A review of the role of lymphography in the management of testicular tumours. The pedal lymphographic findings in 260 patients with testicular tumours are reviewed: 117 patients had a seminoma, 105 had a teratoma and 38 combined tumours. 26 percent of seminomas were associated with a positive lymphogram, corresponding figures being 42 percent for teratomas and 53 percent for combined tumours. The role of the lymphogram is (1) to stage the case so that the extent and form of the treatment can be logically assessed, (2) to plan accurately radiotherapy treatment fields, (3) to observe the results of treatment on serial follow-up films, (4) to detect the recurrence of tumour using "re-fill" lymphography if necessary, (5) to show possible unsuspected metastases involving supraclavicular and mediastinal glands, and (6) to give a prognosis, since a negative lymphogram suggests an excellent chance of survival. Three main types of lymphographic appearances are recognized: nodal, mass replacement and "pseudo-lymphomatous". Nodal deposits are most common. Most positive findings are in the para-aortic chain on the same side as the tumour. Iliac involvement is much less common. Seminomas in this series showed a 96 percent crude three-year survival rate. For teratomas and combined tumours the three-year survival rates were 59 percent and 61 percent respectively, but deaths are uncommon in the lymphographically negative Stage I cases. Bone deposits are rare. Only two were found in this series. We do not perform testicular lymphography, but consider there is a useful role for inferior venacavography when there is poor filling of upper para-aortic nodes at lymphography. The importance of taking follow-up films after the initial examination is stressed.


Histologic type of lung cancer in relation to smoking habits, year of diagnosis and sites of metastases. A study was made of histologic type of lung cancer in relation to smoking habit, year of diagnosis, age and sites of metastasis. It comprised 662 autopsies of men during the period from 1955 to 1972. As classified by the WHO system, 35.2 percent were epidermoid carcinoma, 24.6 percent were small cell carcinoma, 25.2 percent were adenocarcinoma and 14.2 percent were large cell undifferentiated carcinoma. The six non-smokers of the series were all found to be in class 3, adenocarcinoma. No clearcut and consistent relationships were observed. Although there was a steady decrease in the incidence of small cell carcinoma during this time period, this observation did not prove to be statistically significant. Small cell carcinomas increased with amount of smoking but not for all age groups. Adenocarcinomas decreased with advancing age but not in all smoking groups. Metastases were found in 96.3 percent of the cases and the sites most frequently involved were regional lymph nodes, liver, brain, distant lymph nodes, adrenals and bone. Small cell carcinomas showed the greatest percentage of involvement for those major sites and for the same sites, epidermoid carcinoma showed the lowest percentage.


Myocardial ischemic effects of isometric, dynamic and combined exercise in coronary artery disease. The electrocardiographic effects isometric (handgrip) and combined isometric-dynamic (treadmill-plus-brief-case) exercise were evaluated and compared to a submaximal treadmill stress test in 140 patients with known or suspected coronary artery disease. Only 3 of 90 patients developed ischemic ST changes during handgrip, as opposed to 25 positive treadmill tests (p less than 0.01). Of 19 of 50 patients who were positive during the standard treadmill test, only 17 showed positive findings during the combined treadmill-briefcase test. Analysis of hemodynamic responses showed significant (p less than 0.01) differences between the handgrip and treadmill tests in terms of heart rate response (control 83 plus or minus beats/minute, handgrip 105 plus or minus 4, treadmill 151 plus or minus 6), diastolic blood pressure (control 80 plus or minus 2 mm Hg, isometric 93 plus or minus 3, treadmill 81 plus or minus 3) and heart rate-systolic pressure product (control 9940 plus or minus 564 units, handgrip 15022 plus or minus 779, treadmill 22270 plus or minus 1147). In comparing treadmill and combined treadmill-briefcase tests, significant differences were seen in systolic blood pressure (control 114 plus or minus 2 mm Hg, treadmill 143 plus or minus 3, briefcase 155 plus or minus 3), diastolic blood pressure (control 83 plus or minus 2 mm Hg, treadmill 82 plus or minus 2, briefcase 89 plus or minus 2) and rate-pressure product (control 10134 plus or minus 373, treadmill 19624 plus or minus 777, briefcase 21201 plus or minus 798). Isometric exercise alone is much less likely to produce myocardial ischemia than vigorous dynamic exercise. Higher arterial diastolic (coronary perfusion) pressure may retard the development of myocardial ischemia during isometric or combined isometricdynamic exercise in coronary patients.


A prospective study of complications after tracheostomy for assisted ventilation. A prospective study of 40 patients having elective tracheostomy for ventilatory assistance used fiberoptic bronchoscopy and radiologic examination to assess tracheal healing after extubation. Ten percent of patients had bleeding complications of tracheostomy and 17.5 percent had tracheostomy management problems. Sixteen percent of survivors had asymptomatic stomal site tracheal narrowing and 8 percent required tracheal resection for symptomatic stomal site tracheal stenosis, 16 percent had asymptomatic tracheal defects at the cuff site. Stomal healing was seen to consist of gradual stomal shrinkage, resolution of tracheitis, and approximation of divided tracheal rings. No statistically significant correlation was demonstrated between various factors operative during ventilatory assistance and subsequent tracheal healing. All patients should have routine endoscopic or radiologic tracheal assessment after-tracheostomy.


Hypersensitivity studies in popple (Aspen tree) peelers. In the course of investigation of the relationship between hypersensitivity pneumonitis and the wood industry 45 popple peelers were studied. Four roentgenograms consistent with diffuse lung disease were found. All cases were in examinees who were also dairy farmers. Questionnaires revealed no instance of clinical symptoms of hypersensitivity pneumonitis. Gel immunodiffusion studies were positive to various antigens in eight cases, but no correlation could be made with pulmonary function or chest roentgenogram abnormalities in relation to occupation. Cultures of the wood and the surrounding environment yielded thermophilic fungi as well as other known antigenic material. It is concluded that the occupation of popple peeling does not represent an increased risk of development of hypersensitivity pneumonitis.


Mortality from heart disease in coal miners. A study of 3,726 Appalachian coal miners was undertaken to determine the standard mortality ratio (SMR) for heart disease and to ascertain the effect of smoking, excess weight, and the level of physical activity on deaths due to this cause, SMR's were calculated for all forms of heart disease and also separately for ischemic heart disease. For heart disease as a whole, SMR's of 73 for working and 104 for nonworking miners were obtained. It was found in both working and nonworking miners that obese smokers had the greatest risk of dying of heart disease (SMR's of 142 and 144, respectively). In the nonsupervisory underground work categories of face, transportation, and maintenance, an increase of SMR was observed, with face having the lowest and maintenance workers having the highest SMR. Use of all men from seven Appalachian states vs all US men as a standard population tended to slightly reduce the calculated SMR's.


Echocardiographic Mimics of aortic root dissection. Echocardiograms were recorded in two patients with suspected aortic root dissection. In the first patient with a massive pulmonary embolus, a simultaneous recording of the mitral ring and posterior aortic wall created a pattern similar to true posterior aortic wall dissection; in the second patient with severe generalized atherosclerosis, thickened aortic walls recorded echocardiographically were found at autopsy to be atherosclerotic plaques. These cases emphasize the potential for the false positive ultrasonic diagnosis of aortic root dissection.


Electrocardiographic findings in brain death; description and presumed mechanism. Electrocardiogram changes and pharmacologic responses were studied in 28 cases of brain death. Cardiac activity in this condition is possibly determined by the dynamic balance between the depressant action of hypothermia and the stimulating action of the sympathetic nervous system (without any vagal or central influence). The electrocardiographic alterations are the results of this dual influence, and are probably characteristic of this condition. In the initial stage of brain death the ECG shows J waves in the terminal part of the QRS, prolongation of the QT interval and the ST-T changes; in the advanced stages, progressive showing of the heart rate and the depolarization and repolarization processes are observed (manifested by gradual accentuation of the findings mentioned above); in the terminal stage dynamic electrocardiographic changes (among them, progressive depression of sinus activity, atrial fibrillation, atrioventricular and intraventricular conduction disturbances and severe ST-T changes) appear. It is possible that additional factors, like metabolic changes and possible myocardial damage in some instances, may have some influence on the electrocardiographic pattern. Final conclusions cannot be drawn from these preliminary observations. The atropine test was found to be an efficient and simple diagnostic aid in cases of brain death.


Wolff-Parkinson-White syndrome type B with His depolarization occurring after the QRS. Further evidence that WPW-QRS is a fusion beat. His bundle electrograms were recorded in a patient with Wolff-Parkinson-White syndrome (type B) during atrial pacing studies and during the induction of premature atrial depolarization at varying coupling intervals. Early ventricular depolarization (preexcitation) occurred simultaneously with the His depolarization, suggesting that conduction occurred via both the Kent and the normal A-V nodal-His-Purkinje pathway during sinus rhythm. Atrial pacing at increasing rates showed progressive advance of the His spike into the QRS and increasing duration of the delta wave until the appearance of broad bizarre QRS complexes with prolonged P-J intervals, suggesting major, if not total, depolarization of the ventricle by the Kent pathway. PAD's induced at coupling intervals of 360, 330, and 300 msec caused progressive delay of the His bundle depolarization, with the His spike occurring after the QRS at S(1)-H intervals of 230, 265, and 325 msec, respectively, and Q-H intervals of 123, 160 and 220 msec, respectively. These findings suggest that during sinus rhythm the QRS was a fusion beat. With early premature atrial stimulation, conduction occurred solely via the Kent pathway, with conduction via the normal A-V nodal pathway encountering increasing delay. The finding of His depolarization occurring after the QRS suggests retrograde myocardial-His block, and may explain the absence of paroxysmal supraventricular tachycardias in this patient.


Electrocardiographic observations in bradycardia and tachycardia-dependent atrioventricular block. Relationship to supernormal phase of intraventricular conduction. This report describes the clinical course of a patient with bradycardia and tachycardia-dependent atrioventricular block. Bradycardia dependent A-V block (phase 4 block) was transient and precipitated by spontaneous slowing of the sinus rate, atrial and ventricular extrasystoles; The degree of slowing (critical RP interval) required to induce A-V block increased progressively over a three-day period. Bradycardia-dependent A-V block was terminated mostly by critically times spontaneous or paced ventricular escape beats, but normally conducted atrial impulses also appeared to restore A-V conduction on several occasions. The tachycardia-dependent component was manifested by an unusual fatigue phenomenon in the His-Purkinje system seen only at an atrial pacing rate of 150 per minute. These observations document the presence of both bradycardia and tachycardia-dependent A-V block in the presence of a normal H-V time and also illustrate the dynamic nature of both phase 4 block and the period of "supernormal" intraventricular conduction.


