Myogenic microvascular responses to change of transmural pressure. A mathematical approach. The recently described static and dynamic myogenic responses in the sympathectomized skeletal muscle microvessels to a given transmural pressure (PT) change applied at different rates (dPT/dt) (Grände & Mellander 1978), were further analysed in this study with a mathematical approach. The hypothesis that myogenic reactions are triggered by and related to wall tension was also tested. The mathematical model was based on a force-equilibrium in the microvessel wall including passive forces related to vascular transmural pressure, elasticity, and wall-viscosity, and active myogenic forces related to wall tension and its rate of change. Great resemblance was demonstrated between microvascular resistance curves obtained with the model and corresponding curves observed in vivo, indicating that the model quite adequately can describe myogenic microvascular resistance responses to transmural pressure stimuli. The results support the myogenic hypothesis in general and, in particular, the concept of an important rate-sensitivity in myogenic microvascular control and are compatible with the view that myogenic reactions are triggered by and related to change of wall tension. The model, in addition, provided data for certain microvascular variables which are difficult to assess by in vivo observations, e.g. Young's modulus of elasticity, wall tension, its rate of change, and internal vessel radius, and it offered a means to define more precisely the role of physical factors like effects of Poiseuille's and Laplace's laws in vascular resistance regulation.


Blood flow in the reproductive tract of the domestic hen following treatment with a pituitary gonadotropic inhibitor. The effect of pituitary gonadotropic inhibitor--methallibure on the weight and blood flow through reproductive tract was studied in immature hens. It was found that methallibure lowers the weight of the reproductive tract and simultaneously inhibits (about 2--3 times) the blood flow through the ovary and oviductal segments. However, the action of methallibure is of short duration and it is limited to the time of its administration only.


Effect of glucagon on the metabolic rate in growing chicken. The investigations were carried out on 70 growing broiler chickens. The chickens were kept on a higher and the other ones on the lower level of nutrition. As a result of this the rate of growth was different in both groups. Glucagon had a strong calorigenic effect, reaching a peak 30 min after its injection. This effect of glucagon increased progressively with the growth and development of birds reaching a maximum in chickens aged about 7 weeks, and weighing approx. 1200 g. In the birds examined 2 hours after feeding the calorigenic effect of glucagon was most expressed in birds maintained on the low nutrition levels. The fall of RQ after glucagon injection may suggest that this hormone has a strong lipolytic action.


Effects of duct ligation on choline acetyltransferase activity in salivary glands of rats. Duct ligation was found to cause a decrease in the weights of submaxillary and parotid glands examined 3 weeks postoperatively. Choline acetyltransferase activity in ligated glands was compared with that in unligated contralateral glands. The enzyme activity was also measured in the glands from both sides of unoperated control animals. Interference in the assay of choline acetyltransferase by other acetylated compounds was avoided by introducing suitable control incubations. Ligated submaxillary glands showed a small decrease in the activity of choline acetyltransferase both when compared with contralateral glands and with glands of control rats. In parotid glands the enzyme activity was found to be lower only when ligated and contralateral glands were compared. Structural changes in the nerves and reduced traffic of impulses in them may have to be considered as explanations for the reduction in enzyme activity in duct-ligated glands.


On the mechanism of central effect of thyroxine on body temperature in dogs. The effect of intraventricular injection of thyroxine 1 microgram/animal on body temperature was studied in dogs under resting conditions: at normal ambient temperature, at high ambient temperature (35 degrees C) and during administration of pyrogen. Besides, changes in body temperature were elucidated in dogs performing physical exercise following I.V. T4 injection in the same dose. Thyroxine exerted its central action on body temperature only in dogs performing physical exercise.


Conversion of arachidonic acid to prostaglandins in homogenates of human skeletal muscle and kidney. The capacity of human skeletal muscle and kidney homogenates to synthetize prostaglandins (PGs) from exogenous precursor was investigated. Low-speed supernatants of muscle as well as renal medullary and cortical homogenates were incubated with 14C-labelled arachidonic acid (14C-AA) prepared as a sodium salt. 14C-PGs in the incubates were extracted, separated with thin-layer chromatography (TLC) and quantified by radioscanning. In the skeletal muscle incubates 14C-AA was converted into 14C-PGs with a time-dependent yield, most effectively after 10--15 min incubation. Well-defined radiopeaks parallel to unlabelled standards of PGD2, PGE2, PGF2 alpha and 6-keto-PGF1 alpha were obtained in the chromatograms. PGE2 was the main PG formed, constituting over 50% of 14C-activity, whereas 6-keto-PGF1 alpha, PGD2 and PGF2 alpha were found in considerably lower proportions. In the renal medullary incubates, PGE2 likewise accounted for the largest part of 14C-PGs formed, but significant relative amounts of PGF2 alpha and PGD2 were also found. A minor peak, corresponding to 6-keto-PGF1 alpha and thus indicating formation of PGI2, was also obtained. In contrast to the medulla, no 14C-PGs could be found in the renal cortical incubates. The results demonstrate the existence of a considerable tissue specificity in the quantitative and qualitative expression of PG biosynthesis in man.


Stimulating effect of physical effort on the excretion of 5-hydroxyindoleacetic acid. The excretion of 5-hydroxyindoleacetic acid, after work load, was studied. The physical effort evoked an increase in the excretion of 5-hydroxyindoleacetic acid. Under the control conditions no changes in the excretion of the investigated metabolite were found.


Hemodynamic changes during the development of sodium-induced hypertension in subtotally nephrectomized rats. Hemodynamic changes during the development of sodium-induced hypertension were investigated in male Sprague-Dawley rats after about 70% of the renal mass was removed. Throughout the four experimental weeks, subtotally nephrectomized rats on a high sodium diet (750 mEq/kg) showed a continuous rise in blood pressure up to the mean value of 178 +/- 9 mmHg. In sham-operated animals on the high sodium supply the blood pressure did not increase as compared to sham-operated controls on the standard sodium diet (150 mEq/kg). In the hypertensive group, the primary changes were urea retention and a concomitant increase of serum osmolarity, but the serum sodium concentration remained at the normal level. These changes were followed by sustained enlargement of extracellular fluid and relative intravascular volumes, together with a simultaneous increase of heart rate and blood pressure. During high sodium intake, the plasma renin activity in subtotally nephrectomized rats was suppressed to one fifth of that in sham-operated animals, but the renin substrate activity did not increase markedly.


Potentiation of the mechanical behavior of the human skeletal muscle through prestretching. Force-velocity and power-velocity curves in a vertical jump involving movements around several joints were derived from vertical ground reaction forces and knee angular velocities. The jumps were performed with weights from 10 to 160 kg added on the shoulders. The obtained curves from a semi-squatting static starting position resembled those reported for isolated muscles or single muscle groups. Vertical jumps were also performed in the conditions where the shortening of the leg extensors was preceded by prestretching of the active muscles either through a preparatory counter-movement or dropping down on the force-platform from the various heights ranging from 20 to 100 cm. Prestretching modified through a range of velocities the force-velocity and power-velocity curves by increasing both the ground reaction forces and the calculated mechanical power. Thus the results are similar to those reported in isolated muscles. In studies with isolated muscle preparation the nervous connections have not been intact and therefore it is suggested that increase in the performance of the skeletal muscles through prestretching, in the conditions of the present study, was attributed to the combined effects of the utilization of stored elastic energy and the reflex potentiation of muscle activation.


