation proceeds, there is a decrease in the complexity of polyadenylated mRNA sequences in testis cells and the relative abundance of individual mRNAs varies over a more narrow range. Heterologous hybridization reactions demonstrate that a substantial fraction of polyadenylated RNA sequences present in early testis cytoplasm is absent from late testis cytoplasm. Nevertheless, all the sequences of late testis mRNA are represented in the population of early testis mRNA molecules.


Inhibition by CO of hepatic benzo[a]pyrene hydroxylation and its reversal by monochromatic light.

Inhibition by CO of benzo[a]pyrene hydroxylation was studied in hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin, from animals treated with vehicle (saline or corn oil, respectively), and in a reconstituted microsomal cytochrome P-448 system prepared from rats treated with 3-methylcholanthrene. In all preparations the hydroxylation was inhibited by CO, and this inhibition was most effectively reversed by irradiation with monochromatic light of 450 nm wavelength. These observations provide direct evidence that the oxygen-activating component of all the examined benzo[a]pyrene hydroxylase systems is a P-450-type heme protein. The only striking difference observed in these systems was the low CO sensitivity of the benzo[a]pyrene hydroxylase reaction in microsomes from animals treated with 3-methylcholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Half-maximal inhibition occurred at CO/O2 ratios of 9--12, rather than at 1--2, which is the usual range for P-450-linked mixed-function oxidase reactions. In contrast, the reconstituted benzo[a]pyrene hydroxylase system, with purified cytochrome P-448 from 3-methylcholanthrene-induced rats, exhibited a considerably higher sensitivity towards CO (CO/O2 ratio approximately 1), well within the range for mixed-function oxidase reactions. It is concluded that the observed diminished CO sensitivity of microsomal benzo[a]pyrene hydroxylase in 3-methylcholanthrene- or 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats results from alterations in the composition and/or structural organization of the microenvironment of cytochrome P-448 in the endoplasmic reticulum in response to the inducing action of polycyclic aromatic hydrocarbons and related agents, and is not related to changes in the heme protein P-448 per se. The detailed nature of these changes is the subject of ongoing studies.


Conformations of purine ribosyl 5'-nucleotides bound to glycogen phosphorylase b. A proton T2 relaxation time investigation.

The conformation of 5'-nucleotides in the active site of glycogen phosphorylase b has been deduced from linewidth measurements of protons H-1', H-8 and H-2. It is shown by selective deuteration of the purine ring in position 8 that the orientation of the base is anti in the case of strong activators like AMP and syn in that of weak activators like IMP. The orientation correlation time of the nucleotides in the active site is nearly that of the enzyme, i.e. 160 ns at 21 degrees C.


Studies on the accessability of ribosomes to inactivation by the toxic lectins abrin and ricin.

The rate of protein synthesis in HeLa cells was measured at various periods of time after addition of abrin and ricin to the medium and compared with the concurrent ability of the isolated ribosomes to support poly(U)-stimulated synthesis of polyphenylalanine in a cell-free system. Similarly, the endogenous synthesis in unfractionated cell-free systems from HeLa cells and rabbit reticulocytes was compared with the ability of the isolated ribosomes to support poly(U)-stimulated polymerization of phenylalanine. In the intact cells and the unfractionated cell-free systems protein synthesis decreased progressively with the time after addition of toxins or toxin A chains. In contrast, the ability of the isolated ribosomes to support polyphenylalanine synthesis was only moderately reduced initially and then remained constant or even increased. The activity of isolated monosomes decreased progressively with time after addition of toxin A chain, whereas polysomes were only partly inactivated and the extent of inactivation varied from one experiment to another. The results indicate that the inactivation of one or a few ribosomes per polysome stops the translation of mRNA. It is suggested that the intact ribosomes thus trapped are inaccessible to the toxins and that the isolation of polysomes results in release of functionally intact ribosomes capable of supporting poly(U)-directed polymerization of phenylalanine.


The immunochemistry of peptidoglycan. Antibodies against a synthetic immunogen cross-reacting with an interpeptide bridge of peptidoglycan.

An albumin-peptide conjugate was synthesized, which carries pentaglycine peptides with C-terminal glycine residues as found in the interpeptide bridges of the peptidoglycan of many staphylococci. Immunization of rabbits with this synthetic immunogen yielded antisera containing predominantly antibodies against the peptide moiety of the conjugate. The quantitative precipitin and the Ouchterlony agar gel reaction with several synthetic protein-peptide-conjugates, immunoaffinity chromatography of the antisera on Sepharose-(Gly-Gly-Gly-Gly-Gly)n and hapten inhibition studies with several synthetic peptides and peptide derivatives demonstrated that the antibodies were highly specific for oligoglycine peptides with C-terminal glycine. These antibodies also reacted strongly with staphylococcal peptidoglycans with an interpeptide bridge composed of pentaglycine peptides or of pentaglycine peptides in which part of the glycine residues were replaced by L-serine. In contrast, all the peptidoglycans lacking interpeptide bridges composed of glycine residues gave no precipitin reaction at all. The final proof for identical determinant groups of albumin-(CH2CO-Gly-Gly-Gly-Gly-Gly)31 and the staphylococcal peptidoglycans applied in the precipitin reaction was furnished by double gel diffusion studies and by hapten inhibition of the precipitin reaction between antisera to albumin-(CH2CO-Gly-Gly-Gly-Gly-Gly)31 and the corresponding peptidoglycans. For rapid screening of the different peptidoglycans, a latex agglutination test was elaborated. Purified antibodies were adsorbed to latex particles, and the titers with the particular peptidoglycans were then determined. The test was highly sensitive, in that 10 nanograms of peptidoglycan could still be detected.


Transport of hexoses across the liver-cell membrane.