Tracheal tube cuffs and tracheal dilatation. Although tracheal tube cuffs are well known to injure the trachea, attempts to design safer cuff systems have been only partially successful. In 14 dogs, we compared three models of high residual volume, low pressure cuffs, which are considered to be among the safest. Two were air-filled cuffs -- a maintained pressure cuff and a balloon reservoir cuff -- and the third was foam-filled. Tracheal dilatation was considerably more severe with mechanical ventilation than with spontaneous breathing, but the foam cuff produced significantly less dilatation (P less than .005) than the air-filled cuffs.


Remote interpretation of chest roentgenograms. A series of 98 chest films was interpreted by two physicians on the basis of monitor display of the transmitted television signal representing the roentgenographic image. The transmission path was 14 miles long, and included one active repeater station. Receiver operating characteristic curves were drawn to compare interpretations rendered on television view of the image with classic, direct view interpretations of the same films. Performance in these two viewing modes was found to be quite similar. When films containing only hazy densities lacking internal structure or sharp margins, were removed from the sample, interpretation of the remaining films was essentially identical via the two modes. Since hazy densities are visible on retrospective examination, interpretation of roentgenograms at a distance via television appears to be a feasible route for delivery of radiologic services.


Iatrogenic arteriovenous fistula: a complication of percutaneous subclavian vein puncture. A case of iatrogenic subclavian arteriovenous fistula is reported. An intracath had been inserted percutaneously into the left subclavian vein to monitor the central venous pressure during aortic valve surgery. On the second postoperative day a thrill and continuous murmur were detected at the left subclavian region. Left subclavian arteriogram and catheterization studies confirmed the diagnosis of subclavian arteriovenous fistula. The lesion was treated surgically with satisfactory results.


Endobronchial tamponade therapy for intractable hemoptysis. The management of intractable hemoptysis, short of surgery, is poorly defined. A technique is described utilizing a bronchofiberscope and a Fogarty catheter that not only provides visualization of the source of bleeding, but also furnishes a means of controlling the bleeding. This technique can also be used through a rigid bronchoscope.


Right juxtaposition of the atrial appendages. We present an infant with right-sided juxtaposition of atrial appendages who had open heart surgery for ventricular septal defect and patent ductus arteriosus. Of 12 cases thus far reported, ventricular d-loop was observed in nine, and normal position of great vessels in four. Contrary to previous views, this condition may not be accompanied by severe conotruncal anomalies.


Severe hemolysis with a fabric-worn cloth-covered aortic valve prosthesis. A patient developed severe hemolytic anemia one year after insertion of a cloth-covered aortic valve prosthesis (Starr-Edwards No. 2320). The cloth over the three struts was disrupted but showed coverage with mostly organized collagen. Hemolysis stopped after replacement with a porcine heterograft. Fabric wear seems to augment the hemolysis in patients with cloth-covered artificial valves.


Pulmonary granulomas in a patient with pulmonary veno-occlusive disease. A patient with pulmonary veno-occlusive disease is described. Lung biopsy revealed noncaseating granulomas in conjunction with the typical vascular changes of this entity. This concurrence has not been previously described.


Interaction of rifampin and warfarin.

Interaction of rifampin and warfarin. A 72-year-old man who had been taking rifampin daily for several months was concurrently administered warfarin daily for ten weeks. During this period, the prothrombin time (PT) rose remarkably little as the dosage of warfarin was increased. With difficulty, satisfactory anticoagulation was achieved by giving warfarin 20 mg daily. On discontinuation of rifampin therapy, the PT increased significantly, and subsequent stabilization of the PT within therapeutic range required treatment with warfarin 7.5 mg daily.


Systemic-to-pulmonary artery fistula following actinomycosis. We report a case of pleuropulmonary actinomycosis in a child followed by a most unusual complication: the appearance of a systemic-to-pulmonary artery fistula in the area where the abscess was drained. Fifteen months after successful treatment with penicillin and surgical drainage, a continuous murmur was heard over the scar. Aortic angiography showed multiple connections between the intercostal arteries and the left pulmonary artery through an angiomatous lesion in the left lower lobe. This resulted in a considerable left-to-right shunt. Possible pathogenic mechanisms are discussed.


Simulated paraspinal tumor or abscess by rounded atelectasis of the lower lobe. Lower lobe atelectasis may simulate paraspinal tumor or abscess when margins of the completely collapsed lobe become rounded laterally and the inferior edge separates from the diaphragm. We believe this unusual appearance relates to (1) influence of the pulmonary ligament and (2) total collapse of the lobe to its minimum possible volume. Three cases of different etiologies are herein presented.


[Cine-angiographic determination of ventricular volumes with the help of a computer (author's transl)]. A computerised method of determining ventricular volumes from cine-angiograms in two planes was developed. The heart is divided into a large number of sections by computer analysis, the volumes being obtained from the corresponding diameters in the two planes. Using a computer markedly facilitates calculations and the results are immediately available. Data for ventricular and stroke volumes agree well with those reported in the literature.


[Ga-67 citrate scanning in the management of Hodgkin's disease (author's transl)]. 159 potential areas of involvement in 26 patients with histologically proven Hodgkin's disease were examined by Ga-67 scanning. 137 areas (86%) were correctly assessed. An uptake was noted in 29 of 48 areas with active diseases, no uptake in 108 of 111 areas without active disease (97%). Best results were obtained from scans of mediastinum and lungs, particularly for differentiating between active disease and fibrosis. Para-aortic and pelvic regions often gave false-positive results because of the elimination of the tracer substance via the large bowel. Results of Ga-67 scanning in other regions were equivalent to those obtained by other diagnostic tests. Ga-67 citrate scanning thus offers an advantageous means of determining the exact stage of the disease and therefore its treatment.


[Primary malignant nephrosclerosis (author's transl)]. Primary malignant nephrosclerosis shows a haemolytic-uraemic symptomatology and can be differentiated from secondary malignant nephrosclerosis on clinical and histological grounds. The disease was observed in 4 patients: a 25-year-old man and 3 women aged 19, 28 and 49 years. The disease is characterized by a fulminating course, malignant hypertension with progressive retinopathy, and development of progressive renal failure with subsequent irreversible anuria. In addition haemolytic anaemia or posthaemolytic states as well as consumption coagulopathy occur. In 2 cases schizozytes and in particular helmet-shaped forms could be demonstrated. On histology an obliterating necrotizing vascular change is seen which is limited to the kidneys as was demonstrated in one case by angiography. Therapeutic attempts included antibiotics, steroids, heparin, streptokinase, antihypertensive drugs, and haemodialysis. The 3 female patients died, the man survived after bilateral nephrectomy.


[Thrombotic occlusion of an arteriovenous Cimino shunt in acute pancreatitis (author's transl)]. An arteriovenous (Cimino) shunt in both right and left forearms clotted during an episode of acute pancreatitis in two patients on chronic haemodialysis. Systemic hypercoagulability (circulating fibrin monomers, shortening of r and k time in the thrombelastogram and shortening of the PTT-time) occurred in association with inhibition of fibrinolysis (prolongation of euglobulin lysis time). Localized thrombosis at the shunt is thought to be due to superimpostition of systemic hyper-coagulability on a local increase in platelet adhesiveness.


[Atypical suprarenal aortic stenosis as a cause of hypertension in young people (author's transl)]. In nine of ten hypertensive patients with "atypical" suprarenal aortic stenosis (aged 20 to 51 years, mean 28.5 years), operative treatment of the stenosis reduced blood pressure to normal. In the tenth patient, combined vascular and reno-parenchymal hypertension was effectively treated by drugs, the dosage of which could be reduced after resection. Aorto-aortic bypass was the operative procedure of choice because of its lower risk and better results than other methods. In a review of 346 cases of atypical coarcation reported in the literature, two-thirds were found to be located above or at the level of the renal arteries, causing marked hypertension. Surgical procedures and results in 136 operated cases are tabulated and discussed.


[Diagnosis and indications for surgery after blunt abdominal trauma (author's transl)]. Diagnosis aiming at early operation is the central problem after blunt abdominal trauma. Peritoneal lavage represents an important progress in diagnostic tests but it is fully informative only if the technical details (e.g. infusion of not less than 1,000 ml) are observed. Experience with 129 cases proved it to be a simple procedure with a low complication rate which can be performed also in difficult circumstances and has a high accuracy (more than 95%). It can be used also in smaller clinics with only limited diagnostic facilities.


[Transvenous cholangiography in the differential diagnosis of biliary stasis (author's transl)]. Transvenous cholangiography is an alternative to the direct puncture of the biliary tract. It was successfully performed in 13 of 21 patients of a personal series. The method does not require stand-by facilities for operation and is suitable for differentiating intra- from extrahepatic causes of biliary stasis, as well as for the demonstration of cause and localization of obstructive jaundice. Subcapsular liver haematoma with a rupture into the peritoneal cavity and bilihaemia were the main complications (one case of the former). The procedure is contraindicated in acute cholangitis and after cholangitic episodes.


[Regional pulmonary blood flow and its regulation in patients with obstructive lung disease (author's transl)]. Regional blood flow was measured in 47 patients with obstructive lung disease, using iso-intensity zone scanning after injection of 131I macro-aggregates in the supine (27 subjects) or sitting (20 subjects) position. In most of the patients there was a shift of pulmonary blood flow to the upper lung fields. The shift was related to pulmonary artery pressure and pulmonary arteriolar resistance.


[Polychemotherapy of Hodgkin's disease (author's transl)]. 204 patients with Hodgkin's disease not previously treated were given vincristine, chlormethine, procarbazine and prednisone (protocol H2-65) for six months, followed by monthly vinblastine injections. Additional prophylactic radiotherapy was given to 50 non-randomised patients. Three-monthly reinduction treatment was administered to a further 50 patients during the year following the original induction cure, afterwards only every six months, and no treatment after four years. Among 109 patients in stage III complete remission occurred in 53% and partial (incomplete) remission in 36%. Among the 58 patients in stage IV, 21 had complete and one incomplete remission. Among 37 patients in stages I and II, 33 went into remission. The remission curves reached a plateau in the 42nd month in 74 plus or minus 6% of those in complete and 56 plus or minus 8% of those in incomplete remission (P less than 0.03). Increasing age had an unfavourable prognosis: the more progressed the anatomical stage the less favourable the prognosis. Surprisingly, stage IV (lymphocyte-poor) had a better prognosis on polychemotherapy than other histological forms. Signs of clinical activity did not influence prognosis, but biochemical signs of activity are unfavourable for remission duration (P less than 0.01). Patients who also had radiotherapy had longer remissions (P less than 0.01). Exacerbations occurred in 38, never beyond the 42nd month. Recurrence occurred in 21 of them in the dame lymphatic region as was affected at the beginning of the disease, while in the other 17 patients an extralymphatic episode occurred. There was a positive correlation between histological form and type of recurrence.