Shortening velocity, active force and homogeneity of contraction during electrically evoked twitches in smooth muscle from rabbit urinary bladder. Force-velocity relations obtained by the quick release technique were studied at different times during the twitch at 25 degrees C in electrically stimulated longitudinal smooth muscle from rabbit urinary bladder. The results show that maximal shortening velocity (Vmax) and maximal tension (Po) reach their highest values during the rising phase of the twitch. Maximum Vmax was calculated to be 0.30 +/- 0.04 1/s (S.E., n -= 9). Vmax declines rapidly with time and at the peak of the twitch it is only about 70% of the maximum value. On the other hand Po at the peak does not differ significantly from its maximum value during the rising phase. In the relaxation phase of the twitch, both Vmax and Po decrease progressively. Photographic studies of preparations marked with charcoal grains did not show any considerable inhomogeneity of contraction during isometric twitches, maximum movement of grains never exceeding 4% of total muscle length. No yield at the ends of the preparations were seen. The different time course of Vmax and Po can therefore not be explained by longitudinal inhomogeneity of activation or deactivation of the preparations.


Influence of D-or DL-propranolol and chlorpromazine on habituation of phasic electrodermal responses in schizophrenia. Propranolol was found to share the properties of the racemate in facilitating habituation of the electrodermal orienting reflex in schizophrenic patients. This effect appeared independent of influences on levels of skin conductance and non-specific responses. Chlorpromazine did not normalise orienting activity. If the findings from open clinical studies that D-propranolol has anti-psychotic properties are confirmed, the fact that dextro propranolol has only minimal cardiovascular effects may give it important advantages as an anti-psychotic agent. Controlled clinical studies to prove its therapeutic action and neurobiological studies to determine its central mechanisms of action are warranted.


First admissions for psychosis in Turku. A time trend study. Patients over 15 years of age from Turku hospitalized for psychosis for the first time during the years 1949-50, 1959-60 or 1969-70 were investigated. The incidence of hospitalized psychoses (per 100,000 inhabitants) was 115, 136 and 160, respectively. The increase in incidence was greater in women than in men. The incidence remained approximately the same in patients aged 30 to 59, but increased in the younger and older groups. The incidence of functional psychoses increased; in schizophrenia, however, it declined, while in paranoid and effective psychoses it increased. In organic psychoses, the admission frequency of psychoses of old age rose in the 1950's, but declined in some measure in the 1960's. The incidence of psychosis increased for single persons. The ratio of the incidence between single and married persons rose in men, whereas in women it fell. This was particularly pronounced in schizophrenics. The incidence of psychosis was highest in unskilled laborers. The overrepresentation of schizophrenia and paranoid psychoses seemed to have become more pronounced in this occupational group.


Affective disorders and ABO blood types. Results of the present study provide evidence of: 1) a positive association between bipolar affective disorder and blood type O and a corresponding negative association between the former and blood type A, 2) a positive association between unipolar affective disorder and blood type O, and 3) a positive association between involutional depression and blood type A and a corresponding negative association between the former and blood types B and O. Sex does not appear to modify the ABO blood types' distribution in patients with bipolar, unipolar affective disorder, or involutional depression, and the same holds for early- or late-onset of the illness in patients with bipolar or unipolar affective disorders. Findings in the present study do not support the validity of the bipolar-unipolar distinction of affective disorders, and provide evidence in favour of the view that involutional depression is a genetically distinct nosological entity.


Prediction of lithium response.

Prediction of lithium response. Even though lithium has been established as an effective agent in the management of primary affective disorders, not all manic-depressive patients respond favourably to lithium therapy. Therefore we attempted to delineate lithium responders from non-responders in a group of 54 manic-depressive patients on the basis of an assessment which included 64 variables and the results showed that only two thirds were pure responders. Females, patients with prior manic episodes, onset of the illness initially with a manic episode, and premorbid psychothymic personality were all indicators of favourable long-term lithium response. Patients with retarded depression, severe anxiety, though disorder and those with higher scores on the Psychopathic Deviate and Paranoia scales of the MMPI were poor lithium responders. It should be noted, however, that only a few of the differences between responders and non-responders were statistically significant. Our study suggests a number of predictive variables for the identification of lithium responders.


[Memory alterations in non-korsakoff's chronic alcoholics (author's transl)]. There is a memory deficit in non Korsakow chronic alcoholics, mainly in fixation and learning. Retaining less structured and significant elements is particularly altered. Part of the troubles may be due to deterioration of recall mechanisms.


[Study of intravenous amitriptyline in acute depressions (author's transl)]. The author has performed an open study of 27 patients with an acute depressive state, hospitalized and treated with slow intravenous perfusions of amitriptyline. Similar perfusions of chlorimipramine act certainly more rapidly on depression, but conversion to oral dose raises some problems regarding active dosis. Intravenous amitriptyline reduces latency, is more sedative and without major intolerance, such as hemodynamic. Conversion to oral diffused forms (Redomex diffucaps) consolidates the results obtained by parenteral administration, and the antianxiety component permits the use of this drug in monotherapy.


Ultrasound and clinical diagnosis of deep vein thrombosis of the leg. The diagnostic precision of clinical evaluation and of ultrasound examination in the diagnosis of deep vein thrombosis was obtained by ascending phlebography. The diagnostic specificity and diagnostic sensitivity of clinical examination was 0.72 and 0.78 and with ultrasound 0.73 and 0.70. With no other examination than phlebography is it possible to demonstrate major central thrombosis in the leg with certainty.


Hepatobiliary scintigraphy with 99Tcm-HIDA in patients with jaundice. In order to assess the clinical value of 99Tcm-HIDA for hepatobiliary scintigraphy 23 patients with hepatocellular disease and 44 patients with obstructive biliary tract disease were examined. Positive information was obtained in 14 and 23 patients, respectively. False results mainly depended on inadequate imaging of the liver in the case of severely impaired function, whatever the cause. Spontaneously ameliorated obstruction leaving an impaired hepatocellular function may give misleading results. A malignant tumour widely involving the liver and impressing the bile ducts may also create the appearance of obstruction. If HIDA scintigraphy be limited to patients with serum bilirubin levels between 40 and 250 mumol/l the diagnostic specificity and sensitivity of 90 per cent and 78 per cent, respectively, is reached in demonstrating obstruction, when the prevalence is 0.58.


Angiography and scintigraphy in patients with possible liver malignancy. Angiography and 99Tcm-scintigraphy were performed in 100 adult patients with suggested primary or secondary liver malignancy. The results were compared to the final diagnosis obtained by biopsy, surgery, autopsy or long term clinical follow up. The reasons for false positive and negative diagnoses are discussed in detail.


Angiographic findings in adrenal masses. The angiographic findings in 34 patients with adrenal lesions were reviewed, including 11 adrenal metastases, 9 adrenal pheochromocytomas, 4 adrenal cortical carcinomas, 4 adrenal cortical adenomas, 3 cases of adrenal hyperplasia and 3 cases of adrenal invasion from carcinoma of the upper pole of the kidney. The results indicate differential diagnostic difficulties in distinguishing among these various entities by angiography.


Angiography of the testicular artery. IV. Magnification angiography in intrascrotal abnormalities. Magnification angiography of the testis with selective injection into the testicular artery has been performed in patients with different lesions in the scrotum, either real or suggested. Characteristic angiographic appearances were found in epididymitis, testicular torsion, tumor, hematoma and hydrocele.