The uptake of radioactively labelled hexoses into the cellular space of isolated liver cells has been studied using silicone layer filtering centrifugation. From the hexoses tested, D-glucose is transported most rapidly followed by D-galactose and D-fructose. The rate of L-glucose transport is only 5% of that of D-glucose. This transport enables the concentration of free aldohexoses in the cellular space to reach the external concentration. For D-glucose the rate of transport into the cell largely exceeds the rate of metabolic conversion. This is different with D-fructose where the rate of transport is considerably lower but the rate of metabolism higher. Here the transport may even be a limiting step. The transport of D-glucose and D-galactose shows a saturation characteristic, whereas D-fructose appears not to be saturatable. The Km for D-glucose is found to be 30 mM. All these hexoses compete with each other for transportation. The temperature dependency of D-glucose reveals an activation energy of 22 kcal (92 kJ)/mol (4-18 degrees C) and 7 kcal (29 kJ)/mol (18-37 degrees C). The transport of D-glucose, D-galactose and D-fructose in inhibited by cytochalasin B, phloretin and phlorizin. It is not dependent on Na+ ions. Preliminary results showed no stimulation of the transport by insulin. It is concluded that D-glucose and other hexoses are transported by carrier-mediated diffusion across the plasma membrane of liver cells. This transport shows a large resemblance to the transport of D-glucose into human erythrocytes.


Poly(A)-containing RNA in neuroblastoma: immature and differentiated cells in culture.

We have analysed the poly(A)-containing RNA from neuroblastoma cells at two different developmental states: either as round, immature neuroblasts grown in suspension, or as differentiated cells exhibiting the morphological properties of mature neurons, when attached to a culture dish. Suspension-grown and monolayer cells were pulse-labelled with tritiated uridine. The profile of cytoplasmic poly(A)-containing RNA from suspension cells is highly heterogeneous with peaks ranging from 16-30 S. The profile obtained from differentiated cells appears somewhat distinct from the previous one. This is evidenced by a relative decrease in the 26-S peak and a virtual disappearance of the 16-S component. In order to compare the 'steady-state' patterns of poly(A)-containing RNA in these two developmental stages, polysomal RNA was prepared from unlabelled cells. Following sucrose gradient sedimentation, each fraction was hybridized to [3H]poly(U). Examination of the two RNA hybridization profiles reveals striking similarities suggesting that 'steady-state' messenger populations include, on the average, the same subspecies. The 16-S fraction, which was not observed after the pulse-labelling of the monolayer culture, is detected here by hybridization to [3H]poly(U) when using polysomal poly(A)-containing RNA from monolayer cells as substrate. These results suggest that terminal differentiation of neuroblastoma cells is not accompanied by major alterations of the transcription program and is paralleled by a marked stabilization of the 16-S species.


4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric-acid aminotransferase in mammalian brain.

Incubation of rat brain 4-aminobutyrate aminotransferase with 4-amino-hex-5-enoic acid, a substrate analog of 4-aminobutyric acid, results in a time-dependent irreversible loss of enzymatic activity. In the presence of 0.1 mM inhibitor the half-life of the inactivation process is approximately 6 min. Low concentrations of L-glutamic acid or 4-aminobutyric acid protect against this inactivation, while 2-oxoglutarate prevents this protection, suggesting that only the pyridoxal form of the enzyme is susceptible to inhibition by 4-amino-hex-5-enoic acid. The irreversible inhibition of mammalian 4-aminobutyrate aminotransferase by 4-amino-hex-5-enoic acid is selective. There is no inhibition of this enzyme from Pseudomonas fluorescens with the inhibitor at mM concentrations. Even at 10 mM there is no irreversible inhibition of mammalian glutamate decarboxylase or of aspartate aminotransferase, while alanine aminotransferase is inhibited over 500 times more slowly than rat brain 4-aminobutyrate transaminase.


Deoxyribonuclease activity associated with adenovirus 5 and 7.

A DNase activity was found associated with isolated components of adenovirus types 5 and 7. The enzymatic activity was associated with the purified virus and viral components extracted from the soluble material of infected cells. The DNase activity of adenovirus type 5 was maximum at pH 5.5 and 7.0 whereas adenovirus 7 was active only at pH 7.0. Both DNases were shown to be located in the penton fraction.


Biosynthesis of cyclopentenyl fatty acids. Cyclopentenylglycine, a non-proteinogenic amino acid as precursor of cyclic fatty acids in Flacourtiaceae.

In seeds of Hydnocarpus anthelminthica of Flacourtiaceae, cyclopentenylglycine and cyclopentenyl fatty acids are found naturally. The non-proteinogenic amino acid may serve as precursor of cyclopentenyl fatty acids via aleprolic acid, the starter molecule for these long-chain compounds. After administration of cyclopentenyl[2-14C]glycine to maturing seeds of H. anthelminthica, labelled cyclopentenyl fatty acids were synthesized. Comparative activities were observed, when [1-14C]aleprolic acid was supplied to the seeds. Incorporation studies with [1-14C]acetate revealed that the chain-lengthening systems for straight-chain and cyclic fatty acids were still functioning in mature seeds. Endosperm and embryo of H. Anthelminthica seeds synthesized cyclopentenyl fatty acids from cyclopentenyl[2-14C]glycine, [1-14C]aleprolic acid and [1-14C]acetate. In embryonic tissue, a dilution experiment proved the following path for cyclopentenyl fatty acid biosynthesis: cyclopentenylglycine leads to aleprolic acid leads to cyclopentenyl fatty acids. The conversion of cyclopentenylglycine to aleprolic acid may occur via transamination and oxidative decarboxylation; activated aleprolic acid is then lengthened by C2-units to cyclopentenyl fatty acids.


Measurement of progesterone and pregnenolone 16alpha-hydroxylase activities by a tritium-exchange method.

A new isotropic method, based upon the stereospecific replacement of a proton (3H) by a hydroxyl group, has been developed for the measurement of progesterone and pregnenolone-16alpha-hydroxylase activity. The incubation medium consists of a phosphate buffer (pH 7; 150 mM), NADPH (1 mM), nicotinamide (10 mM) and magnesium chloride (4 mM). Tween-80 (1 mg/ml) is used to solubilize saturating concentrations of [16-3H]progesterone (200 micronM) or [16-3H]-pregnenolone (50 micronM). The microsomal fraction isolated from a male rat liver is used as the enzymic source. The enzymatically released tritium is recovered in the incubation medium as molecules of tritiated water which are distilled under reduced pressure. The amount of radioactivity present in the water exactly reflects the 16alpha-hydroxylase activity. The method is easy to perform and is completely independent of any further metabolism of the 16alpha-hydroxylated products.