[Perimembranous glomulonephritis in heapatitis associated with hepatitis B antigen (author's transl)]. Hepatitis B (HB) antigen was persistently found in two children with perimembranous glomerulonephritis. Soluble immune complexes were demonstrated in both instances. These circulating immune complexes were found only in serum fractions enriched with HB antigen. Immunohistology of sections of kidney demonstrated immune complexes in a granular pattern in the subepithelial regions of the glomerular capillary walls. Fluorescent HB antigen was found in the same region. HB antigen was also detectable in urine. Participation of the complement system in the progress of the disease was demonstrated quantitatively by a decrease in complement factors C1q, C4 and C3 in peripheral blood. Histological, including electromicroscopic, studies in both cases revealed diffuse thickening of the glomerular basement membrane with dense deposits of different extent, and spikes of the basment membrane. These studies strongly suggest an interrelationship between hepatitis with HB antigen and glomerulonephritis.


[Clinical and serological aspects of the pseudo-LE syndrome (author's transl)]. Fifteen women with pseudo-LE syndrome were studied. The dissease is characterized by recurrent attacks of fever, myalgia, arthralgia, visceral manifestations (pericarditis, myocarditis, pleurisy, pleural effusion and lung involvement). A prominent feature was an abnormal liver function with elevated GOT and GPT levels in serum, and impaired bromsuophalein elimination. The incidence of varicosities and thrombophlebitis was markedly increased. There was a correlation between complement-fixing antimitochondrial antibody (AMA) titres and the degree of activity of the disease. A reverse correlation was observed between antimitochondrial antibody titres and the absolute lymphocyte count in peripheral blood. In all instances the antimitochondrial antibodies were of polyclonal origin, belonging mainly to immunoglobulin class IgG and, in a few patients, IgM, IgA, or IgD. AMA titres, lymphocyte counts in peripheral blood, sedimentation rate, serum iron level and alpha1- and alpha2-globulins proved to be valuable in following the course of the disease. Other values (C-reactive protein, alpha1-acid glycoprotein, immunoglobulin and beta1c-globulin in serum) were not helpful.


[Value of radioimmuno-assay of triiodothyronie and thyrotropic hormone in the diagnosis of thyroid disease (author's transl)]. Results of a purely in-vitro test were compared with previously available methods in 425 patients. For triiodthyronie, a normal range must be differentiated from the so-called euthyroid range (0.8-2.0 ng/ml) for patients with euthyroid goitre. The accuracy for triiodothyronine is then more than 95% and in hyperthyroidism 97.5%. It is, therefore, superior to other in-vitro measurements. But a disadvantage is that it is easily influenced by thyroid and extrahyroid factors. Similar accuracy is obtained for the TRH function test (thyrotopine-releasing hormone). Noteable is a negative TRH test in 20% of patients with euthroid goitre. The significance of triiodoathyrone determination is decreased in autonormous adenoma, in which the TRH test has an accuracy of 96.5%. In rare diseases of the thyroid all diagnositc possibilities must be taken into account. In ordinary practice stepwise course is suggested. RT-3U, T-4, T-3 and thyroid scan with 99mTc pertechneate are useful as basic tests. PBI is still thought to be important. The second step involves the TRH test rather than 131I function test. Triiocothyronine determination is best for therapeutic and follow-up perposes, a situation in which TRH test is of limited value.


[ECG changes and serum-digoxin concentration in digitalis toxicity (author's transl)]. Seventy-six patients with clinical and ECG evidence of digitalis toxicity and serum-digoxin concentrations over 2.5 ng/ml were investigated for possible correlation between certain ECG changes and the level of serum digoxin, but no correlation was found. However, radioimmunological determination of digoxin level proved to be a reliable means of deciding whether abnormalities of impulse formation or conduction were due to digitalis. In only one case (during haemodialysis) was there a fall in potassium level below normal, with signs of digitalis toxicity electrocardiographically. In five other patients with serum digoxin levels above 6 ng/ml high potassium values were found. Caution in the administration of potassium is advised: it should be given only if it is demonstrated to be below normal. Fifty-one of the patients had impaired renal function.


[Hepatitis in drug addicts (follow-up study with biopsies) (author's transl)]. Viral hepatitis, proven by biopsy in 44 patients known to be drug addicts or confirmed drug takers had serial clinical, biochemical and (half of them) biopsy studies between 1971 and 1974. At the time of the first biopsy the period of addicition averaged 28.8 months. 30 of the 44 patients had had jaundice. At the time of the last biopsy, 20 of the 44 had chronic persisting and three had chronic active hepatitis, i.e. more than half had a chronic form. A further 12 patients had "hippie" hepatitis, a special form of acute viral hepatitis with piecemeal necrosis, histological evidence of possible change to a chronic state. There was no case of complete healing during the period of observation. The high rate of chronic hepatitis is thought to be due to partially insufficient immune response. The clinical and even biochemical course in most of the patients was remarkably mild. Severe clinical forms are rare and were not observed at all in the described group. It would therefore, seem that the prognosis is generally good, in contrast to chronic hepatitis in non-addicts.


[Termination of pregnancy on psychiatric grounds (author's transl)]. 303 psychiatric opinions were given between 1947 and 1969 regarding the termination of pregnancy. 45,2 per cent of the applications were supported, 53,4 per cent were rejected. In 10 per cent of the cases neurological disorders were present. 79 per cent of the women had psychiatric disorders among which reactive depressions had a definite majority of 89 per cent. Endogenous psychoses only represented a marginal group. Among the reactive depressive group young unmarried women in their first pregnancy with environmental conflicts and an increased readiness to express suicidal tendencies could be separated from a second group of older married women with one or more children, with fear of the future resulting from the feeling of an imminent in ability to cope, and restraint in the formulation of suicidal thoughts. The frequency of preceding suicidal attempts and the percentage of abnormal personalities were equally high in both groups. The investigated group must clearly be considered to a suicide-endangered high risk group. If abnormal personality traits, preceding suicide attempts, family and social conflicts with existing suicidal tendencies, and a reactivated state of depression occur together a reactive depression must also be considered an important criterium for a supportive attitude.


[Enzymatic determination of total cholesterol in serum: accuracy and comparison with other methods (author's transl)]. Cholesterol can be specifically measured without difficulty and without complex reagents by means of a newly developed enzymatic colour test. Intensive technical evaluation confirmed its accuracy. Manual use gave a day-to-day coefficient of variation  of 2-3 per cent; the sensitivity at a cholesterol concentration of 200 mg/dl was E equals 0.153 (gamma equals 405 nm), with a linearity up to 1000 mg/dl. Recovery of added pure cholesterol solution was 100 plus or minus 2 percent. A quantitative study of 53 representative drugs, anti-coagulants and metabolites was performed both in test tube and on patients. Accuracy of the result was unaffected by any of the substances (alpha equals 0.05). Comparison with the multi-step extraction method used at present as a reference (Abell-Kendall) gave a regression equation of y equals 0.99 times plus 1.1 (x axis: extraction method; y axis: enzymatic colour test). The direct chemical method after Liebermann and Burchard gave, in part, markedly differing results because of considerable systematic and accidental errors.


[Changes in cerebral blood flow and oxidative cerebral metabolism after extensive acute head trauma (author's transl)]. Total cerebral blood flow and oxidative cerebral metabolism were measured at normal pCO2, hypocapnia and hypercapnia in 15 unconscious patients in the acute phase after head trauma. In the basal position (normal CO2) measurements were within normal limits and did not correspond to the severity of the clinical picture. But on altering arterial pCO2 there were market changes in oxidative cerebral metabolism, which suggests an abnormal cerebral regulatory mechanism. Measurement of the same functions 14 days later indicated, on the one hand, persistence of changes, but, on the other, a return to normal of previously markedly elevated cerebral glucose uptake. Comparing cerebral blood flow and metabolism between patients who survived and those who died in the acute phase after brain damage, there were no significant differences.


[Tumour-like calcification and metastic calcification in teritary hyperparathyroidism (author's transl)]. Tertiary hyperparathyroidism in a 47-year-old woman was accompained by metastatic and "tumour-like" calcifications. The latter were characterized by tumours of different-sized calcium-containing pseudocyts, surrounded by a cell-rich tissue predominantly containing fibroblasts, histocytes and foreign-body giant cells, which in their cytoplasm contained Cossa-positive particles. Pathogenesis and aetiology of the disease are largely unknown.


[Haemodialysis in the treatment of acute boric acid poisoning (author's transl)]. 40 g boric acid was by error given instead of glucose solution to a 62-year-old man during an oral glucose test. During an 18-hour dialysis 8.32 g boric acid was eliminated, 8.6 g by forced diuresis and at least 9 g by gastric lavage. A large amount of the poison was also found in the vomitus. The most important signs of posioning were slight metabolic acidosis, total anuria for 14 hours and normochromic anaemia. There was no residual kidney damage or other effects of the poisoning.


[Carcinogenesis due to mustard gas exposure in man, important sign for therapy with alkylating agents]. Sulphur-mustard and nitrogen-mustard are known to act as carcinogens in animal experiments. A similar effect in humans was demonstrated in 245 workers previously exposed occupationally to mustard gas and followed for over 20 years. There was a statistically significant increase in malignant tumours, especially bronchial carcinoma, bladder carcinoma and leukaemia. These findings underline the need for using alkylating agents of the mustard type exclusively in the treatment of malignant neoplasms. Immunosuppression with alkylating agents in the treatment of chronic inflammatory diseases associated with a long life expectancy is no longer justified.