Appearance of trabecular bone in the femoral neck (Singh index). Relation to vertebral bone mass post mortem. In 89 consecutive cases trabecular bone mass of the second or third lumbar vertabra was subjectively estimated in post mortem specimens, using frontal section 1 cm in thickness. The trabecular appearance of the femoral neck (Singh index) at radiography and the thickness of the femoral cortical bone were also determined. Agreement between vertebral bone mass and either of the two radiologic indices was present in only two thirds of the cases, and most often these indices underestimated the presence of vertebral osteoporosis. The results indicate that neither of these radiologic indices can be used for clinical guidance of the diagnosis of vertebral osteoporosis in the individual case.


Facial bone scintigraphy. IV. Diagnosis of bone involvement by purulent sinusitis. Facial bone scintigraphy demonstrated bone tissue involvement by purulent maxillary sinuitis in 11 patients examined. In no case was bone involvement demonstrated by radiography. Bone scintigraphy in this respect appears more sensitive than does conventional radiography.


Thin bony walls of the temporomandibular joint. Morphologic properties and tomographic reproduction. The morphology of two thin bony walls in the medial third of the mandibular fossa is described on the basis of successive microtome sections of undecalcified temporomandibular joint specimens. The requirements for reproduction on thin bony walls at tomography with hypocycloidal movement are defined and discussed.


Influence of radiation dose on image quality. When the speed of a recording medium is doubled the background quantum mottle is increased by a factor square root 2. However, the signal/noise ratio is changed not in proportion to the square root of the exposure, but in a linear fashion, i.e. by a factor 2. The change in the depiction of objects with a very high attenuation difference in relation to its surroundings appears not to be linear, but proportional to the square root of the exposure. Such objects (metal wire meshes, lead bar grids) should thus be avoided in routine evaluation of image quality since they give incomplete information as to image impairment when high-speed recording media are used.


Autopsy findings in carcinoma of the esophagus. At autopsy of 82 cases of carcinoma of the esophagus over a period of 25 years metastatic tumor was found in 42 cases (51%) and residual tumor in the esophagus in 56 cases (86%). The most frequent site of metastases was in the lymph nodes, followed by liver, lung, and adrenal gland. Direct extension of the tumor to adjacent structures was established in 30 cases (36%), and the most frequent structure involved was the trachea. Five cases had a second primary and two cases a second separate lesion at another level of the esophagus.


Bone mineral content in hyperthyroid patients after combined medical and surgical treatment. Bone mineral content (BMC) and bone mineral concentration (BMC') of the forearm were determined by photon absorptiometry in 20 untreated hyperthyroid patients and in 33 patients previously treated for hyperthyroidism. In untreated hyperthyroidism a significant decrease was found in both BMC and BMC'. In treated hyperthyroidism BMC and BMC' were normalized. The findings suggest that a previous hyperthyroid state is not a risk factor for development of spontaneous fractures providing the hyperthyroid state is effectively treated.


Peripheral reticulocyte count as biologic dosimetry of ionizing radiation. Experiments in the mouse. The flow of reticulocytes in the peripheral blood reflects the bone marrow activity and can be used for evaluation of radiation injury. Using an apparatus capable of microfluorometric quantification of reticulocytes in suspension, the peripheral blood reticulocytes of mice exposed to various doses of ionizing radiation were examined. A dose dependent reticulocytopenia was observed. The advantages of this method in biologic dosimetry over that of evaluating chromosomal aberrations, and its applicability for screening a human populations, are discussed.


Bronchial angiography in the staging of bronchogenic carcinoma. Selective bronchial angiography was performed in 26 patients with bronchogenic carcinoma in connection with intraarterial infusions of cytostatic drugs. The angiographic extension of the tumor was correlated to data obtained at surgery, mediastinoscopy or autopsy. Bronchial angiography is not suitable as a routine procedure in the preoperative evaluation of patients with bronchogenic carcinoma but may contribute to a more precise staging of the tumor.


Basal cell carcinoma treated with MTDQ and irradiation. Patients with basal cell carcinoma of the skin were treated with combined MTDQ (6,6'-methylene-bis-(2,2,4-trimethyl-1,2-dihydroquinoline)) administration and irradiation. Significantly better results were obtained with a skin exposure of 2 000 R combined with MTDQ than with the same dose alone. The results were comparable to those obtained with an exposure of 4 000 R. MTDQ administration induced decrease of tissular malonaldehyde concentration and suggested the peroxide-decomposing action of the radiation sensitizer.


Coronary arteriography in 486 patients--arteriographic pathology and prognosis. The coronary arteriographic findings and prognosis in a series of 486 non-surgically treated patients were analyzed. A semiselective injection was used. The number and causes of deaths were obtained from the census registry after a follow-up period of 7--12 years. The material comprised normal arteriograms in 26% of the patients, wall irregularities at most in 17%, obstruction of at least half the diameter in 37%, and unclassifiable arteriograms in 19%. A mean of 1.8 obstructed arteries per patient was found in the group with obstructive arterial lesions and among these patients the left anterior descending artery was most often engaged. In the same group the cardiac mortality at seven years was 20%. There were no significant differences between deceased and survivors with regard to clinical data. The arteriograms themselves offered more information about the prognosis. Normal arteries or wall irregularities at most implied excellent prognosis with regard to death in coronary heart disease. The seven-year mortality was 36% among patients with coronary artery occlusions, which is significantly higher than 14% among those with arterial stenosis. Materials from the USA and Canada have displayed a much higher mortality than our study in spite of comparable arteriographic findings.


Sick sinus syndrome treated with permanent pacemaker in 109 patients. A follow-up study. During the last decade implantation of permanent pacemakers has become the treatment of choice for patients suffering from the sick sinus syndrome (SSS). We have followed up 112 SSS patients treated with permanent pacemakers in Haukeland Hospital in the period 1966--76. The pacemakers were later removed from three of the patients. In the remaining 109 patients the SSS was characterized by tachy-bradyarrhythmias (TBA) in 44 and bradyarrhythmias (BA) in 65. Before implantation, 68 patients had syncopes and 27 severe dizziness. After implantation, symptomatic improvement was apparent in 104 patients; only three still had syncopes. During the follow-up period (mean 34.4 months), 29 patients died (yearly mortality 9.3%). There was no significant difference in total mortality between patients with TBA and with BA. Concomitant disturbances in atrioventricular (AV) conduction occurred in 35.8% of the patients. Among 79 of 80 patients still alive, five had developed total AV block, 19 had stable atrial fibrillation, 12 of these were possibly pacemaker-independent (ventricular rate greater than 60/min). Systemic embolization was observed in 16 patients, more frequently in the TBA (12/44) than in the BA group (4/65) (p less than 0.001). It is concluded that permanent pacemakers have an excellent symptomatic effect in patients with SSS. The prognosis is mainly determined by the presence or absence of coronary heart disease and/or heart failure.


Aortic valve replacement in elderly patients. During the years 1965--75, 98 patients more than 65 years of age had aortic valve replacement in our hospital, 24 ball valves and 74 disc valves inserted in their aortic orifice. Actuarial analysis of survival in these patients shows that the operative risk is slightly higher in elder than in younger patients. The survival curve for the following years for those who had disc valve implantation runs parallel to that of younger patients, while those who had ball valve implantation showed a more rapid fall in survival after 3 years. After 10 years, only 30% of patients with ball valve transplantation were alive.