The reduction by dithionite of Fe(III) myoglobin derivatives with  different ligands attached to the iron atom. A study by rapid-wavelength-scanning stopped-flow spectrophotometry.

1. The reductions of a number of sperm whale Fe(III) myoglobin-ligand complexes by sodium dithionite in a phosphate buffer pH 6.4, were investigated by using rapid-wavelength-scanning stopped-flow spectrophotometry. The ligands were azide, cyanide, fluoride, imidazole, thiocyanate and water. 2. The reduction of Fe(III) myoglobin cyanide led to the transient formation of Fe(II) myoglobin cyanide but no intermediate species were observable during the reductions of the other derivatives. The final product of the reaction in all cases was unliganded Fe(II)myoglobin. 3. Invesigation of the effect of dithionite concentration on the rate of reduction indicated that the SO2- radical ion was the active species in reducing the azide, cyanide, fluoride and thiocyanate derivatives. 4. Comparison of the observed rates of reduction at different ligand concentrations with those predicted for a pathway of reduction involving prior dissociation of the ligand, allowed us to estimate the rate of reduction with the ligand in position (outer-sphere reduction). There was a large variation in the relative rates of outer-sphere reduction in the order imidazole greater than CN- greater than SCN- greater than N3- greater than F-. The fluoride derivative was so resistant to outer-sphere reduction that the reaction with SO2- proceeded only by a pathway involving dissociation of F- before reduction. It was calculated that any direct reduction of this complex was at least 100 times slower than that of the azide derivative. 5. The results are discussed in terms of the possible rôle of the axial ligands in haem proteins and it is suggested that the pathway of the electron to the Fe(III) centre may be via the ppi orbitals of these ligands.


Complexity of the structure of particles containing heterogeneous nuclear RNA as demonstrated by ribonuclease treatment.

Brain ribonucleoprotein particles containing heterogeneous nuclear RNA (hnRNA) and a large number of polypeptides ranging from 23000 to 150000 molecular weight were treated with pancreatic and T1 ribonucleases at low (0.1 or 0.5 microng plus 5 or 25 units/ml), high (2 microng plus 100 units/ml) and very high (20 microng plus 1000 units/ml) concentrations. At low enzyme concentration, a large fraction of the particle material accumulated at 35-45 S. The accumulation was more marked for proteins in the 30000-38000 molecular weight range. Heterogeneous complexes containing a large spectrum of proteins with a characteristic distribution were disclosed between 60 and 200 S. At high ribonuclease concentration the total quantity of proteins at 35-45 S decreased, but the proteins of 30000-38000 molecular weight predominated. Heterogeneous complexes were also present. Finally at very high enzyme concentration, the particles were almost entirely hydrolyzed. Only a small amount of heterogeneous complexes subsisted at 30-190 S. The RNA content of the remaining ribonucleoprotein complexes as well as its size decreased upon ribonuclease treatment as shown by CsCl density determination and electrophoretic analysis. The results suggested that the stability of the complexes depended upon protein-protein as well as RNA-protein interactions. They also showed that sequences up to 200-300 nucleotides were protected by proteins against ribonuclease. The results were compatible with the existence of at least 3 constituents in the particles. The previously defined monoparticle population accumulating at 35-45 S was heterogeneous in respect to ribonuclease sensitivity and protein composition. The 30000-38000 molecular weight proteins accumulating at low ribonuclease and predominating afterwards were assumed to belong to monoparticles alpha. Monoparticles beta contained a larger range of proteins more easily released by the enzymes. The heterogeneous complexes were a third constituent whose relationship with the monoparticles war not established yet. A large fraction of the particle phosphoproteins was associated to these complexes. On the basis of our experiments in vitro it is assumed that monoparticle alpha can be preferentially isolated from the nuclei under conditions where endogeneous ribonuclease is high and (or) not inhibited. This might explain why, in certain cases, only one or a few proteins were described in nuclear particles instead of the complete set present in the native particles.


A neurolinguistic model for the study of aphasia.

After having briefly discussed some of the most important models that are now used to understand or to classify the aphasic troubles, the authors explain the neurolinguistic model they are actually using to study some aspects of aphasics' verbal and nonverbal behavior. This theoretical model distinguishes proper linguistic from extralinguistic disturbances in the various clinical forms of aphasia. The existence in aphasia of extralinguistic components that might, in some way, influence verbal performances, is accepted by most authors. Much less obvious is the existence, at least in some clinical forms of aphasia, of proper linguistic (competence) disturbances. Our theoretical model assumes that in most clinical forms of aphasia some impairment of the semantic (lexical) structures of language exists, and it maintains that this trouble can be found both at the expressive and at the receptive level, both in verbal and in nonverbal tasks. Th results of some experimental investigations which give some support to this theoretical model, are briefly discussed.


Effects of neonatal seizures on ontogeny of reflexes and behavior. An experimental study in the rat.

18 newborn rats received two electroshock seizures daily for 10 days. Their neurochemical and behavioral development was compared to that of littermates fo the same sex and similar weight, which were either untreated or treated with the same total amount of electrical current at subconvulsive intensities. While the two control groups were behaviorially or neurochemically indistinguishable, experimental rats reached several behavioral milestones (swimming, free-fall righting, auditory startle, visual placing) significantly later than controls and had smaller brains, containing significantly less DNA, protein or cholesterol than either control group. This study demonstrates that in the rat neonatal seizures are followed not only by impaired neurochemical development of the brain but also by delays in the animal's behavioral development.


Wernicke's disease. A catamnestic study of 50 patients.

A catamnestic study of 50 patients with Wernicke's disease showed that nearly all patients retained residual symptoms and that the prognosis as to life expectancy and social functioning was poor, even after early institution of vitamin B-complex medication. It is advisable to give vitamin B-complex prophylactically in cases of chronic alcoholism combined with insufficient nutrition.


Absence of drug-induced beta-activity in the electroencephalogram. A sign of severe cerebral impairment.

In 53 chronic epileptics with severe EEG abnormalities and under treatment with barbituric anticonvulsants, little or no fast activity was found in 44 patients. The serum concentration level (mostly phenobarbital) was in the therapeutic range in 11 and in the excessive range in 14 patients while no levels were obtained in the remaining 19 patients. Despite the lack of drug-induced fast activity, fast repetitive spike discharges and seizures with prolonged fast spike activity were demonstrated. The absence of the fast drug response is regarded as a sign of serious cerebral impairment due to the severity of the epileptic condition. The latter could be further enhanced by toxic drug levels.