[Clinical experimental studies in patients with asympathicotonic hypotension]. Three patients with postural hypotension (two of the idiopathic type, one possibly due to familial dysautonomia) were found to have not only the pathognomonic postural hypotension, without rise in heart rate, cardiac output and peripheral vascular resistance, but also a similarly abnormal regulatory mechanism on ergometric stress when recumbent. There was a delayed-response to the bloodpressure fall on Valsalva a manoeuvre, and the blood volume was reduced. A combined effect of these factors explains that these patients have a more marked impairment of physical capcity than might be expected merely from the orthostatic hypotension. The actions of noradrenaline, adrenaline, phenylephrine, isoproterenol, angiotensin and tyramine on blood pressure and heart rate were different from normal. Plasma-renin activity was reduced in all three patients and could not be raised. Urinary excretion of adrenaline and noradrenaline was markedly diminished. Reactions to noradrenaline and tyramine, as well as the excretion pattern of the catecholamine metabolites suggest a disorder of active adrenaline liberation. Furthermore, different disorders of catecholamine metabolism underlie idiopathic orthostatic hypotension and familial autonomia. Therapeutic trials with fludrocortisone, beta-receptor blockers and levodopa brought improvement, but long-term results are not yet available.


[Ruptured aneurysm of the aortic sinus of Valsalva (author's transl)]. Three cases of ruptured aneurysm of the aortic sinus of Valsalva  (one each into the right atrium, right ventricle and pulmonary artery) are reported and clinical as well as haemodynamic features described. It is pointed out that the right sinus is most frequently involved, the non-coronary one only rarely, and the left one only quite exceptionally. The clinical findings depend on the size, site and direction of the rupture and its haemodynamic consequences. Rupture occurs most frequently into the right attrium or ventricle, much more rarely into the pulmonary artery or left ventricle. Cardinal clinical signs are retrosternal pain, marked shock with dyspnoea and tachycardia or rapidly progressive cardiac failure. Auscultation reveals either a continuous systolic-diastolic murmur or a holosystolic crescendo-decrescendo murmur followed by a high-frequency diastolic murmur, maximal parasternally in the second to fourth left intercostal spaces. As effective surgical treatment is available, early diagnosis is essential.


[Transoral Doppler ultrasound echography under local anaesthesia for the assessment of vertebral artery blood flow (author's transl)]. Uncalibrated flow in the vertebral arteries was registered with a bidirectional CW Doppler ultrsound apparatus. It was applied to 20 patients, results being compared with aortic arch angiograms in which the extracranial part of all four cerebral vessels was seen. In 14 the vertebral arteries had a symmetrical flow and lumen, a similar symmetrical result being obtained with the Doppler. Hypoplasia of one vertebral artery was present in two patients the distinct asymmetry being recorded by the ultrasound. Three patients with central stenosis in one subclavian artery and subclavian "steal" were found to have reverse flow by the Doppler method in the vertebral artery on the side of the stenosis. Endarterectomy was performed on the affected subclavian artery in two of these patients: post-operative vertebral ultrasound recordings demonstrated a return to physiological flow direction in both vertebral arteries.


[Prenatal diagnosis of a case of metachromatic leucodystrophy (author's transl)]. Metachromatic leucodystrophy was diagnosed from cell-free amniotic fluid (marked deficiency of arylsulphatase A) in the 20th week of pregnancy of a woman whose two previous children also had the disease. The pregnancy was immediately terminated. Subsequent amniotic cell culture also revealed a very low arylsulphatase concentration corresponding to the values found in amniotic fluid. An about four-fold increase of metachromatic material was found in the formalin-fixed brain of the aborted fetus.


Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. III. Thyroxine secretion. The effects of complete and anterior disconnection of the medial basal hypothalamus (MBH( on TSH secretion in the rhesus monkey were assessed by measuring serum thyroxine concentrations. Following complete MBH disconnection, serum thyroxine concentrations declined to 50% of preoperative control levels within 7 days. In 6 of 10 animals, thyroxine levels remained depressed throughout the postoperative observation period of 60 to 150 days. In the remainder, serum thyroxine concentrations returned to control levels after 3 weeks. Anterior disconnection of the MBH had variable effects on thyroid function. In 4 of 7 animals, serum thyroxine concentrations declined for 5 days following the operation but returned to preoperative levels within the next 3 weeks. In 2 others, serum thyroxine levels did not change while in the remaining animal thyroxine concentrations increased transiently to twice preoperative levels before returning to normal values. Thus, in the monkey, as in the rat, anterior MBH disconnection has little consistent effect on thyroid function, while complete isolation of the MBH causes a moderate decline which is most readily attributable to a decrease in thyrotropin secretion. The variations in the effects of anterior and complete MBH disconnection on thyroid function could not be confidently correlated with variations in the placement of the cuts.


Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. IV. Prolactin secretion. The effects of anterior and complete hypothalamic deafferentation on prolactin secretion in the rhesus monkey have been assessed. Complete disconnection ofthe medial basal hypothalamus (MBH) had no apparent effect on serum prolactin concentrations, in either intact or ovariectomized monkeys, nor did it diminish the stimulation of prolactin secretion induced by sodium pentobarbital anesthesia. Anterior disconnection of the MBH in intact females was also without effect on prolactin secretion. When the MBH was inadvertently damaged during the complete disconnection procedure, serum prolactin levels increased approximately 5-fold in otherwise intact animals while remaining unchanged in ovariectomized monkeys, thereby suggesting that ovarian hormones may modulate the secretion of prolactin in response to a reduction of hypothalamic inhibitory influences. In contrast, basal serum prolactin concentrations were not notably influenced by ovariectomy or estrogen administration nor were the patterns of prolactin secretion related to the phases of the menstrual cycle. The results of these studies suggest that the consequences of complete MBH disconnection on prolactin secretion are essentially the same in the rhesus monkey and in the rat, although major differences exist between these species with regard to the influence of estrogen on the production of this hormone.


Development of a radioimmunoassay for porcine relaxin using 125I-labeled polytyrosyl-relaxin. Tyrosine was incorporated into highly purified porcine relaxin employing the reagent N-carboxy-L-tyrosine anhydride. The resulting polytyrosyl-relaxin contained 1.67 mol of tyrosine per mol of relaxin, retained its original biological activity, and was readily radioiodinated to specific activities ranging from 80 to 100 muCi per mug. High affinity antibodies applicable in final dilutions ranging from 1:50,000 to 1:200,000 were developed in rabbits against unconjugated highly purified porcine relaxin. A double antibody radioimmunoassay for porcine relaxin sufficiently sensitive to routinely measure from 32 to 1000 pg of pig relaxin was developed. Using this radioimmunoassay, peripheral serum concentrations of porcine relaxin were found to be less than 1 ng/ml during early pregnancy. Serum concentrations of porcine relaxin were high during late pregnancy. The mean concentration of porcine relaxin one day before parturition was 38 ng per ml. Within a day following parturition relaxin concentrations fell to a mean concentration of 2.1 ng per ml.


Inhibition of the ovarian augmentation reaction by a chemical antiestrogen. Inhibition by antiestradiol serum of ovarian weight gain and follicular growth in hypophysectomized immature rats given FSH and hCG suggested that gonadotrophin induced endogenous estrogen secretion plays a role in the ovarian augmentation reaction. We have studied the effects of a chemical estrogen antagonist, cis-clomiphene, on ovarian weight response to gonadotrophins in hypophysectomized immature female rats. We found that this antiestrogen inhibits the ovarian response to FSH and hCG. To our knowledge, this is the first demonstration of a direct effect of a chemical antiestrogen on the ovary, a result consistent with a role for intraovarian estrogen in follicular growth.


Interaction of estrogen and gonadotrophins on follicular atresia. We have investigated folluclar atresia by giving hypophysectomized immature female rats (HIFR) diethylstibestrol or gonadotrophins with and without the chemical antiestrogen CI-628, making total counts of normal and atretic follicles greater than 125 muM in diameter, and using a simple model to analyze data. Our results show an antiatretic effect of estrogen, independent of its well-documented mitogenic effect on preantral follicles. We have also shown that CI-628 acts as an anti-estrogen to block follicular proliferation, while acting as an estrogen to inhibit atresia. In addition, we have observed an increase in atresia caused by gonadotrophins, in opposition to their estrogen-mediated positive effect on follicular growth.


Further studies on the action of prolactin on fluid and ion absorption by the rat jejunum. The influence of administration of ovine prolactin in vivo on intestinal fluid and ion transport in vitro was investigated using intact and hypophysectomized male rats. Prolactin administration significantly stimulated fluid, sodium,potassium, calcium, magnesium and chloride transport across everted jejunal sacs. The last two ions were affected less than the others. Hypophysectomy caused a significant decrease in fluid and sodium absorption, but prolactin treatment for 2 days restored normal absorption rates but not uniformly in all sacs. Prolactin action on fluid and sodium absorption showed a dose-dependent tendency, maximal stimulation resulting from administration of 1.0 to 2.0 mg prolactin daily; higher doses failed to elicit significant response. The stimulatory action of prolactin was inhibited by a simultaneous administration of vasopressin which when given alone had no effect on intestinal absorption. In the absence of glucose or in the presence of phlorizin, fluid transport was inhibited, the reduction being more dramatic in the presence of phlorizin. Similarly, either application of ouabain or partial replacement of sodium with isotonic choline chloride reduced fluid transport. Although these in vitro treatments nullified the stimulatory effects of prolactin, only phlorizin and ouabain significantly decreased sodium transport. These results suggest that the effects of prolactin on intestinal transport may be dependent on increased movement of sodium.


Induction of ovulation by LH and FSH in the presence of antigonadotrophic sera. Surges of both LH and FSH are secreted on the day of proestrus in the rat; both surges are blocked by pentobarbital (PB), WHICH ALSO BLOCKS OVULATION. The purposes of the present study were (a) to see if antisera to ovine LH or FSH would prevent ovulation from endogenously secreted rat hormones; (b) to see if exogenous ovine LH or FSH alone can cause ovulation in the presence of antiserum to ovine LH or FSH, when endogenous hormone secretion is suppressed by PB. Antisera were assessed for anti-OAAD or anti-hCG augmentation activity against ovine and/or rat pituitary hormones. (a) With respect to tests against endogenously secreted hormones, antisera to LH block ovulation, but antisera to FSH do not, regardless of their potency against exogenous hormones. (b) Antisera to either ovine LH or FSH can prevent ovulation to either exogenous ovine hormone, in relation to their ability to block LH on OAAD bioassay, but not in relation to their ability to block FSH on the hCG augmentation test. However, one antiserum to FSH, which had very low anti-OAAD activity,was able to prevent ovine FSH, but not ovine LH, from causing ovulation, suggesting that not all of the ability of exogenous FSH to cause ovulation is related to intrinsic or contaminating OAAD activity. These data suggest that LH (as defined by OAAD) is the obligatory ovulating hormone in the rat. Additional data on uteirine intralumenal water in the presence of PB blockade indicate that LH, but not FSH, can induce some estrogen secretion, but that either hormone may cause some progesterone secretion.