Prediction of survival in patients with acute myocardial infarction. A clinical study on 100 consecutive patients. Expected survival after acute myocardial infarction (AMI) in 100 consecutive patients was predicted by three doctors and two nurses at the time of discharge from a CCU. Predictions were compared with various coronary prognostic indices (CPI) and were found to be too optimistic for the first 9 months. Experienced physicians made more reliable predictions than junior physicians and nurses. All patients with a predicted survival of more than 10 years were alive after 1 year and all with predicted death within one month died during the first year. Intermediate predictions were unreliable with reference to the one-year survival. Regardless of which CPI was used, a low index score carried a very low one-year mortality and high index a high mortality. Intermediate index scores were unreliable. A comparison between the predictions and index scores showed that there was no difference in sensitivity and specificity between the methods. Our study thus shows that patients with either a very good or a very poor prognosis will be identified regardless of the method used. The problem of identifying the individual with an intermediate risk remains to be solved.


Early mobilization and discharge of patients with acute myocardial infarction. A prospective study using risk indicators and early exercise tests. Consecutive patients (n=184) surviving 48 hours in a coronary care unit were divided into one rapidly (RM) (n=55, 30%) and one conventionally mobilized (CM) group (n=129, 70%). The selection of RM patients was based on the absence of five early risk indicators (RI), reflecting electrical and mechanical heart dysfunction. During after-care, five late RIs were evaluated, including a submaximal bicycle exercise test to 50 W, which excluded nine (16%) additional patients from the RM group. After excluding four patients for non-cardiac reasons, the remaining 42 RM patients were rapidly mobilized and discharged after a mean of nine days, in contrast to a mean of 19 days in the CM group, comprising 121 patients. No RM patient dies in hospital and only one patient died during a six-month follow-up, compared to 17 (p less than 0.01) and 28 (p less than 0.01) patients respectively, in the CM group. Both reinfarction and mortality increased with the number of positive RIs. The early exercise test excluded four patients from the RM group. Altogether 22 of 45 patients showed some abnormality during exercise. Half of these 22 patients were readmitted due to cardiac complications during the follow-up period. These findings indicate that it is possible to identify a group of patients with AMI suitable for early discharge, and that an early exercise test in selected good risk patients is safe and identifies a group prone to complications during the early follow-up period.


Intraaortic balloon pumping in the treatment of cardiogenic shock complicating acute myocardial infarction. A 5.1% incidence of cardiogenic shock was found in consecutive series of 680 patients with acute myocardial infarction (AMI) during a five-year period. The hospital mortality was 94%. Shock was treated according to a stepwise policy including assisted circulation with intraaortic balloon pumping (IABP). During the five-year period, only five patients, 14% of the shock patients, had shock for more than three hours (the minimal time for attempting medical therapy and preparing for assisted circulation), were below 75 years of age and without terminal diseases. Together with ten AMI patients in shock referred from or treated in other hospitals, altogether 15 patients were given IABP during 1--318 hours (mean 58). Shock was reversed in 12 (80%) of these patients and five (33%) could be weaned off IABP and discharged from the CCU. However, only two patients (13%) were long-term survivors.


Familial occurrence of intracranial aneurysms. Intracranial aneurysms occurring in three families are reported. As a result of the discovery of splenic artery aneurysms in one of the family members the relation between intracranial aneurysms and aneurysms in other sites is discussed. It is put forward that aneurysms might be a part of a generalized connective tissue disease, and the relation between aneurysms and some connective tissue diseases is stressed. At present extensive angiographic investigations in family cases cannot be recommended in every family.


Alkaline phosphatase in women with osteoporosis. Altogether 15 partially independent measurements of bone mass in 100 women with clinical and roentgenological signs of osteoporosis were correlated to the alkaline phosphatase activities of the same individuals. There was a slight but significant negative correlation indicating an increasing alkaline phosphatase activity with decreasing bone mass. This correlation was not caused by interaction of age. There was no correlation or morphological signs of osteomalacia. The changes could not be explained by fractures. It is suggested that a slight increase in the alkaline phosphatase activity in women with a more severe osteoporosis is related to bone resorption.


Bone biopsy in women with spinal osteoporosis. Iliac crest biopsies were obtained from 110 women, 62 of whom had been clinically and radiologically classified as osteoporotics. The amount of osteoid surface was measured by a histological planimetrical method. It was demonstrated that the amount of osteoid does not differ between osteoporotic women and control women and that osteomalacia is rare in both groups.


Multiple attacks of jaundice associated with repeated sulfonamide treatment. Four women who were treated with sulfonamides because of recurrent urinary tract infections experienced adverse liver reactions with jaundice during their third, fourth and fifth course of treatment, respectively. In spite of this, sulfonamide treatment was reinitiated some years later. Adverse liver reactions with jaundice recurred on all occasions. The clinical picture of the liver reactions was indistinguishable from that of viral hepatitis and a hepatitis-like reaction was also seen histologically. Signs of fibrosis appeared histologically after a third attack of jaundice associated with sulfonamides in one patient, but otherwise no persisting abnormalities were noted.


Changes in serum triglyceride and cholesterol levels during long-term phenytoin treatment for epilepsy. The effect of long-term phenytoin therapy on serum triglyceride and cholesterol levels in 20 patients with epilepsy was investigated. In patients followed up for six years, phenytoin treatment was associated with an increase in serum triglyceride and cholesterol levels. The most significant increases in lipid levels were measured during the first months of therapy, whereafter values generally tended to decrease. The elevation in serum triglyceride concentration was relatively greater than that in serum cholesterol level. Cholesterol concentrations, however, remained high for a longer period. The results demonstrate that phenytoin therapy for epilepsy is associated with a rise in serum triglyceride and cholesterol levels, the degree of which seems to be related to the duration of the treatment. The changes presumably reflect phenytoin effects on hepatic lipid metabolism.


Immune complex glomerulonephritis in chronic granulomatous disease. Case report of an eighteen-year-old girl. An 18-year-old girl is described who developed advanced renal sclerotic lesions, probably preceded by local focal glomerulonephritis, which coexisted with a Staphylococcus aureus abscess. It is hypothesized that immune complex glomerulonephritis developed, provoked by long-term antigenic stimulation of Staphylococcus aureus. The cause of these long-term bacterial infections was a defect of the phagocytic cells to kill bacteria effectively, a disease known as chronic granulomatous disease. Therapy with intracellularly active antimicrobial agents restored the renal function till no more haemodialysis was necessary.


Temporal arteritis and gangrene of the tongue. A 69-year-old woman, suspected of having polymyalgia rheumatica, was biopsied from the temporal artery to establish the diagnosis. Six hours after the biopsy, she developed progressive gangrene of the tongue and the floor of the mouth, and intensive steroid therapy was initiated. The histological examination of the biopsy revealed giant-cell arteritis. Biopsy or other manipulation of the artery is suggested to be the cause of exacerbation of the arteritis locally. Steroid treatment is proposed in all cases prior to the biopsy. Other studies have not shown that the possibility of obtaining a positive histological diagnosis is reduced during or after steroid treatment. A review of the literature on gangrene of the tongue is given.