Hemifacial spasm associated with dolichomegavertebrobasilar anomaly.

3 patients suffering from long-lasting "cryptogenetic" hemifacial spasm in association with dolichomegavertebrobasilar anomaly, are described. The angiographic examinations confirm the anomaly and put in evidence the patholphysiologic value of segment V4 of the vertebral artery at the same side of the spasm. Classical electromyographic examinations, and methods used to study the blink reflex, seem to rule out the hypothesis of a brain stem involvement as the only and sufficient pathologic mechanism. The peripheral pathogenesis is the most likely one.


Comparative study of efficacy of waking and sleep recordings following sleep deprivation as an activation method in the diagnosis of epilepsy.

In the present work, on the basis of an unselected collection of patients suspected of epilepsy, the diagnostic value of waking and sleep recordings each after 24 h sleep deprivation are compared with one another. Indicative findings of epilepsy were found in 16.7% of the cases in the waking EEG after sleep deprivation. In the sleep EEG after sleep deprivation this amounted to 57.1%. These figures speak for the advantage of the second method. The result is highly significant with a chi2 value of 13.01 (p less than 0.01).


Transient anterior horn cell dysfunction in diphenylhydantoin therapy.

A report on a patient who developed profuse fasciculations following diphenylhydantoin therapy for 30 months with subsequent complete recovery on cessation of therapy is presented. In view of the considerable variability of spontaneous potentials generated in spinal motor neurones, in vitro studies and pathological states with respect to shape, amplitude, frequency and duration, caution is advised in the assessment of the clinical significance of fasciculations. The possibility that our patient represents an instance of a 'reversible form of motor neuron disease' is entertained.


Morphological changes of the adapting small intestine deprived of gastric, duodenal, biliary and pancreatic secretions in the rat.

In order to examine the importance of certain gastrointestinal secretions in the adapting small intestine, four groups of rats were operated upon. In group 1 (controls), laparotomy and suture-marking of the small intestine were carried out. In group 2, a jejuno-ileostomy was established, resulting in a bypass of about 85% of the small intestine. In group 3, in addition to a similar bypass the secretions from duodenum, pancreas an the bile were diverted to the transverse colon. In group 4, in addition to the operations in group 3, the gastric secretion was also diverted to the colon. 14 days after operation, the wet and dry weight per 3 cm intestine and the villus height were determined from a jejunal and an ileal segment in circuit and also from the top of the blind loop. Both shunt-operation alone and shunt-operation with diversion of duodenal, pancreatic and bile secretion resulted in hypertrophy of both jejunum and ileum in circuit. Shunt-operation with diversion of gastric, duodenal, pancreatic and bile secretion resulted in moderate hypertrophic changes of the jejunum and ileum in circuit compared with controls. The top of the blind loop was atrophied in groups 2-4. The experiments demonstrate that the presence of duodeno-pancreatico-biliary secretions is not indispensable for the development of compensatory hypertrophic changes in the small intestine. The importance of gastric secretions in this respect cannot be evaluated because of the serious malabsorption of the experimental animals.


The vectorcardiographic estimation of left ventricular filling pressure following acute myocardial infarction.

High gain vectorcardiograms, in the "timed" mode, have been recorded in 50 patients hospitalized with noncardiac complaints, and in 32 previously well patients following acute myocardial infarction. The terminal component of the atrial vector loop has been analysed in the horizontal, frontal and sagittal planes in all the cases. A technique is described by which the three variables, magnitude, direction and depolarization time of the terminal atrial vector in each plane can be summated to give a numerical value for the total displacement of left atrial activity. This figure is referred to as the "total vector value". In the 32 postinfarction patients the "P-terminal force" was also measured from lead V1 of the scalar electrocardiogram. In these patients both the total vector value and the "P-terminal force" was correlated with the pulmonary diastolic pressure, as an indirect assessment of left ventricular filling pressure. In the immediate postinfarction period the correlation between the total vector value and the pulmonary diastolic pressure was good (r = 0.92), but that between the "P-terminal force" and the pulmonary diastolic pressure was poor (r = 0.11). Alterations in atrial electrical activity recorded by either method correlated poorly with changes in the pulmonary arterial pressure occurring more than 36 h after acute infarction. The "total vector value" provides an accurate noninvasive method for the detection of a rise in the left ventricular enddiastolic pressure within the first 36 h following an acute myocardial infarction. It is superior in this respect to the "P-terminal force" measured from the standard scalar electrocardiogram.


Influence of short-term physical training on exercise tolerance after myocardial infarction.

14 patients with stabilized myocardial infarction were submitted to a functional evaluation before and after 3 sessions of interval training on the bicycle ergometer. With submaximal exercise, myocardial load decreases after short-term training, the heart rate and the blood pressure--heart rate product being significantly lower for the same oxygen consumption. Maximal working capacity, expressed in watts or oxygen consumption, increases significantly after short-term training, the benefit being one-third of that obtained after 6 weeks' training. These early changes in functional capacity are positively correlated with those obtained by a more prolonged rehabilitation program. Leg muscular blood flow during submaximal and maximal exercise tends to increase after short-term training, although this change is not systematic and thus not significant.


Atypical 2nd degree AV block due to bilateral bundle branch block with Wenckebach phenomenon and concealed conduction in the bundle branch system.

A case of bilateral bundle branch block is described with the following features: -- 2nd degree infranodal AV block due to bilateral, intermittently synchronous "phase 3" bundle branch block; -- occasional AV conduction failure due to concealed His bundle extrasystoles; -- right bundle branch block pattern due to retrograde activation from the left bundle branch; -- QRS complexes having normal duration due to uniform slow conduction in both bundle branches; -- Wenckebach phenomenon in the right bundle branch; -- concealed conduction in both branches. The above interpretations are based on the use of His bundle recordings, results of right atrial stimulation and of pharmacological testing. Determinations of the lengths of all H--H intervals, whether H was followed by a ventricular response or blocked, permitted insight into the mechanism of 2nd degree AV block with varying (right and left) bundle branch block.