Effects of human chorionic gonadotropin, human interstitial cell stimulating hormone and human follicle-stimulating hormone on ovarian weights in estrogen-primed hypophysectomized immature female rats. In connection with systematic studies of steroid and peptide hormone interactions during follicular growth, we have measured ovarian weight responses to graded doses of highly purified human chorionic gonadotropin (hCG), human interstitial cell stimulating hormone (hICSH)in hypophysectomized immature female rats (HIFR) treated with diethylstilbestrol in silastic capules (desc) implanted subcutaneously. Our results are consistent with earlier reports of enhancement of ovarian weight responses to hCG and FSH. Contrary to results of similar experiments reported by others, we have found that estrogen treatment of HIFR enhanced ovarian weight response to ICSH. In addition, we report for the first time that small doses of hCG and hICSH inhibit ovarian weight responses to estrogen in HIFR. Our observations on effects of small doses of hCG and hICSH and the long-known fact that ovarian interstitial cells are stimulated in HIFR given similar doses of these hormones lead us to hypothesize that ovarian interstitial cell stimulation is involved in the control of follicular maturation.


Characterization of rat chorionic mammotropin. A placental lactogen or chorionic mammotropin (rCM) has been identified in the serum of pregnant rats by radioreceptor assay (RRA). Two peaks of activity were found, the first between days 11-13 and the second between days 17-21 of pregnancy. Gel filtration of day 12 serum or placental extracts revealed two peaks of lactogenic activity, the first eluting ahead of and the second appearing immediately after 125I-hPRL (human prolactin). On the other hand, when serum or placental extracts from day 17-21 pregnant rats were fractionated in the same manner, only a single peak of lactogenic activity was eluted after 125I-hPROL. The placental concentration of rCM increased from 11 mug/g wet weight at day 12 to 74 mug/g at days 14-15, after which the concentration declined to 29 mug/g on day 21. Electrophoresis of a fraction from G-100 column of a day 12 0r day 20 placental extract or serum with a V-e/V-o ratio of 2.08 revealed a single peak of lactogenic activity by RRA with an Rf equal to 0.43. Large MW rCM (V-e/V-o ratio of 1.35) from serum had an Rf equal to 0.52 whereas the large MW species from placental extracts had a mobility similar to that of small MW fraction. The half-time disappearance rate of serum rCM on day 12 is 19.5 min compared to 1.2 min on days 17-21 of pregnancy.


The importance of the stomach in gastrin-induced hypocalcemia in the rat. Hypocalcemia following gastrin administration occurs in thyroparathyroidectomized (TPTX) as well as thyroid intact rats. Hypophosphatemia does not accompany the hypocalcemia induced by gastrin. These data suggest that a mechanism other than release of calcitonin from the thyroid gland may be involved in this response in the rat. Neither adrenalectomy, nephrectomy, nor excision of the pancreas and small and large intestine altered the hypocalcemic response to gastrin. Gastrectomy, however, eliminated all hypocalcemia following administration of this polypeptide in both thyroid intact and TPTX rats. Removal of the antrum of the stomach did not influence the hypocalcemic response to gastrin. Resection of the proximal 75% of the stomach, however, inhibited the hypocalcemic response to gastrin as did total gastrectomy. Thus, in the rat, the proximal stomach appears to play an important role in mediating this response.


Delta5,3beta-hydroxysteroid dehydrogenase activities in rat trophoblast and ovary during pregnancy. Delta5,3beta-Hydroxysteroid dehydrogenase (3beta-HSD) activity has been measured in homogenates of ovary and trophoblast from 9th to 21st day pregnant rats under conditions where there was little or no further metabolism of the progesterone formed from pregnenolone. Trophoblast 3beta-HSD activity is first detectable on the 11th day of gestation; the specific activity peaks on the 13th day, and falls thereafter. The ovary enzyme activity rises gradually to the 19th day and falls on the 21st day. Decidua homogenates contain very low levels of 3beta-HSD activity, while embryo and yolk sac homogenates do not posses significant amounts. Total 3beta-HSD activities were also determined on a per conceptus basis. At no time during pregnancy does the total trophoblast 3beta-HSD activity exceed 40% the activity of the ovary. This may explain why the progesterone-producing capacity of trophoblast in the rat is inadequate to support normal pregnancy following ovariectomy. The temporal patterns of trophoblast and ovary 3beta-HSD activity suggest that the enzymes are not coordinately controlled in the two tissues.


The iodine requirement and influence of iodine intake on iodine metabolism and thyroid function in the adult beagle. Various aspects of iodine metabolism were studied in adult beagles maintained at iodine intake levels ranging from 480 to 20 mug/day. On the basis of changes in radioiodine metabolism, the minimum daily iodine requirement of the adult beagle was found to be 140 mug. Although striking changes were observed in radioiodine metabolism when iodine intake was reduced to 90mug/day, serum T4 and T3 levels were unaffected. Marked reductions in serum T4 occurred in dogs restricted to an iodine intake of 50 or 20 mug/day, but even at these low levels of iodine intake there were only slight reductions in serum T3 concentration and a eumetabolic state was maintained. Prolonged iodine deficiency (8-12 months) resulted in variable patterns of thyroid histology, which were related to differences in thyroidal 127I content and in the rate of release of radioiodine from the thyroid. The heterogeneity in thyroid morphology and iodine kinetics did not, however, have a significant effect on serum T4 and T3 levels.


Failure of the metopirone (Su4885) suppressed fetal adrenal glands to maintain corticosterone concentration of adrenalectomized pregnant rats. Plasma corticosterone concentrations were measured following adrenalectomy of pregnant rats on the last day of gestation. Plasma corticosterone concentrations decreased 40 and 60 min after adrenalectomy by 36 and 32%, respectively, and regained the preoperative concentration 2 h following operation. When the fetuses were injected with an inhibitor of 11beta-steroid hydroxylase (Su4885) plasma corticosterone concentrations decreased 40, 60 and 120 min following adrenalectomy by 63, 67 and 71%, respectively. The results strongly suggest that the fetal adrenal glands are the source of plasma corticosterone in adrenalectomized pregnant rats.


Suppressed plasma renin activity in adrenal regeneration hypertension. To clarify the role of the enucleated adrenal in the suppression of plasma renin activity (PRA) in adrenal regeneration hypertension (ARH), PRA response to furosemide administration was compared at the 9th experimental week in three groups of rats, which had been subjected to (a) sham operation (control), (b) unilateral nephrectomy, (c) unilateral nephrectomy plus contralateral adrenal enucleation, and given on tap water or high sodium intakes. Urine volume and sodium, and changes in body weight and hematocrit, determined 90 min after administration of furosemide, did not show any significant differences among any of the experimental groups. The basal PRA was significantly decreased in rats of the other groups as compared to the control rats drinking tap water. A decrease in basal PRA was much more pronounced in the unilaterally nephrectomized rats with or without an enucleated adrenal, drinking saline. After furosemide administration, PRA significantly increased in the control rats drinking saline as well as in the unilaterally nephrectomized rats drinking tap water, with or without an enucleated adrenal, but the PRA values in these three groups were only half those of the control rats drinking tap water. An insignificant increase in PRA was found in unilaterally nephrectomized (plus or minus enucleation) rats drinking saline. These findings suggest that the lack of a PRA response in ARH may be due to the pronounced suppression of the juxtaglomerular cells caused by a high sodium intake and the reduction of the renal mass, independently of the corticosteroid(s) secreted by the enucleated adrenal.


Studies in osteoporosis: the long-term effect of oophorectomy and of ammonium chloride ingestion on the bone of mature rats. Adult female rats were subjected to a prolonged period of observation after oophorectomy. The oophorectomized animals and their controls were given a regular diet  ad lib and water or ammonium chloride as their drinking fluid. Oophorectomy did not result in reduced bone density, fat free weight, total ash weight, or calcium content of the bone, thus failing to produce the changes of osteoporosis. Ammonium chloride ingestion caused significant decreases in the same parameters equally in normal and oophorectomized rats. Thus, oophorectomy neither leads to changes of osteoporosis, nor increases the sensitivity of the bone to ammonium chloride-induced osteoporosis.


Characteristics of the prolactin stimulation of uridine metabolism in mammary gland explants. Experiments were carried out to characterize the prolactin stimulation of labeled uridine uptake into mammary gland explants which were initially preincubated for 2 days in medium containing insulin plus hydrocortisone. Prolactin was found to enhance labeled uridine uptake after 4 h but not after 2 h when uridine concentrations ranging between 0.1 muM and 1 mM were tested. The effect of prolactin on labeled uridine uptake also appears to require ongoing RNA and protein synthesis since incubation with a variety of inhibitors of RNA and protein synthesis abolished the prolactin effect. It was further discovered that prolactin  stimulates the labeling of the cellular pools of the phosphorylated derivatives of uridine while the quantity of label present in the uridine and uracil pools was not affected. It is thus possible that the effect of prolactin on labeled uridine uptake may be caused by the enhanced phosphorylation of the uridine. It was also found that the onset of the effect of prolactin on the  phosphorylation of uridine to UTP was not different from the onset of the effect of this hormone on labeled uridine uptake and its incorporation into RNA. Additional studies were carried out to determine if the effect of prolactin on RNA synthesis could be dissociated from its effect on the uptake of precursor substances. For this purpose the effect of prolactin on the uptake of radiolabeled phosphate and its incorporation into RNA was studied. Prolactin stimulated the incorporation of phosphate into RNA after 4 h  but the uptake of phosphate was not affected by the hormone at that time. Further, the effect of prolactin on phosphate incorporation into RNA was temporally identical to the hormonal effect on the incorporation of 3H-uridine into RNA.


Influence of adrenal enucleation of plasma renin substrate concentration in saline loaded and unilaterally nephroadrenalectomized rats. The influence of adrenal enucleation on plasma renin substate (PRS) concentration was investigated by comparison with sham operation (control) or adrenalectomy in unilaterally nephroadrenalectomized rats given 1% saline for drinking. Two days after adrenal enculeation or adrenalectomy, a significant increase in plasma renin activity (PRA), with a concomitant decrease in PRS, was observed. Those changes were less pronounced in adrenal enucleated rats than in adrenalectomized ones. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level at 10 days after adrenal enucleation without increasing further, while that in the adrenalectomized rats remained low as before. These results suggest that the fall in PRS occuring immediately after adrenal enucleation may be due both to enhanced PRS consumption resulting from increased PRA and to diminished PRS production caused by corticosteroid deficiency, and that restoration of corticosterone secretion by the enucleated adrenal gland may account for recovery of PRS.