Medulloblastoma in childhood. Survival and functional results. The authors report on a series of 57 medulloblastomas in children operated upon -etween 1964 and 1976. Among these children, 44 completed the treatment with radiotherapy to the whole central nervous system. The postoperative mortality rate in 10.5%. Postoperative deaths occurred mainly in infants or when a tumour involved the brain stem. The five-year survival rate is 54% in the whole series. It rose to 71% in the patients who completed the treatment with radiotherapy. The study shows that the life of survivals is frequently impaired by mental or behavioural disturbances. IQ varies from 70 to 90 in 58% of the children; it is below 70 in 31%. Behavioural disturbances are found in 93% of cases. 82% have defective spatial orientation, dysphasia, or dysgraphia. In order to evaluate the responsibility of X-ray therapy for the development of these sequelae, the results have been compared to those of a series of cerebellar astrocytomas surgically removed, but not irradiated. The comparison shows that radiotherapy is at least partially responsible for the mental and behavioural disturbances. No relation was found between these disturbances and a persistent ventricular dilatation or an endocrine dysfunction. However the endocrine assessment showed growth hromone deficiency in 65% of the children, short stature in 55%, and compensated hypothyroidism in 58%.


Transarticular (transpedicular) metal plate fixation for stabilization of the lumbar and thoracic spine. The operation of metal plate fixation of the articular column with the screws traversing the anterior vertebral arch (ventral pedicles) and anchored within the vertebral body is described in detail. The method can be recommended as easy to perform. It gives sufficiently stable fixation in cases where instability of the thoracic or lumbar spine can be expected during an operation from the dorsal approach. Four cases are presented to illustrate the indications and method.


Vertebral thoracic osteoclastoma. A case report with emphasis on roentgenological findings. A rare case of vertebral osteoclastoma in the body of T8 is presented. Attention is drawn to its unusual radiological features, not previously reported, and to the relative inefficiency of radiotherapy. The most rational treatment for such a tumour appears to be the widest surgical decompression possible, followed by low-dose irradiation.


Syphilitic normal pressure hydrocephalus. We report a case of presenile dementia with radiological and cisternographical features suggesting normal pressure hydrocephalus, caused by syphilitic infection. Treatment with penicillin resulted in considerable regression of the neurological and psychological signs.


Postoperative ventriculitis in hydrocephalus: treatment with external ventricular drainage. Twenty hydrocephalic children with postoperative ventriculitis were treated with External Ventricular Drainage after removal of the infected shunt. The advantages and disadvantages of this treatment are discussed.


Motor tics of the head and neck: surgical approaches and their complications. Motor tics of the head and neck, especially hemifacial spasm and spastic torticollis, are the substance of this paper. Forty-six cases are presented, and surgical techniques are described. In hemifacial spasm the intracranial neurovascular lysis of Jannetta is a valid operation with the best results to date but has a 7 1/2% risk of unilateral deafness. The extracranial submastoid partial section of Scoville is completely safe and gives excellent results, but there is a probability of mild to moderate return of the spasm in one to two year's time. In spastic torticollis the accepted radical operation consists of bilateral anterior rhizotomy of the upper three roots plus bilateral spinal accessory nerve section in the neck. A tragic complication of this operation has recently been observed by ourselves, Sweet, and Hamlin. This complication is bilateral infarction of the medulla (bilateral Wallenberg's syndrome). This has also been reported as occurring following chiropractic manipulations. For this reason the writer does limited unilateral sectioning of the spinal accessory nerve in the neck and resection of the upper third of the sternomastoid muscle, as a first stage procedure, in those cases in which rotation of the neck is the principal symptom, before doing the radical operation. Safeguards to prevent this complication include preoperative vertebral arteriography and preservation of both motor and sensory radicular arteries under magnification and maintenance of adequate neck support during the early postoperative days.


Persistent embryonic veins in arteriovenous malformations of the posterior fossa. In the arteriovenous malformations of the posterior fossa the arterial feeders and the dural venous sinuses can be identified in anatomical terminology. The arterialised veins which do not conform to adult anatomical descriptions represent the persistent embryonic veins of the metencephalic and myelencephalic segments of the developing brain. These can be identified and described when related to the embryo.


The results of surgical treatment of spondylotic radiculomyelopathy with complete cervical laminectomy and posterior foramen magnum decompression. Twenty-six patients with cervical spondylosis and radiculomyelopathy were treated surgically. Eight patients had cervical laminectomy C1--C7, and 16 patients had complete cervical laminectomy C1--C7 with excision of the posterior rim of the foramen magnum. Follow-up of patients was from two months to eight years. The majority of patients improved markedly, and some of them had excellent results.


Human cells and the finite lifespan theory. Cultures of human diploid fibroblasts are characterized by: i) finite lifespan, ii) marked heterogeneity in the growth potential of individual cells within the culture, iii) considerable variation in lifespans of parallel cultures of the same cell strain. To explain these properties, we have proposed a commitment theory of cellular aging. Cells are assumed initially to be uncommitted (potentially immortal) but, at each cell division, each daughter cell is assumed to have some fixed probability of becoming irreversibly committed to senesce and die after a specific number of cell generations. During the period between commitment and senescence, cells are assumed to multiply normally, so the uncommitted cells are diluted by committed ones and may be lost in subculturing. The theory explains features i) - iii) above and, in particular, suggests why diploid cultures have finite lifespans while transformed or permanent lines grow indefinitely. It also validly predicts the behaviour of mixed cultures of distinguishable but otherwise similar cell types, and that culture lifespan may be significantly decreased by drastic reduction of population size. The important converse prediction that culture lifespan may be extended indefinitely by growing sufficiently large cultures or by selectively isolating uncommitted cells remains to be tested.


Suppression of insulin secretion by protein deprivation in obesity. 1) Protein restricted diets decrease basal plasma insulin levels in obesity. 2) This effect occurs even in the presence of sufficient calories to maintain body weight and while the diet is high in carbohydrate. 3) The decrease in insulin is accompanied by a fall in plasma glucose and in the I/G ratio, suggesting an increase in insulin sensitivity. 4) Excessive protein intake, in addition to carbohydrate, may play a role in the pathogenesis of the hyperinsulinemia and insulin resistance found in obesity.


The prognosis of insulin dependent diabetes mellitus and the importance of supervision. Duration and quality of life are considerably reduced in insulin-dependent diabetic patients, but regular metabolic supervision, education of the patients, and social support can reduce the prevalence of severe late diabetic complications and prolong life by about 10 years.


High carbohydrate, high fiber diets for patients with diabetes. Thirty-three insulin-treated men with diabetes were hospitalized on a metabolic ward and fed control diets (43% carbohydrate) for 6 to 11 days followed by high carbohydrate (70%), high fiber (HCF) diets for 12-35 days. Fasting blood glucose, cholesterol and triglyceride values were significantly lower on HCF diets than on control diets despite significantly (p less than 0.01) lower insulin doses on the HCF diets. HCF diets were accompanied by increased insulin sensitivity and by binding of insulin by monocytes. Patients who responded well to the diet in the hospital have maintained comparable glucose, cholesterol and triglyceride values as well as lower insulin doses for an average of 20 months on maintenance diets (60% carbohydrate). The high carbohydrate and low fat content of these HCF diets seem to play the predominant role in the improved glucose metabolism of these patients whereas the high plant fiber content may be responsible for the reduction in serum cholesterol and triglyceride values. These studies suggest that HCF diets may have an important place in the management of patients with the maturity-onset type of diabetes.


Insulin resistance in patients with insulin independent diabetes mellitus: partial amelioration by the sulfonylurea glipizide. Studies in patients with insulin independent diabetes indicate that treatment with the second generation sulfonylurea glipizide results in partial amelioration of their insulin resistance and that this effect is significant in glipizide's antidiabetic action.


HLA studies in diabetics.