Reassessment of the diagnostic value of the vectorcardiogram in cystic fibrosis (correlation with clinical score, pulmonary function tests and echocardiogram).

In 21 children with cystic fibrosis, the vectorcardiogram (VCG) was correlated with various indices of the severity of the disease. The best correlation was found between (1) the azimuth angle of the spatial QRS loop area, representing the rightward and posterior shift of the main electrical forces, and pulmonary function tests (PFT): FEV1 % predicted (r = -0.671, P less than 0.005) and VC% predicted (r = -0.607, P less than 0.005), and (2) the right ventricular anterior wall index measured echocardiographically (r = 0.472, P less than 0.05). More VCG parameters correlated significantly with PFT than with the echocardiogram. This shows the major influence of pulmonary changes on the VCG of those patients. In several subgroups with different clinical scores, the VCG were analyzed and compared to normal limits of age- and sex-matched controls. In this small series, the VCG was a specific but not very sensitive method for predicting the degree of severity of the disease. Echocardiography and vectorcardiography can be considered as two complementary techniques in the evaluation of cystic fibrosis.


Cardiovascular abnormalities in cutis laxa.

Cutis laxa is manifest histologically by fragmentation of elastic tissue throughout the body. The aorta and other systemic vessels show dilatation, elongation and even aneurysm formation. We report multiple pulmonary artery branch stenoses in a child who had cutis laxa. Pulmonary artery stenoses may be the cause of the pulmonary hypertension and right heart failure observed in patients with this condition.


Eleventh Edgar Mannheimer Lecture. Human fetal and neonatal circulation. Some structural and functional aspects.

Normally the neonatal circulation adjusts itself gradually during the first days of extrauterine life. The different closure rates of the major fetal vascular channels (umbilical vessels, ductus venosus, ductus arteriosus, and foramen ovale) permits smooth alterations in direction and size of shunts, should the balance of vascular resistance and pressure become upset. The study of the influence of placental transfusion on the cardio-respiratory adaptation has again demonstrated the great capacity of the transitional circulation to cope with all the strains involved in the reorganization of the circulatory system at birth. Such a capacity proves the existence of an effective system of integrated baroreceptor--and chemoreceptor--reflexes (peripheral and central).


Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment.

Six male patients withhistologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone 7 mg/kg with 3H-spironolactone 100muCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of 3H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47 +- 4.88%) and from controls (53.68 +- 2.04%). The kinetics of CH2CI2/H2O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH2CI2 soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.


Agranulocytosis during treatment with chlozapine.

Within six months of the introduction of the new antipsychotic drug clozapine in Finalnd, 17 cases of neutropenia or agranulocytosis were recorded amongst about 3000 patients treated. Agranulocytosis was fatal in eight patients, and in addition, two patients developed thrombocytopenia, and one patient leukaemia. As additional cases might well have been overlooked as banal infections, the risk of developing agranulocytosis during clozapine treatment was at least 0.5%. Impaired elimination of the drug or increased susceptibility of granulocyte precursors to clozapine, possibly due to some inherited characteristic, might explain the high incidence of complications.


Serum glycoside concentrations after single or repeated intravenous doses of beta-methyl-digoxin and digoxin.

The aim of the present investigation was to estimate the ratio of the intravenous doses of beta-methyl-digoxin and digoxin required to produce identical serum glycoside concentrations in man. 20 patients on intravenous maintenance therapy were changed from beta-methyl-digoxin to the identical dose of digoxin or vice versa. Each drug was given for 7 days. Serum concentrations 13% higher were found during administraton of beta-methyl-digoxin. Assuming a half life of 60 h after withdrawal, the dose of digoxin producing the same minimum serum concentration was estimated to be 1.16 times higher than that of beta-methyl-digoxin. 18 healthy volunteers received 0.4 mg beta-methyl- digoxin, and 23 the same dose of digoxin, as an intravenous infusion over 2 h. The serum concentrations and urinary glycoside excretion were measured over a period of 32 hrs. During the first hour after the infusion the serum concentration of digoxin declined more rapidly than that of beeta-methyl-digoxin. Thereafter, the ratio of the serum concentrtions did not change appreciably up to the end of the investigation. The area under the serum concentration/time curve was about 13% greater for beta-methyl-digoxin than for digoxin; this difference was not significant. The average renal clearance was 96 +- 9 ml for beta-methyl-digoxin, 151 +- 13 ml for digoxin. Since the total body clearance of digoxin is only about 1.16 times higher than that of beta-methyl-digoxin, the lower renal clearance of beta-methyl-digoxin must partly be compensated by higher extrarenal clearance. From the ratios of the areas under the serum concentration/time curves after single doses of beta-methyl-digoxin and digoxin, and the minimum serum concentrations during maintenance therapy, it was concluded that the dose of digoxin to produce the same average serum concentrations would be about 1.15 times higher than that of beta-methyl-dogoxin. In comparison wtih the large variations in individual dosage of digoxin and beta-methyl-digoxin, this difference is too small to be of practical importance.


Protein binding of salicylate and quinidine in plasma from patients with renal failure, chronic liver disease and chronic respiratory insufficiency.

The plasma protein binding of a representative acidic drug, salicylate, and a representative basic drug, quinidine, has been studied in patients with several diseases that are sometimes associated with uraemia or a change in serum albumin level. Decreased plasma protein binding of salicylate was observed in plasma from patients with uraemia and liver disease. Low albumin levels in these patients could only account inpart for the decreased binding. On the other hand, salicylate binding to plasma proteins appeared to be increased in patients with hypoxia. Decreased plasma protein binding of quinidine was observed in some patients with uraemia and in the majority of patients with liver disease.


On the oscillatory decay of the myotonic action of 9-anthroic acid. Influence of cholinesterase inhibition.