Effects of C21 steroids on sex accessory organs and testes of mature hypophysectomized rats. Adult hypophysectomized male rats were treated with 2 mg/day of testosterone propionate, pregnenolone, 17alpha-hydroxypregnenolone, progesterone or 17alpha-hydroxyprogesterone. The treatment commenced on the day of surgery and was continued for 4 weeks. In all steroid treated animals, spermatogenesis was qualitatively maintained. Sex accessory organs were maintained only in testosterone propionate treated animals. In C21 steroid-treated rats the sex accessory organs showed atrophy similar to untreated hypophysectomized animals suggesting lack of peripheral conversion to androgens. However, administration of 3H-pregnenolone with the last injection of pregnenolone resulted in the isolation of a considerable amount of 3H-testosterone from testicular tissue of the experimental animals. This finding suggests that maintenance of spermatogenesis in pregnenolone treated animals could have been due to testosterone formed in the testes from the exogenously administered pregnenolone.


Effect of frequency of administration on the accumulation and metabolism of (35S) propylthiouracil by the rat thyroid. Repeated administration (every 8 h) of (35S) Propylthiouracil (PTU) resulted in gradual accumulation of unmetabolised PTU by the thyroid gland until the 9th dose was given. Subsequently a plateau-level was attained which was proportional to dose with the two dose levels used. During repeated administration once daily the intrathyroid concentration of free PTU varied markedly in the course of each 24-h period. Chromatographic analysis showed four compounds: PTU, sulphate and two unidentified compounds as well as origin material. The proportions of these compounds were different in the different dose studies. Thus, the ratio of compound Y/compound X was found to be inversely related to dose. The plasma 35S-radioactivity increased throughout the studies and was proportional to dose.


Blockage of cortical spreading depression by picrotoxin foci of paroxysmal activity. 1 per cent Picrotoxin placed on cortex of rat caused paroxysmal ECoG discharges with concomitant increase in [Ke"] from 3 to 6.7 mM with oscillations corresponding to ictal (maximum) and interictal (minimum) spiking. Invasion of the epileptogenic focus by spreading depression was blocked when the amplitude of oscillations of [Ke+] reached 2.6 mM. Epileptogenic activity induced by topical 10 per cent pentazol caused a less marked increase in [Ke+] (4.6 mM) and did not prevent depression from invading the focal area, but did diminish [Ke+] from the normal of 60 to 70 mM to 39 mM. It is concluded that seizure-induced depolarization  of neural elements in deep cortical layers, though inadequate to trigger spreading depression, does prevent it from spreading, in part by activating the sodium pump.


The prognostic implications of suppression-burst activity in the EEG in infancy. Thirty-nine children, seen between 1960 and 1973, showed suppression-burst activity in their original EEG recordings. Follow-up information was available for 19 girls and 10 boys. Suppression-burst activity was seen at a mean age of 4 months. Most of the children (86 per cent) had infantile spasms, and 96 per cent were severely retarded on presentation. Fifteen died (52 per cent), 9 of them before the age of 2, and all had severe retardation and neurological abnormalities. Of the 14 survivors, only 1 attends a normal school (she was only mildly retarded on presentation), 71 per cent are severely retarded, 71 per cent have neurological abnormalities, and 60 per cent continue to have fits. Although hypsarrhythmia itself is not necessarily associated with a bad prognosis, the finding of suppression-burst activity certainly implies a grave outlook.


Benign epilepsy of children with centro-temporal EEG foci. Discharge rate during sleep. The discharge rate (the number of spikes/min) was determined in the awake state and during different stages of induced sleep in 17 children with "benign epilepsy of childhood with centro-temporal EEG foci". Ten patients had seizures only during sleep. The discharge rate of Rolandic spikes was significantly higher during sleep than during the awake state, and 5 patients had Rolandic discharges only during sleep. For diagnostic purposes, EEG recordings during sleep are indicated when children suspected of having this seizure type have a normal EEG when awake. Brief induced sleep is usually adequate. REM sleep was not studied.


Idiosyncratic reactions to the antiepileptic drugs. Idiosyncratic drug reactions can be defined as those adverse drug effects caused by genetically determined enzymatic abnormalities. For the clinician, however, this definition is too limited, and other rare and unusual adverse reactions to the antiepileptic drugs are discussed, including drug interactions, drug allergies, and organ toxicities, as well as true idiosyncrasies. Responsibility for initial recognition and later diagnosis of these reactions falls heavily upon the clinician. In addition to discussing the more common or serious rare reactions, the epidemiology and general mechanisms underlying the reactions are discussed. Treatment involves drug withdrawal, plus general supportive and specific therapy determined by the type and severity of the individual reaction. If primum non nocere should guide the treatment in general, then secundum non plus nocere should guide the treatment of adverse drug reactions.


The effect of early versus late onset of major motor epilepsy upon cognitive-intellectual performance. Performance on the Wechsler Adult Intelligence Scale and Halstead neuropsychological measures were investigated in two groups of adult subjects with major motor epilepsy of early (0 to 5 yr) and later (17 to 50 yr) onset, and in two groups with early and later onset of brain damage without epilepsy. The two groups with early onset earned poorer scores on most tests than did the two groups with later onset. The findings suggest an adverse effect of cerebral dysfunction of early onset, whether accompanied by major motor seizures or not. Subjects with early onset of major motor seizures scored significantly lower on 9 of 14 measures than subjects in any other group, none of which showed significant intergroup differences in the dependent variables employed. The results support the conclusion that early age of onset of major motor seizures is more apt to result in impairment of mental abilities in adult life than is later onset of seizures or early or late onset of brain damage uncomplicated by epilepsy.


Dipropylacetic acid (Depakine) in experimental epilepsy in the alert cat. The effect od dipropylacetic acid (DPA; Depakine) on the bemegride-induced convulsive threshold was investigated in alert cats. Forty-five min after DPA 200 mg/kg, s.c., no significant effect was obtained; 5 min after the same dose iv., protection from bemegride-induced seizures was pronounced. DPA did not decrease focal discharges in sensorimotor cortex produced by topical cobalt, although spread of epileptogenic activity from the focus was inhibited. DPA antiepileptic protection tested by the same procedure was about the same as that given by phenobarbital and less than that given by diazepam.


Extracellular release of cerebral macromolecules during potassium- and low-calcium-induced seizures. Cerebral cortex of cat was incubated with 14C-lysine and 3H-glucosamine. Subsequent superfusion of the surface of the cortex resulted in the release into the superfusate of a variety of 14C- and 3H-labeled compounds including proteins, glycoproteins, and gangliosides. The release of 14C- and 3H-labeled macromolecules could be considerably enhanced by topical addition of 40 mM K+, WHICH INDUCED Epileptiform EEG activity. Peaks in efflux could also be correlated with the onset of seizures induced by superfusion with low (0.75 mM) Ca2+ media. Control experiments in which the cortex was prelabeled with 14C-carboxyl-inulin and 3H2O indicate that the release of macromolecules was not a direct consequence of the altered blood flow that may occur during convulsions.


Debranching enzyme from rabbit skeletal muscle. Purification, properties and physiological role. Debranching enzyme was purified 150-fold from rabbit skeletal muscle by a three-step procedure which utilised ammonium sulphate precipitation, ion-exchange chromatography on DEAE-cellulose and "hydrophobic" chromatography on Sepharose-NH(CH2)4NH2. The preparation was completed within three days, and 200 mg enzyme was isolated from 1000 g muscle, which represented an overall yield of 60%. The preparation was homogeneous by the criteria of polyacrylamide gel electrophoresis and ultracentrifugal analysis. The sedimentation coefficient, s20,w, was 8.1 S. The amino acid composition was determined, and the absorption coefficient, A280 1%, measured refractometrically was 17.5. The subunit molecular weight determined by gel electrophoresis in the presence of sodium dodecyl sulphate was 166000 and this value was supported by sedimentation equilibrium in the presence of 6 M guanidinium chloride (1550oo). The molecular weight of the native enzyme measured by high-speed sedimentation equilibrium was 164000, showing that the debranching enzyme is a monomeric protein at the concentrations which exist in muscle (0.7 mg/ml). The results indicate that the two different enzyme activities which are associated with debranching enzyme, 1,4-glucan-4-glycosyltransferase and amylo-1,6-glucosidase, reside on the same polypeptide chain. Protein-glycogen particles isolated from skeletal muscle showed seven major protein-staining components by polyacrylamide gel electrophoresis, one of which was identified as debranching enzyme. ,our of the other components were the alpha and beta subunits of phosphorylase kinase, glycogen phosphorylase and glycogen synthetase. A new titrimetric assay for debranching enzyme was developed; it was used to demonstrate that the maximum potential activity of debranching enzyme is only 5--10% that of phosphorylase at the concentrations of the two enzymes in skeletal muscle. Since the activity of debranching enzyme is unaffected by every mechanism which leads to the activation of glycogen phosphorylase and phosphorylase kinase, the evidence suggests that the hormonal control of muscle glycogenolysis by adrenalin might be confined to a stimulation of rate of degradation of the outermost branches of glycogen.


Microsomal 12alpha-hydroxylation of 7alpha-[12alpha, 12beta-2H2]hydroxy-4-cholesten-3-one. The synthesis of 7alpha-[12alpha, 12beta-2 H2]hydroxy-4-cholesten-3-one is described. It was shown with different techniques that this compound was 12alpha-hydroxylated by the microsomal fraction of a rat liver homogenate without marked isotope effect, indicating that cleavage of the C--H bond is not the rate-limiting step in this hydroxylation. The rate of 12alpha-hydroxylation was decreased by about 20% when performed in a medium containing deuterated water. The findings were discussed with reference to the specific properties of the 12alpha-hydroxylating system and to the results of previous studies on rate-limiting step in microsomal hydroxylation of steroids.


Kinetic studies dealing with an immobilized bienzyme system. The binding of enzymes into artificial membranes makes possible a study of the interaction between membrane structure and enzyme kinetics within a simple context. Artificial protein membranes bearing a bienzyme system (xanthine oxidase, uricase) are produced by using a co-crosslinking method. The inhibition of uricase was shown to be dependent not only on the concentration of inhibitor in the bulk solution, but also on the kinetic properties of the membrane-bound enzymes. In the presence of xanthine oxidase inside the structure the uricase inhibition by xanthine is less important than in solution. Under defined conditions the activity was found to be higher in the presence of inhibitor than in its absence. Due to diffusion limitations this specific bienzyme system is more efficient when immobilized inside a membrane than when in solution.