HLA studies in diabetics. The studies of HLA in diabetes mellitus have strongly supported the subdivision into (at least) two genetically distinct groups: The juvenile onset (or perhaps better the insulin dependent) type DM, which shows a marked association to the HLA system, and the maturity onset type with a weak or no association to HLA. The HLA system has provided tools to test specific genetic models for the insulin dependent DM. A model involving one disease susceptibility locus closely linked to the HLA-loci and with a recessive susceptibility allele in linkage disequilibrium with some of the HLA factors has been proposed by others. This model cannot be totally rejected on the basis of the available data, but it is made less likely, especially because it leads to very low estimates of the penetrance which is discrepant from independent estimates, based both on studies on monozygotic twins and other families. In addition suggestive but not yet conclusive evidence of an excessive risk for HLA-Dw3/Dw4 heterozygotes is in conflict with this model.


On the genetic heterogeneity of juvenile hyperglycemia. We have briefly discussed immunogenetic studies of families with hyperglycemia which suggest the existence of at least four types of the disease: a) juvenile, insulin-dependent, ketosis prone diabetes determined by an autosomal recessive gene with 50% penetrance and in linkage with the HLA; b) juvenile, insulin-dependent, ketosis prone diabetes probably determined by an autosomal dominant gene; c) unidentified types of juvenile, insulin-dependent diabetes whose pathogenesis may be related to the HLA associations reported; and d) maturity onset type of hyperglycemia in the young, probably determined by an autosomal dominant gene. There are probably other forms of juvenile hyperglycemia. Some may depend on genes unrelated to the HLA, others may be mostly or totally environmental, rather than genetic.


Estimation of urinary kininogenase activity using bovine serum low molecular weight kininogen. Estimation of urinary kininogenase activity by radioimmunoassay of generated kinin was studied. Bovine serum low molecular weight kininogen was proved not to cross-react with kallidin antibody and also bradykinin antibody. This kininogen was used as substrate measuring urinary kininogenase activity. Separation of released kinin from the kininogen was not required in the present method. Urinary kallikrein activity was found to be significantly decreased in essential hypertension, in chronic glomerulonephritis and in patients who had received renal transplantation. On the contrary, an increase in urinary kallikrein was found in primary aldosteronism and in Bartter's syndrome. The present method was very useful for measuring kininogenase activity.


A simple radioassay for human urinary kallikrein. We have developed a sensitive, highly selective assay for human urinary kallikrein (HUK) that uses Pro-Phe-Arg-[3H]benzyl-amide as substrate. The substrate was prepared from Pro-Phe-Arg-3-iodo-benzylamide by dehalogenation in 3H2 gas. HUK is measured by its ability to release [3H]benzylamine. The pH optimum is 9.5. Urokinase, plasmin and thrombin do not interfere. The assay can measure as little as 5 ng of HUK in a 15 min incubation at 37 degrees C. Typically, we use 50 microliter of dialyzed urine for HUK assays. Reactions are terminated by adding 0.1 M NaOH, and reaction product is separated from substrate by partitioning with an equal volume of toluene. A sample of the toluene phase is submitted for liquid scintillation counting. As judged by separations obtained on molecular sieve chromatography (Sephacryl), only one urinary enzyme possesses the ability to hydrolyze our substrate. The enzyme MW 45,000, is inhibited by Trasylol but not by soya bean trypsin inhibitor (SBTI). It is reactive with and is inhibited by antibodies prepared against pure HUK.


Glandular kallikrein in plasma and urine: evaluation of a direct RIA for its determination. To determine whether there is glandular kallikrein in plasma, untreated as well as acetone-treated and heated-acidified rat plasmas together with rabbit anti-rat urinary kallikrein were used in counterimmunoelectrophoresis. Precipitation bands were observed with untreated and acetone-treated plasma, suggesting that glandular kallikrein is present in plasma. This enzyme, however, cannot be quantified in the untreated plasma by a new direct RIA since kallikrein inhibitors present in plasma appear to interfere with this assay. Destroying the inhibitors by acetone treatment or by heat and acidification of the plasma partially solves this problem. In the second part of the study, this RIA as well as a kininogenase and an esterase assay were used to measure urinary kallikrein in DOCA-salt treated rats and in control rats. There is a significant correlation between urinary kallikrein measured by the direct RIA and by a kininogenase method (r = 0.75, p less than 0.001) in both DOCA-salt treated and in the control rats. Although the results obtained by the direct RIA and an esterase method significantly correlate in the control rats (r = -0.048, p greater than 0.1). This suggests that part of the urinary esterase activity in the Doca-salt rats is due to urinary enzymes other than kallikrein and that the esterase assay is not reliable for the determination of urinary kallikrein in pathological situations. However, the direct RIA and the kininogenase assay are suitable for this purpose.


Assay methods for prekallikrein and kininogens and their applications. Prekallikrein activity in plasma was assayed using a synthetic peptidyl fluorogenic substrate (carbobenzoxy-L-phenylalanyl-L-arginine 4-methylcoumarinyl-7-amide), after activation of prekallikrein by acetone and kaolin. For total kininogen assay, the pretreatment of plasma at pH 2.0 was the best to eliminate bradykinin potentiators and kininase activity, before addition of trypsin to convert kininogen to bradykinin. Assay method of high molecular weight (HMW) kininogen was established by conversion of HMW-kininogen to bradykinin through activation of Hageman factor by glass powder and that of low molecular weight (LMW) kininogen was also by treatment of HMW-kininogen-depleted plasma in the same way as that for total kininogen. The marked reduction of prekallikrein and HMW-kininogen, not of LMW-kininogen, was found in pleural fluid of rat carrageenin pleurisy, and in plasma after i.v. injection of bromelain in rats. Members of the pedigree of hereditary angioneurotic edema patients also show low levels of prekallikrein and kininogens in plasma.


Assay of angiotensin I by fluorescence polarization method. Fluorescence polarization technique was applied for the assay of angiotensin I (Al) in human plasma. In this assay system, fluorescein labeled Al (F-Al), which retained the original antigenicity, and antibody to Al was allowed to interact in a cuvette in the instruments yielding an increase in the fluorescence polarization (P) value. Non-labeled Al in the sample blocked the binding of F-Al to the antibody resulting lower P value. Log of antigen concentration and P value was found to exhibit reverse linear proportionality between 0.05 ng to 2 ng/ml of antigen (Al) concentration. The present method was compared with standard radioimmunoassay method and the result showed that data were compatible with each other. The calculation of P value is automated and three cavity filter and optics of the instrument gave reliable results. The method is fast (less than 2 min), sensitive (less than 10 picomole/ml) and simple (no separation step before readout of the results).


Chemical relations between renal and urinary kallikrein of rat. The ratio in micron-Moles between each aminoacid residue of both hydrolized renal and urinary kallikrein of rat, is about 1.00 +/- 0.3. Except for Glu, His and Glucosamine a good proportion between all residues of both enzymes was obtained. It is probable that the different molecular weight, respectively 40,000 for the renal kallikrein and 32,000 for the urinary enzyme, is an artefact of the different procedures used for the purification of rat kallikrein.