The effects of the myotonic agent, 9-anthroic acid (ANCA), and the acetylcholinesterase (AChE) inhibitor, soman, on the isolated phrenic nerve--diaphragm preparation of the rat have been studied. ANCA induced after-contractions which followed the twitches evoked by either direct or indirect stimulation. In the intermittently stimulated muscle the height of the after-contractions decreased rather rapidly and in an oscillatory fashion. The maximum height of each after-contraction was attained after the twitch had reached its peak. AChE inhibition changed the shape of these after-contractions in the indirectly, but not in the directly stimulated diaphragm. After AChE inhibition, the after-contractions decreased more slowly and in a non-oscillatory manner. Similar phenomena were observed in vivo in the gastrocnemius--soleus muscles. The effects of ANCA in the AChE-inhibited and in the non-inhibited diaphragm could be mimicked by incubation in low chloride media. Addition of ouabain to the non-inhibited diaphragm treated with ANCA, caused an immediate and striking enhancement followed by a rapid loss of the after-contractions, whereas the twitches remained fairly constant. In the AChE-inhibited diaphragm treated with ANCA, ouabain caused no increase but only a rapid and complete decay of the after-contractions with a decrease of the twitches. It is suggested that after inhibition of the AChE in the ANCA-treated muscle fibre, the site of initiation of the repetitive action potentials which cause the after-contractions shifts from the transverse tubular system to the motor end-plate. Moreover, it is suggested that the sodium pump is involved in the gradual decay of the myotonic action of ANCA.


Effects of mazindol and d-fenfluramine of 5-hydroxytryptamine uptake, storage and metabolism in blood platelets.

Mazindol induced a dose-related inhibition of the uptake of labelled 5-hydroxytryptamine (5-HT) by guinea pig blood platelets. It was more potent than d-fenfluramine. Mazindol and d-fenfluramine decreased 5-hydroxy-indoleacetic acid formation in intact platelets but not in sonicated ones. The inhibitory effects of both drugs appeared to the competitive in nature and were markedly reduced in platelets suspended in plasma instead of in Tyrode solution. Mazindol neither decreased the stored endogenous 5-HT nor caused efflux of the labelled amine from preloaded platelets, whereas d-fenfluramine induced a significant release of the amine. It is concluded that mazindol, like  d-fenfluramine, competes with 5-HT for the same transport mechanisms at the cytoplasmic membrane level but this effect is not accompanied, as is the case with d-fenfluramine, by a concomitant release of the amine.


Non-mast cell histamine levels in rat tissues after histidine loading.

The i.p. administration of L-histidine in doses of 500 and 1000 mg/kg, caused prolonged high levels of histidine but did not influence the levels of histamine in the non-mast cell tissues such as the stomach, lungs and liver in the rat. After polymyxin B or 48/80 treatments as well as in anaphylaxis, the levels of histamine in the lungs and liver were greatly reduced but histidine administration failed to alter noticeably the concentrations of histamine in these organs. Similarly, the low contents of histamine in the stomach of 48/50-treated or polymyxin B-treated rats remained unchanged in the presence of excess histidine. Histidine loadings however produced a marked increase in histidine decarboxylase activity of the glandular stomach and a simultaneous elevation in the serum histamine concentrations. Results suggest that the increased level of serum histamine is the consequence of the increased activity of histidine decarboxylase in the tissues and a rapid elimination of the newly formed histamine into the blood. This led us to consider that the flux rather than the formation of histamine might be regulatory for the actual concentration of the non-mast cell histamine, especially in stomach tissue.


Convulsant-anticonvulsant interactions on seizure activity and cortical acetylcholine release.

The effects of leptazol and bicuculline on the efflux of endogenous acetylcholine (ACh) from the surface of the cerebral cortex have been related to EEG activity in urethane-anaesthetised rats. During seizure activity there was a calcium dependent increase in ACh efflux which was related to increase EEG activity and clonic muscle movements. ACh release and EEG activity were reduced during convulsive activity by trimethadione but not phenytoin. Phenobarbitone reduced convulsive EEG activity but left ACh release relatively unaffected. Blood pressure changes induced by convulsant and anticonvulsant drugs were not consistently related to EEG activity or ACh release. It is suggested that ACh efflux from the cerebral cortex is closely related to the activity of neurones within the cortex where it is released from nerve endings. Comparison of EEG changes induced by anticonvulsants and urethane during control and convulsant activity showed that only trimethadione produces anticonvulsant activity unaccompanied by general CNS depression.


Pharmacological studies of facial motoneurones in the rat.

Experiments were performed on 39 male albino rats anaesthetized with pentobarbitone sodium and paralyzed with gallamine triethiodide. Facial motoneurones consistently showed a progressive alteration of spike shape and decrease in spike firing frequency during the continuous microelectrophoretic application of the excitant amino acids D,L-homocysteate, L-glutamate, L-aspartate, and kainate, but infrequently during that of N-methyl-D-aspartate. The relative potencies of these excitants on facial motoneurones are reported. The potential usefulness of N-methyl-D-aspartate to produce amino acid-evoked motoneurone action potentials is discussed. The microelectrophoretically-applied depressant amino acid antagonist strychnine selectively and reversibly blocked the depressant effects of glycine on facial motoneurones. The depression of amino acid-induced firing of facial motoneurones by stimuli to the lingual or glossopharyngeal nerves were reversibly antagonized by microelectrophoretically applied strychnine but not by bicuculline.


Lack of protection of ischemic myocardium by verapamil in conscious dogs.

To determine whether coronary dilatation and decreased myocardial oxygen requirements resulting from administration of verapamil, a calcium and slow current antagonist, protect ischemic myocardium in conscious dogs, we studied 15 treated and 15 control animals after coronary occlusion. Verapamil (0.2-0.7 mg/kg/h) was given by continuous infusion for 17 h beginning 5 h after the initial plasma creatine kinase (CK) elevation after coronary occlusion. Observed infarct size and infarct size predicted before verapamil were estimated from hourly plasma CK values and infarct size was estimated also from myocardial CK depletion measured directly, 24 h after occlusion. Changes in heart rate, blood pressure, and frequency of premature ventricular complexes (recorded every 30 min) after occlusion were similar in treated and control dogs. Coronary flow after verapamil, measured with radioactively labeled microspheres, did not increase in ischemic zones but increased by 90% in normal myocardium (p less than 0.05). The differences between observed and predicted infarct size estimated from plasma CK changes in treated and controls were similar (3.0 +/- 2.2 (S.E.) and 2.0 +/- 1.4 CK-g-eq), and myocardial CK depletion was also comparable in the two groups (25 +/- 2% and 23 +/- 2%). Thus although verapamil, administered five hours after the initial plasma CK elevation, increased coronary flow in normal myocardium, it did not augment flow in ischemic tissue or limit the extent of infarction.