Extracellular enzyme system utilized by the fungus Sporotrichum pulverulentum (Chrysosporium lignorum) for the breakdown of cellulose. 2. Activities of the five endo-1,4-beta-glucanases towards carboxymethylcellulose. A complementary discussion is given of an earlier presented theory for viscometric determination of enzymic activity towards polymer substrates. Five different, purified endo-1,4-beta-glucanases from the fungus Sporotrichum pulverulentum have been characterised with respect to their molecular activities(Am) and Michaelis-Menten constants (Km). The errors in the Am and Km values are discussed. The Am value seems to be more valuable as a distinguishing parameter than the Km value.


Structure-activity relationship in the urokinase hydrolysis of alpha-N-acetyl-L-lysine anilides. The absence of both nonproductive binding and substrate activation and also the good solubility of the substrates make the urokinase-catalysed hydrolysis of specific anilides a very suitable reaction for substrate structure-enzyme activity studies. Derivatives of alpha-N-acetyl-L-lysine anilide with high sigma minus-value substituents in the aniline ring were synthesized. Rate constants kappa-cat. and apparent Michaelis-Menten constants K-m (app.) are presented. From the substituent dependence of kappa-cat. and from the fact that kappa-cat. is 13 to 37 times smaller than the deacylation rate constant it is concluded that the rate-limiting step proceeds prior to deacylation. The catalytic rate constant kappa-cat. obeys a linear free-energy relationship of the Hammett type with Q equals +0.72. Two different mechanisms implied by the results obtained from the model reaction (specific base and general acid-base catalysed hydrolysis of N-acetylglycine anilides under extreme conditions) are proposed in order to account for this positive and low Q-value. In the first mechanism the breakdown of an enzyme tetrahedral intermediate is rate-limiting, while in the second one its formation controls the overall rate. The discrimination between the two mechanisms, however, could not be found.


Translation of mRNA for 3,4-dihydroxyphenylalanine decarboxylase isolated from epidermis tissue of Calliphora vicina R. -D. in a heterologous system. Dependence of mRNA concentration on the insect steroid hormone ecdysone. RNA was isolated from the epidermis of Calliphora vicina larvae by phenol--chloroform extraction. The RN A sedimenting in sucrose gradients between 5 and 18 S was submitted to chromatography on oligo(dT)-cellulose columns. The fraction binding to the oligo(dT) is able to stimulate protein synthesis in a system consisting of mouse liverribosomal subunits, pH-5 factors from rat liver and initiation factors from rabbit reticulocytes. Optimal Mg2+ concentration for the translation of insect mRNA is 3.5 mM, that of K+ 76 MM. Initiation factors prepared from epidermis of Calliphora larvae are less efficient in the translation of insect mRNA than initiation factors isolated from reticulocytes. The pH-5 fraction from epidermis inhibits protein synthesis independent of the source of the mRNA fraction used. One of the proteins synthesized in the reconstituted system under the direction of insect mRNA has been identified as 3,4-dihydroxyphenylalanine (DOPA) decarboxylase by immunoprecipitation with specific antiserum against DOPA decarboxylase and comigration in dodecylsulphate-acrylamide electrophoresis with pure DOPA decarboxylase. Both mRNA from white prepupae and from 6--7-days-old larvae contain sequences coding for DOPA decarboxylase. However, white prepupae contains 3--4 times more DOPA decarboxylase-mRNA than 6--7-days-old larvae. The content of DOPA decarboxylase mRNA is proportional to the amount of active DOPA decarboxylase molecules present in the animals from which the mRNA was isolated.


The amino-acid sequences of three cystine-free cyanogen-bromide fragments of human serum transferrin. The amino acid sequences of three fragments obtained on cyanogen bromide cleavage of human transferrin have been determined. Two of the fragments are small (4 and 7 residues) and had not been isolated in previous studies of the CNBr fragments of transferrin. The sequence of the larger fragment (53 residues) was elucidated by examining peptides isolated from digests of the fragment with trypsin, chymotrypsin or thermolysin. This region of transferrin appears to contain the sites of three previously-reported substitutions in the D1 and D-chi genetic variants.


Conformational changes in fibrous elastin due to calcium ions. A column packed with calcium-free bovine aorta elastin provided good separations of mixtures of bile salts when water was the moving phase. Tritium-labelled cholesterol was applied to the column using dilute solutions of taurodeoxycholate in Tris-NaCl buffers as solvent. The cholesterol was quantitatively eluted as a narrow peak in a rising gradient of taurodeoxycholate. When Na+ in the buffer was replaced by Ca2+ elution of the labelled cholesterol was delayed. Control experiments in which the elastin fibres were replaced as the column packing by an inert stationary phase consisting of n-butanol immobilized by silane-treated Celite showed that the effect of the change from Na+ to Ca2+ on the solvent properties of taurodeoxycholate was small and in the opposite direction. The experiments indicated that the replacement of sodium by calcium as the ionic environment of fibrous elastin produced a configurational change towards increasing hydrophobic character.


The hormonal control of activity of skeletal muscle phosphorylase kinase. Phosphorylation of the enzyme at two sites in vivo in response to adrenalin. Phosphorylase kinase was activated 5--10-fold in vivo by an intravenous injection of adrenalin. Sodium fluoride an inhibitor of phosphorylase kinase phosphatase, was required to prevent the reversal of this process; the activated and non-activated forms of the enzyme were indistinguishable by dodecylsulphate gel electrophoresis. This suggested that the activation had resulted from a phosphorylation of the enzyme, and that it was not a consequence of the well known activation by proteolytic cleavage that can be demonstrated in vitro. Phosphorylase kinase activated in vivo was purified and digested with trypsin, and the two tryptic peptides which contain the serine residues which are phosphorylated in vitro by the action of cyclic-AMP (adenosine 3':5'-monophosphate) dependent protein kinase, were isolated. It was found that the same nine-amino-acid segment of the beta chain and the same seven-amino-acid segment of the alpha chain had become phosphorylated in vivo in response to adrenalin, as were phosphorylated in vitro. The degree of phosphorylation of each of the two sites was at least 50%. The data provide direct proof that the activation of phosphorylase kinase which occurs in vivo in response to adrenalin results from a phosphorylation of the enzyme. They also indicate that the novel form of regulation associated with the phosphorylation of the alpha subunit, the stimulation of protein dephosphorylation by "second site phosphorylation", can now be regarded as a new form of enzyme control mechanism which operates in vivo. The regulation of phosphorylase kinase activity was studied in the protein - glycogen complex from skeletal muscle. The enzyme could be rapidly converted to a phosphorylated form in a cyclic-AMP-stimulated reaction upon addition of magnesium ions and ATP, but the conversion of phosphorylase b to phosphorylase a in the complex still showed an absolute requirement for calcium ions. The implications of these findings and major problems in the hormonal control of skeletal muscle glycogenolysis which are not yet resolved, are discussed.


Canalicular bile production in man.

Canalicular bile production in man. Bile flow, erythritol clearance (measured after administration of 14-C-erythritol) and bile acid excretion were studied in 8 non-icteric patients operated upon for gallstone disease without biliary obstruction in whom a T-tube had been inserted. Bile flow increased from the 2nd (0.27 plus or minus SEM 0.01 ml/min) to the 7th (0.50 plus or minus SEM 0.05 ml/min) postoperative days and remained stable thereafter. Because the values obtained between the 7th and the 15th postoperative days (average: 0.46 plus or minus SEM 0.02 ml/min) were not lower and were of the same order of magnitude as those previously reported in the literature for quantitative bile collections, it was assumed that bile collection had been complete. Bile-to-plasma concentration ratio of erythritol was 0.77 plus or minus SEM 0.04. The regression line between erythritol clearance and bile flow had a slope of 0.99 (indicating that increments in clearance were followed by equivalent increments of flow) and an intercept for a zero-clearance of 0.11, suggesting a ductular/ductal secretion of 0.11 ml/min. The relationship between erythritol clearance and bile acid excretion suggested that canalicular bile was formed both of a bile acid-dependent flow (11 mul of water being excreted per mumol of bile acid secreted) and a bile acid-independent flow of 0.16 ml/min (or 35 percent of the average bile flow). These findings indicate that erythritol clearance provides a valid estimate of canalicular bile flow in man and that the three bile fractions previously postulated in animals (canalicular bile acid-dependent, canalicular bile acid-independent and ductular/ductal) may also be present in man.


Studies on urea cycle enzymes in rat liver during acute uraemia. Activities of urea cycle enzymes were measured in the liver of starved rats 12 and 48 h after bilateral nephrectomy. Control experiments (sham-operated, starved rats) revealed that the activities of only two enzymes of the cycle are altered in the uraemic state: argininosuccinic acid synthetase (EC 6.3.4.5.), which is considered to be rate limiting for urea production and carbamyl phosphate synthetase (EC 2.7.2.5.). Alterations in ornithine concentration of the liver, a possible cause of an increased urea production rate, could not be detected previously (21). Our present results do not support the concept that a decrease of the activity of ornithine-delta-amino transferase (EC 2.6.1.13), leading to an increase in the ornithine content of the liver is responsible for the accelerated urea production rate in the liver of acute uraemic rats.


Liver inclusions in erythropoietic protoporphyria. Needle-like inclusions have been found, by electron microscopy, in the livers of two unrelated patients with erythropoietic protoporphyria. Since they have not been noted in other hepatic conditions but do occur in the livers of protoporphyric mice it is suggested that they represent markers for protoporphyric liver disease. Paracrystalline inclusions that have been previously described in Wilson's disease and porphyria cutanea tarda were also present in the hepatocytes of one of these patients.


Effect of cholesterol feeding on cholesterol biosynthesis in maternal and foetal rat liver. Hepatic cholesterol biosynthesis has been studied in rat foetuses whose mothers had been fed on a cholesterol rich diet during the last week of gestation. Foetal liver was found to be capable of synthesizing cholesterol from acetate in vitro. The rate of incorporation of labelled acetate into digitonin precipitable sterols, fatty acids and CO(2) in foetal liver was much higher than that found in maternal liver. Cholesterol feeding reduced the rate of sterol synthesis in maternal liver but it did not have any appreciable effect on foetal liver. In order to investigate whether this lack of feed-back control in foetal liver could be attributable to an obstacle to the placental transfer of dietary cholesterol. 14-C-cholesterol was administered to the pregnant rats and its distribution in maternal and foetal liver and plasma was studied. Our results indicate that placental transfer of cholesterol from mother to foetus occurs very slowly so that only a small proportion of labelled cholesterol is found in foetal plasma over a 48 hour period following the administration of radioactive cholesterol. Cholesterol transferred from the mother into the foetal plasma is efficiently taken up by the foetal liver. These findings would suggest that the low amount of dietary cholesterol transferred from the mother into the foetal plasma is not sufficient to activate the control mechanism of the cholesterol biosynthetic pathway in the foetal liver.