The primary structure of porcine glandular kallikreins. The amino acid sequence of the A- and B-chains of porcine pancreatic kallikrein B is presented and compared to that of porcine trypsin. The overall homology between both enzymes is 37% identical residues in corresponding position and 51% chemically similar resideus. Comparison of the sequences with the crystal structure of bovine trypsin reveals that the trypsin "autolysis loop" is enlarged in kallikrein by two residues but lacks the basic residue at the cleavage site. Substitutions at the calcium-binding site of trypsin which include Arg 70 for Glu 70 possibly interfere with ion binding. Insertions between trypsin residues 95 and 96 obviously form a new kallikrein "autolysis loop" containing the site of cleavage between the A- and B-chains. One carbohydrate moiety is attached to this surface loop at Asn 95, the second to Asn 239 at the same edge of the globular molecule. The residues at the surface of the substrate binding site are substituted to an extent of 85% while the residues forming contacts to the trypsin inhibitor (Kunitz) are highly preserved. Immunodiffusion studies as well as identity of the N-terminal sequences of pancreatic, submandibular and urinary kallikrein reveal the same genetic origin of the three glandular kallikreins.


Substrate specificity of porcine pancreatic kallikrein. The primary specificity of porcine pancreatic kallikrein is directed predominantly against arginyl and much less so against lysyl bonds. In addition, the enzyme exhibits pronounced secondary specificity for a bulky residue, preferentially phenylalanine, in position P2 of substrates. This feature is found also in porcine submandibular and urinary and in human urinary kallikrein, but not in bovine trypsin. Residues in P3 and P1' and P1' to P3' also affect hydrolysis by pancreatic kallikrein distinctly more than tryptic hydrolysis. The hexapeptide Pro-Phe-Arg-Ser-Val-Gln with the sequence of bovine kininogen around the C-terminus of kinin contains all the structural elements essential for the interaction with kallikrein, and even glutamine appears dispensable. In contrast to ester models for this site, peptidyl methionine esters with the structure of kininogen towards the N-terminus of kinin, notably bulky leucine in P2, are very poor kallikrein substrates, and appear to be of no value as models for the cleavage of kininogen under formation of kallidin.


Rat stomach kallikrein: its purification and properties. From rat stomach, kallikrein was purified by chromatographies on columns of p-aminobenzamidine-Sepharose, DEAE-Sephadex A-50 and Sephadex G-150 and by isoelectric focusing, measuring its activities to hydrolyse prolylphenylalanyl-arginine-4-methyl-coumarine amide (Pro-Phe-Arg-MCA) and to release kinin from rat heated-plasma. The purified stomach kallikrein showed a single band on Disc electrophoresis at pH 7.0. The molecular weight of the kallikrein was calculated to be 29,000 by gel-filtration on a column of Sephadex G-50. The kallikrein was stable between pH 6 and 11 and hydrolysed Pro-Phe-Arg-MCA optimally at pH 11.0. The Pro-Phe-Arg-MCA hydrolysing activity of rat stomach kallikrein was inhibited by DFP and Trasylol, but not by trypsin inhibitors from soyabean, limabean and ovomucoid. These properties of rat stomach kallikrein was clearly distinguishable from those of partially purified rat plasma kallikrein, but similar properties to other glandular kallikreins from other species. From these results, it was concluded that kallikrein is present in rat stomach, which can be classified into glandular kallikrein.


A simple, large scale process for purifying human urinary kallikrein, based on reverse osmosis and ammonium sulfate precipitation. A simple, large scale process for the purification of human urinary kallikrein is described which is based upon concentration by reverse osmosis, ammonium sulfate precipitation, and gel filtration on a column of Sephadex-G-150. The yield in protein is higher than any reported in the literature to this date; the purified enzyme seems to be identical to that reported by Figueiredo and Mares-Guia at the Kinin-Symposium in Paris, 1978, based on the procedure of Hial, et al., (1974).


Purification of horse renal kallikrein and chemical relations with horse urinary kallikrein. Kallikrein was purified from horse kidney by several steps of chromatographic procedure and by affinity chromatography on Sepharose-Concanavaline. Horse urinary kallikrein was previously purified by DE-32 hydroxylapatite and by Sephadex G-100 gel filtration. On the purified final sample of renal and urinary kallikrein the aminoacid composition and the gel electrophoretic molecular weight were determined. The ratio in micronMoles between each aminoacid residue of both hydrolyzed renal and urinary kallikrein of horse is about 1,00 +/- 0,30. Except for Pro, 1/2 Cys and basic aminoacid residues a good proportion was obtained. It is confirmed that the different molecular weight, respectively 47,500 for renal kallikrein and 28,000 for the urinary enzyme is an artefact of the different procedures used for the purification of horse kallikrein.


Substrate specificities of acid kininogenases. Two kinin forming enzymes were extracted from bovine spleen and separated from cathepsin B1 and B2 by DEAE-Cellulose chromatography. Since these catheptic kininogenases were found to release kinins from kininogens at acidic pH's, these were named acid kininogenase I and II. The presence of SH compounds was not necessary for I to have a kinin forming activity, while it was necessary for II. These have only minor difference for electrophoretic behaviors as can be seen, e.g., from a small difference in pI values, but could be separated by polyacrylamide gel electrophoresis. Their production of kinins from bovine crude bradykininogen was highly reproducible. Kininogenase I was proved to react on bovine HMW kininogen and also to release some kinin from LMW kininogen and leukokininogen. From the study of several substrates, these enzymes were revealed to have very low tryptic and little esterolytic activities and to have affinity to some hydrophobic amino acids.


Preparation of intrinsically-labelled kinins. As part of a program to prepare bradykinin (H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH) labelled at high specific radioactivities, we have synthesized three analogs for dehalogenation in tritium gas: [4-Br-Phe5]-bradykinin (BK), [4-Br-Phe8]-BK and [4-Br-Phe5,8]-BK. The analogs were synthesized by the Merrifield solid-phase method and were purified by molecular sieve and partition chromatography. The analogs themselves possess biological activity (as assayed for effects on mean arterial blood pressure and isolated rat uterus). [4-Br-Phe8]-BK was 1.5 to 3 times as active as bradykinin. [4-Br-Phe5,8]-BK was approx. 22% as active as BK and [4-Br-Phe5]-BK was approx. 18% as active. [4-Br-Phe5]-BK was submitted to catalytic dehalogenation with 10% Pd/C and 5% Rh/CaCO3 in H2O and DMF (1:1) plus 10 Ci of 3H2. [4-3H-Phe5]-BK was obtained at 6.7 Ci/mmole in an overall yield of 15%. [4-3H-Phe8]-BK was prepared similarly to yield an intrinsically-labelled peptide with a specific radioactivity of 21 Ci/mmole.


Significance of adrenergic alpha-effect on salivary kallikrein secretion in the submandibular gland of the dog. The effects of the sympathetic nerve stimulation and the administrations of sympathomimetics on the secretion of salivary kallikrein induced by the chorda tympani stimulation were examined quantitatively and qualitatively in the submandibular gland of the dog. The secretion of salivary kallikrein may be mediated through both adrenergic alpha- and beta-receptors. The activities of salivary kallikrein secreted by either the chorda tympani stimulation or isoproterenol were not inhibited by soy bean trypsin inhibitor in vitro, but those secreted by the sympathetic nerve stimulation and noradrenaline or adrenaline were markedly inhibited in vitro. These results suggested that secretion of glandular kallikrein was induced by the chorda tympani stimulation and the sympathetic beta-stimulation, and secretion of plasma kallikrein was induced by the sympathetic alpha-stimulation.