Aspects of the spasmogenic effects of acetate esters on ileal smooth muscle.

Acetate esters, such as aspirin methylester, aspirin and resorcinol monoacetate, induced contractions of guinea-pig ileum. Their actions were selectively antagonized by atropine, but were not affected by ganglion blocking agents, conduction blockers, aging with cooling, anoxia or antihistaminics. On the other hand, N-acetates, such as acetanilide and p-acetaminophenol, and no contractile action on the ileum. These acetate esters thus seemed to have a cholinergic action, and not a direct action on muscle or other known specific receptors for endogenous active substances. The contractions induced by the acetate esters were selectively potentiated by low concentrations of choline, whereas those induced by acetylcholine, nicotine, 5-hydroxytryptamine and histamine were not. However, N-acetates did not induce the contractions even in the presence of choline. Organophosphorus cholinesterase inhibitors, such as diisopropyl fluorophosphate and paraoxon, selectively and irreversibly inhibited the actions of aspirin and N,O-diacetyl-p-aminophenol with or without choline. From these results, it is concluded that the acetate esters with or without choline act through the cholinergic system. However, their actions cannot be explained in terms of known mechanisms, such as acetylcholine release, cholinesterase inhibition or a direct muscarinic action. Therefore, the acetate esters, including phenyl acetate which was supposed to be a releaser of acetylcholine, seem to have a hitherto undescribed type of cholinergic action whose mechanism is unknown. It seems that organophosphate-sensitive esterase(s) in the preparation may be essential for initiation of the actions of the acetate esters with or without choline, but the mechanism of the effect of choline is unknown.


Effect of verapamil on experimental arrhythmias.

Verapamil 0.25-1.0 mg/kg i.v. did not significantly elevate the ventricular fibrillation threshold in dogs. It did not antagonize the deslanoside arrhythmias, but inhibited transiently the arrhythmias induced by either electrical stimulation of the posterior hypothalamus or bilateral carotid occlusion in cats. Effect of verapamil on the aconitine-induced rapid firing of the isolated atria and ventricles of the young rabbit and chick embryos was also studied with the microelectrode technique. In doses of 5, 10 and 20 microng/ml, it suppressed the rapid firing of the cardiac preparations, with exception of the ventricles of the rabbit. Antiarrhythmic action of verapamil in such high concentration seems to be due to non-specific inhibitions of Na+ channels of the myocardial cells.


Some effects of mazindol, an anorectic drug, on rat brain monoaminergic systems.

Mazindol was devoid of effect both on rat brain steady state levels of 5-HT, 5-HIAA and tryptophan and on the rate of synthesis of 5-HT in the rat brain. Mazindol had no effect on rat brain 5-HT uptake in vivo as determined by the effect of drug pretreatment on the ability of p-chloroamphetamine to lower central 5-HT levels. A large dose of mazindol caused a slight transient decrease in rat brain levels of NA and DA. Blockade of rat brain catecholamine uptake was quantified by studying drug effects on the ability of intraventricularly administered 6-hydroxydopamine to lower brain NA and DA content. Mazindol was an extremely potent inhibitor of rat brain NA uptake in vivo, being 4-5 times more potent than desipramine. Mazindol also blocked rat brain DA uptake. Doses of mazindol needed to release alpha-methyl-m-tyramine from the rat striatum were appreciably greater than the corresponding doses of d-amphetamine. The neurochemical profile of mazindol bears a much closer resemblance to that of d-amphetamine than to that of fenfluramine.


Peptide antagonists of angiotensin-induced adrenal catecholamine release.

The effect of analogs of angiotensin (modified with an Ile-substituted for Phe) was studied in the isolated, retrogradely perfused adrenal of the cat. Continuous differential analysis of norepinephrine and epinephrine output was quantified with an automated trihydroxyindole procedure. [Ile8]-angiotensin I and [Ile7]-angiotensin III exhibited negligible secretory activity, in contrast to the stimulatory effects of [Ile8]-angiotensin II (10-20% activity relative to angiotensin II). [Ile8]-angiotensin I blocked angiotensin II-induced catecholamine secretion and a pA2 value of 8.50 was obtained. [Ile7]-angiotensin III was an especially potent antagonist of angiotensin II and a pA2 value of 10.4 was calculated for this heptapeptide analog. The pA2 value for [Ile8]-angiotensin II, a partial agonist in the adrenal medulla was 9.33. These three analogs were equally effective against secretion induced by the corresponding unsubstituted homologs (Ang I and Ang III). These data suggest that all these angiotensin peptides interact with a common receptor. [Ile8]-angiotensin I and [Ile7]-angiotensin III had no effect on adrenal medullary responses induced by KCl, nicotine and bradykinin. These structural analogs of angiotensin are pure competitive antagonists of angiotensin in the cat adrenal chromaffin cell.


Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs.

Cardiovascular effects of several imipramine analogs were investigated in the anesthetized mongrel dogs. Significant reduction in the cardiac output produced by lower doses (2.5 mg/kg, i.v.) of imipramine and 2-OH-DMI was not due to a depression of myocardial contractility. In contrast, 2-OH-imipramine (1.25 mg/kg) and DMI (2.5 mg/kg) significantly reduced contractility within 10 min after i.v. administration; however, significant decrease in the cardiac output did not occur until after 60 min. Higher doses (5 mg/kg) of imipramine, DMI and 2-OH-DMI significantly attenuated cardiac rate, contractility and output within 5 min after i.v. administration. 2-OH-imipramine, 2.5 mg/kg, i.v., depressed contractility and cardiac output to a degree equivalent to that produced by 5 mg/kg of imipramine, DMI and 2-OH-DMI. 3-Chloro-imipramine (5 mg/kg, i.v.) induced decrease in the cardiac output was essentially due to a significant reduction in the heart rate since the effects of this compound on the contractility were transient in nature. 3-Cl-8-OH-metabolite of this compound had no significant effects on the cardiovascular system. The results of this investigation demonstrated that the complex cardiovascular effects of tricyclic antidepressants observed in these studies were perhaps due to a direct and/or autonomically mediated effects on the heart and vasculature. Further, the data support the conclusions that the activity of the parent compounds together with that of the metabolites contributes to overall changes observed. While all the agents are capable of reducing cardiac output, 2-OH-metabolite of imipramine appears to be most toxic on the myocardium and 3-Cl-imipramine possessed only transient effects on the contractile properties.