Therapeutic use of transfer factor.

Therapeutic use of transfer factor. Transfer Factor (TF) was produced by ultrafiltration of repeatedly frozen and thawed, pooled buffy coats of healthy blood donors. One unit of TF Zürich was defined as the cell extract originating from 1 - 2 x 10-9 leucocytes. In collaboration with physicians and immunologists, 409 units TF have been given to 45 patients. Besides local pain and occasional fever no side effects were observed. Immune conversions and beneficial clinical effects were seen in 11 and 10 patients, respectively, out of 12 patients with chronic candidiasis. Immune conversion was also observed in patients with multiple sclerosis, while the clinical effects cannot yet be judged. The series also included patients with subacute sclerosing panencephalitis, HBAg-positive disorders, various immunodeficiency diseases, malignant malanoma and miscellaneous tumours. Immune conversion occurred only occasionally and the clinical effect was either non-existent or not judgeable. In the discussion the results of other investigators using TF therapy are included.


Changes in insulin immunoreactivity across the coronary circulation in man during infusions of glucose and a fat emulsion. The extraction of immunoreactive insulin by the human heart has been examined using the technique of coronary sinus catheterisation. The subjects were 12 male volunteers. During the study infusions of a fat emulsion and glucose were given in an effort to create a "steady fed state". The higher arterial insulin immunoreactivities which were observed during the infusions were associated with greater arterial coronary sinus differences in insulin immunoreactivity. The possibility of insulin degradation by the heart is discussed. During prolonged exercise the process of insulin removal by the heart appeared more active.


Collagen biosynthesis in normal human skin, normal and hypertrophic scar and keloid. A comparison of the rates of synthesis of collagen in normal skin, normal and hypertrophic scars, and keloids has been made by measuring the rate of incorporation of [14-C]-proline into peptide-bound [14-C]-hydroxyproline by tissue minces in vitro. The rate of synthesis of collagen, as measured by this technique, was significantly higher in skin than in normal scars whether the incorporation of radioactivity into hydroxyproline were expressed in terms of wet weight of tissue, weight of tissue DNA or weight of tissue hydroxyproline. The abnormal scar types exhibited similar rates of collagen synthesis, which were significantly higher than the rate in normal scars. Although the rates in both abnormal scar types appeared to be similar to that in normal skin when expressed in terms of wet weight of tissue, and weight of tissue hydroxyproline, they were seen to be lower than in skin in terms of weight of tissue DNA. The rate of synthesis of proteins generally, as measured by total radioactivity in non-diffusible peptides, was highest in normal skin and hypertrophic scar and lowest in keloid. The ratio of radioactivity in non-diffusible hydroxyproline to total non-diffusible radioactivity was almost twice as high in keloid as in normal scar, with intermediate values being observed in hypertrophic scar and normal skin. This indicated that collagen accounted for a higher proportion of the proteins being synthesised in keloid than in normal scar. The results confirm previous conclusions, from determination of the activity of the enzyme collagen proline hydroxylase, that the excessive accumulation of collagen in hypertrophic scars and keloids may, at least in part, be due to abnormally high rates of collagen synthesis in comparison to normal scars.


Insignificance of gluconeogenesis in human blood platelets. Human blood platelets contain no detectable activity of the enzymes fructose diphosphatase (EC 3.1.3.11), phospho-enolpyruvate carboxykinase (EC 4.1.1.32) and pyruvate carboxylase (EC 6.4.1.1.). Glucose-6-phosphatase (EC 3.1.3.9) activity is very low. Phosphofructokinase present in human blood platelets, catalyzes a reaction which can be stimulated by AMP in a platelet homogenate, due to the presence of endogenous ADP and myokinase. These enzymes are responsible for the formation of fructose-6-phosphate from fructose-1, 6-diphosphate. Pyruvate kinase (EC 2.7.1.40) in human blood platelets belongs to the M-type, which is not inhibited by ATP, at least not under the conditions applied. The results obtained indicate that gluconeogenesis in human blood platelets is not present in the way which has been established for liver and kidney.


Histamine receptors in the synovial microcirculation. This study was designed to investigate the respective roles of H(1) and H(2) receptors in the control of the microcirculation by examining the effectiveness of the H(2) receptor antagonist metiamide (Met.) and H(1) receptor antagonist mepyramine is blocking the action of histamine on synovial perfusion. Synovial perfusion was monitored indirectly by calculating the half-life (T1/2 min.) of the clearance rate of 133-Xe from canine diarthrodial joints. The 133-Xe clearance rate, unaffected by metiamide alone, was consistently increased by histamine alone. Metiamide produced a dose related effect on the histamine response with consistent abolition of response at high dose ratios of metiamide to histamine variable response at intermediate and a pronounced histamine response at low dose ratios. Mepyramine produced no such antagonism of the histamine response and in certain doses, by itself caused an increase in 133-Xe clearance rate. This effect of mepyramine was thought to be related to its histamine releasing properties a view supported by the reduction in this vasodilator response following certain doses of metiamide. The response of the 133-Xe clearance rate to histamine returned approximately one hour after treatment with metiamide (500 mug) and metiamide did not antagonise the effects of alpha and beta adrenergic agents on the 133-Xe clearance rate. Thus, this study has provided evidence for the presence of H(2) but not H(1) receptors in the synovial microcirculation.


Red cell metabolism in transient haemolytic anaemia associated with Zieve's syndrome. Reversible haemolytic anaemia associated with decreased red cell half-life and reticulocytosis was studied in 10 patients with Zieve's syndrome. Since the underlying cause of the red cell destruction is as yet unknown, we determined the critical metabolic functions of the red cells in order to define the assumed intracorpuscular defect causing haemolysis. The glucose metabolizing enzymes had normal or raised values. - In view of the diminished ATP and raised 2,3-diphosphoglycerate (2.3 DPG) levels - a combination which suggests a pyruvate kinase (PK) deficiency - additional procedures were carried out in order to detect an abnormal activity of the red cell PK. Studies of biochemical properties of PK such as thermostability, Michaelis-Menten constants, and activation and inhibition tests brought results markedly deviating from the norm.-Fractions containing old cells particularly disclosed PK instability. A defective red cell matabolism resulted which was measurable through ATP-instability, altered glucose utilization and lactate production. - Experimental cell aging procedures led to a markedly decreased red cell metabolism. These assays revealed that mutations of PK-control mechanisms might be involved as factor triggering haemolytic anaemia of Zieve's syndrome.


Effects of insulin and of NSILA-S on the perfused rat heart: glucose uptake, lactate production and efflux of 3-0-methyl glucose. 200 muU of insulin per ml perfusion medium stimulated glucose uptake and lactate production by the isolated perfused rat heart about 5 and 10 fold, respectively. Nonsuppressible insulin-like activity (NSILA-S) extracted from human serum had almost the same maximal effects. Mol per mol the two substances were equally effective and, correspondingly, the dose-response curves were very similar. NSILA-S accelerated the efflux of 3-0-methyl glucose from the heart cells to the same extent as insulin. It can be concluded that NSILA-S acts on heart muscle in a very similar way to that of insulin.


Cardiovascular profile of 5-methyl-2-phenyl-4-imidazole-acetonitrile (MCN-2378), a cerebral vasodilator. I.v. administration of McN-2378 appeared to preferentially increase cerebral blood flow as opposed to systemic (femoral) blood flow in two strains of monkeys. This cerebral vasodilation was not affected by theta-adrenergic blockade. In the anesthetized dog, the compound transiently lowered systemic arterial pressure with an associated transient decrease in femoral vascular resistance and increased heart rate. Cardiac output in the anesthetized dog was also transiently elevated. Although the compound contains a nitrile group, there is no evidence to suggest that cyanide release is mediating the cerebral vasodilation.


Effect of prostaglandins E1, E2 and F2alpha and pentagrastin on the gall bladder pressure in dogs. The effect of prostaglandins E1, E2 and F2alpha on the gall bladder pressure was studied in anesthetized dogs with and without clamping of the cystic duct. Both PGE1 and PGE2 lowered the gall bladder pressure when the initial pressure was higher than 5 mm Hg, but caused no significant change when the initial pressure was lower than 3 mm Hg. On the other hand, PGF2alpha increased the gall bladder pressure regardless of its initial pressure. When the cystic duct was clamped, PGF2alpha markedly increased the gall bladder pressure while both PGE1 and PGE2 increased it slightly. This observation suggests that the smooth muscle in the gall bladder is markedly stimulated by PGF2alpha and stimulated to a lesser degree by PGE1 or PGE2. Furthermore, PGF2alpha appears to constrict, and PGE1 or PGE2 appears to relax the sphincter of Oddi. Pretreatment with indomethacin did not affect or slightly potentiated the cholecystokinetic effect of the three prostaglandins but abolished that of pentagastrin, suggesting that prostaglandins are possible mediators for the cholecystokinetic action of the gastrointestinal hormones.


Dopamine metabolism in the tuberculum olfactorium. The occurrence of the major dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the tuberculum olfactorium of the rat was demonstrated by gas chromatography. The ratio of DOPAC to HVA in the tuberculum olfactorium was greater than the ratio of these metabolites in the striatum. The effect of pargyline and probenecid on dopamine metabolite levels was similar for both the tuberculum olfactorium and striatum.


A comparsion of the effects of prazosin and hydrallazine on blood pressure, heart rate and plasma renin activity in conscious renal hypertensive dogs. Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.


The effect of harmaline on force of contraction of the rat isolated atrium. In rat isolated right atria, beating spontaneously at 30 degrees C, harmaline 8.3 times 10-5 M slowed atrial rate and enhanced force of contraction. The velocity of development of tension (dT/dt) increased and time to peak tension was lengthened. Electrical drive of otherwise quiescent left atria showed that (1) within the range of change of rate induced by harmaline the reduction of frequency of stimulation increased dT/dt and peak tension developed, and (2) at a constant rate of stimulation harmaline produced a prolongation of time to peak tension and an enhancement of peak tension. We concluded that two mechanisms are responsible for the inotropic action of harmaline on rat atrium: (1) an increase in dT/dt due to the lengthening of the interval between beats; (2) a direct action of harmaline on the processes responsible for atrial contraction, which determines a lengthening of time to peak tension.