Mossy and climbing fiber inputs from cutaneous mechanoreceptors to cerebellar Purkynĕ cells in unanesthetized cats.

1. Mossy and climbing fiber inputs from cutaneous mechanoreceptors to Purkynĕ cells of vermis and pars intermedia of the cerebellar anterior lobe were studied in locally anesthetized, paralyzed cats prepared for painless recording sessions. In this preparation the mossy fiber and climbing fiber pathways remain fully functional. Simple spikes and climbing fiber discharges were recorded simultaneously through extracellular glass micro-electrodes and thereafter filtered off from each other for separate, computer-assisted analysis. Controlled mechanical stimulation (air jets, taps, pressure) was performed on the foot pads of all four limbs and on the hairy skin of the limbs and the body. 2. Long term recording of the spontaneous activity of 110 Purkynĕ cells revealed a simple spike activity of 85 imp./s +/- 49 imp./s (mean +/- S.D.) and 1.00+/-0.78 climbing fiber responses per second. 3. Taps to foot pads and air jets to hairy skin revealed that most of the short latency responses via mossy fibers resulted from activation of the receptors of the ipsilateral forefoot. With the same stimuli climbing fiber discharges from the ipsilateral feet were more frequently evoked than from the contralateral feet. Both via mossy and climbing fibers the contralateral hindlimb gave the smallest contribution. 4. Simple spike responses were evoked more commonly by pad stimulation (tap stimuli) than by hair stimulation (air jets). For both types of stimuli excitatory responses were more frequent (3:1) than inhibitory ones. Similarly, pad stimulation was more effective than hair stimulation in inducing climbing fiber responses. Ipsilateral stimuli were much more effective than contralateral ones in evoking both simple spike and climbing fiber responses. 5. Steady pressure stimuli modify the Purkynĕ cell discharges via mossy and climbing fiber pathways. Excitatory and inhibitory effects often of very long duration have been observed via both pathways. Again the ipsilateral forelimb was more effective than the other limbs. Mossy fiber responses were at least three times as common as climbing fiber responses and excitatory responses were more frequent than inhibitory ones. 6. There is no apparent relation between the spontaneous discharge rates of the Purkynĕ cells and the response magnitudes of the mossy fiber and climbing fiber induced excitatory and inhibitory changes inthe impulse pattern of Purkynĕ cells during steady pressure stimuli.


Somatotopic studies on the vermal cortex of the cerebellar anterior lobe of unanaesthetized cats.

1. In unanaesthetized cats with intact neuraxis the relation between the cutaneous receptive fields of Purkynĕ cells and the position of these cells in the vermis of the cerebellar anterior lobe was studied with the specific question whether this cerebellar area exhibits any kind of somatotopy in the absence of central anaesthesia. To establish the receptive fields the skin of all four limbs and of the trunk was probed with mechanical stimuli (taps, air-jets, pressure). The recording sites in the vermis were determined histologically. 2. In regard to the mossy fiber transmitted input none of the four limbs showed a dominant representation in one or more of the lobules rostral of the fissura prima or in a parasagittal section. For the ipsilateral limbs there is a greater mossy fiber input to lobule V from the forelimb than from the hindlimb (84:59%), and a reversed preponderance for lobule II (45:80%) but this indication of a somatotopic arrangement is not unequivocally paralleled by the other mossy fiber inputs. 3. Also in regard to the climbing fiber input no distinct somatotopical arrangement has been detected. Again it has been noted that the ipsilateral inputs have a somewhat greater input to lobule V from the forelimb than from the hindlimb (35:22%), and the reverse finding holds true for lobule II (10:45%). 4. The overall results did not change appreciably when the  responses were grouped according to their latencies or when the Purkynĕ cells were classified according to the patterns of convergence of their receptive fields. 5. The absence of a distinct somatotopic organization in the vermis is a direct consequence of the considerable convergence from the cutaneous mechanoreceptors of the limbs onto the individual Purkynĕ cells which occurs via the mossy and the climbing fiber pathways. It is suggested that this convergence indicates that the vermal Purkynĕ cells are particularly involved in coordinating the motor activity of forelimbs and hindlimbs.


Role of Ia afferents in the soleus motoneurones. Inhibition during a tibialis anterior voluntary contraction in man.

Variations of the soleus H-reflex were studied during voluntary isometric or anisometric contractions of the tibialis anterior in man. At the onset of isometric contractions there was a weak inhibition of the soleus H-reflex, which was not related to the force of the tibialis anterior contraction. 110 msec after the onset of the EMG activity, the inhibition became secondarily more marked and was then related to the force of the contraction. This secondary potentiation of the H-reflex inhibition is brought about by group I fibres activity, since it was markedly reduced during ischemia of the leg. It persisted during local muscular fatigue, this indicating that Ib fibres from tibialis anterior are not involved and that, by the process of elimination, group Ia fibres must be responsible for the supplementary secondary inhibition. It is concluded that the early inhibition is only due to suprasegmental activity, whereas during the secondary part of the inhibition there is a supplementary inhibitory action brought about by Ia fibres from tibialis anterior. The secondary potentiation of the inhibition is therefore likely to be produced via the gamma loop.


[Effect of azabutyrone and its analogs on catecholamine metabolism in the brains of rats].

The action of the neuroleptic azabutyrone and its analogues on the accumulation and disappearance of 3H-norepinephrine and 3H-dopamine was studied in test on rats by using 3H-thyrosine, a tagged precursor of catecholamines. Azabutyrone is shown to be capable to speed up the dopamine circulation rate, as well as that of norepinephrine in the brain of rats. By comparison with azabutyrone the diazabicyclodekanyl derivative produces a more marked effect on the criculation of amines. A further "weighting" of the diazabicyclic radical and also substitution of chlorine for the fluorine atom in the para-position of the phenyl ring of butyrophenone leads to weakening of this effect.