Possible relationship between salivary kallikrein and water-Na-K secretion stimulated by tityustoxin (TsTx). Intravenous injection of purified scorpion toxin (TsTx) brings about the appearance of salivary flow with high levels of Na and K and kallikrein in the saliva of the rats. In experiments performed in vivo a positive correlation between Na and partially with K and kallikrein was observed in parotid and submaxillary saliva. After ouabaine, saliva K was increasing, whereas Na decreased, and a parallel decrease of kallikrein was observed. Adrenergic and cholinergic blocking drugs also showed a marked reduction in the output of Na (atropine), and partially of K (atropine or phentolamine), with a correlation in theoutput of kallikrein per min. The results of the present investigations support the hypothesis that salivary kallikrein-kinin system is probably involved in salivary control of Na, partially K and water secretion.


Effect of kallikrein-kinin system on ion transport across rat small intestine. The flow of glucose and valine from the mucosal to the serosal side of rat intestine was stimulated significantly by kallikrein-kinin system. To elucidate the mechanism of this function the effects of kallidin on the transmural potential difference (PDt) between the serodal and the mucosal sides and the transepithelial resistance (Rt) of rat jejunum segment were investigated by electrophysiological procedures. The glucose-evoked PDt was not significantly altered by addition of kallidin to the mucosal fluid. Meanwhile, PDt which evoked by glucose was significantly shifted under the presence of 10-1-10(2) ng kallidin in the serosal fluid. The valine-evoked PDt was also changed by addition of 10 ng kallidin into the serosal fluid. However, the addition of glucose to the mucosal and kallidin to the serosal fluid did not affect on the Rt of the jejunum segment. These results suggest that kinin stimulated Na+ transport at the baso-lateral membrane of the intestinal absorptive cells, and the transports of other substances were enhanced consequently.


The interaction of kallikrein with urokinase in peripheral circulatory disorders. A microcirculatory observation. Kallikrein and urokinase were used successively in dogs and patients with peripheral vascular disturbance. It was found that kallikrein showed similar pattern of peripheral dye solution curve with that of urokinase. However, its action was slower than urokinase.


Determination of various semen parameters and sex hormone levels in subfertile men during kallikrein therapy. Thirty-one (31) subfertile men with idiopathic iligozoospermia were treated by a daily oral medication of 600 units of pancreatic kallikrein (Padutin(R) 100) over a period of 3 months. Total sperm output increased significantly with a maximum 3 months after initiation of therapy. In addition, quantitative and qualitative sperm motility improved during treatment and was still improved 2 months after withdrawal of therapy. Compared to other regimens, oral administration of 600 units kallikrein for a period of 3 months yielded better results than shorter medication periods or lower dosage. Quantitative determination of several serum proteins occurring in seminal plasma before, during and after kallikrein therapy showed a significant increase of alpha 1, x-antichymotrypsin. Thus, kallikrein treatment seems to affect, to a certain degree, the secretory activity of the accessory glands or the blood-seminal plasma barrier. Determination of serum gonadotropins and serum testosterone levels showed a significant increase of LH and testosterone during kallikrein treatment, whereas FSH was unaffected. Thus, systemic kallikrein administration induces significant changes of the pituitary-gonadal axis influencing spermatogenesis and epididymal sperm maturation. However, the local action of kinins as pharmacological active tissue hormones has to be considered too.


Metabolic changes after application of kallikrein in an ergometrical test. Kallikrein given in a dose of 3 times 200 KE daily over 7 days caused under our test conditions an increase of ATP in blood and a decrease of lactate and especially of pyruvate. Glucose showed under this condition a higher utilization with a lowering of glucose in blood and an increase of the RQ. The acid-base metabolism follows these tendencies. In other experiments we did not find such effects, so the results must be specific to kallikrein.


Participation of kallikrein, coagulation/fibrinolysis parameters in the development of glomerulonephritis. Masugi nephritis was induced in dogs in which platelet count, fibrinogen, antithrombin activity, plasma prekallikrein and immediate plasmin inhibitors were coincidentally decreased immediately after the injection of nephrotoxin serum. It was found that the grade of decrease of urinary kallikrein excretion following these immediate reactions were parallel with the grade of renal damages. By the pretreatment with heparin or the defibrination with snake venom, however, the histological findings of Masugi nephritis showed rather severe damage. Based on the consumption of coagulation factors, kallikrein, kinin and their inhibitors in the development of this nephritis, it was postulated that inauguration of coagulation and activation of kallikrein contributed to the development of glomerulonephritis. The treatment or prevention of this coagulation process with heparin or snake venom, however, gave untoward effects on the pathological process in this experiment.


Autoreversal of bradykinin response in the perfused isolated canine hind limb. The vascular effects of synthetic bradykinin were studied in perfused isolated canine hind limb preparations. Repeated low doses of bradykinin or high doses administered at sufficiently long time intervals elicited dose-related hypotensive responses. In contrast, administration of bradykinin at short time intervals led first to diminishing hypotensive responses followed by frank increases in perfusion pressure. This autoreversal of bradykinin response tentatively was explained on the basis of known effects of bradykinin on prostaglandin synthesis with specific reference to PGF2 alpha.


An approach to the chemical quantitation of kinins for the assay of kininogenases. A method was developed for the rapid isolation and identification of kallidin produced by hog pancreatic kallikrein on a partially purified bovine plasma kininogen preparation. By means of a reversed phase chromatography on a C18-silica gel column, kallidin was rapidly concentrated from the reaction mixture, and subsequently resolved on a thin-layer plate of silica gel 60. Fluorescamine was used to locate the kinin. Efforts to elute the kinin from the TLC plates for quantitation were not successful.


Methods for the determination of glandular kallikrein by means of a chromogenic tripeptide substrate. A chromogenic peptide substrate H-D-Val-Leu-Arg-pNA (S-2266) has been used for the determination of glandular kallikrein derived from pancreas, urine and saliva. The conditions used have been optimized. The methods developed are simple and shown to have good reproducibility.


Histamine H1-and H2-receptors in coronary arteries of pigs. Histamine exerts its action in smooth muscle via in two types of receptors. In coronary arteries of pigs both types of receptors are also involved in responses to histamine. Histamine initiates by an interaction with H1-receptors a contraction and with H2-receptors a relaxation. The histamine-induced contraction is reduced by the competitively antagonistic action of mepyramine. Metiamide potentiates dose-dependently the histamine-caused contraction in the absence and presence of mepyramine. The proportion of H2-receptors in relation to H1-receptors is calculated.


Anomalous biological effects of salicylates and prostaglandins. While some salicylates (salicyclic acid and salicylaldehyde, especially) are as potent as aspirin as acute, orally-active anti-flammatory drugs in the rat, they are either inactive or far less potent as PG synthesis inhibitors when added directly to isolated platelets or when given orally. Although PGE1 and PGE2 produce anti-ulcerogenic effects when given to rats in the presence of selected non-steroidal anti-flammatory drugs, they fail to inhibit the acute anti-flammatory and anti-nociceptive effects of these drugs. They are anti-flammatory and anti-nociceptive under certain experimental conditions. PGE1 and PGE2 can also behave as hypothermic agents when given subcutaneously. Related studies, using PG synthesis stimulators in vivo and in vitro (substituted phenylureas), also cause anti-nociception and hypothermia. All of these indirect studies, when taken together, infer that PG synthesis inhibition per se fails to explain, entirely, the pharmacologic effects of non-steroidal anti-inflammatory drugs. They also suggest that the precise role of certain PGs in toxicopharmacology is far from simple and straightforward.


Effects of 2-aminomethyl-4-t-butyl-6-iodophenol (MK-447) on granulomatous inflammation: lack of correlation with changes in levels of prostaglandin-like material. MK-447, administered locally to carrageenan-soaked sponges implanted in the backs of rats, either on the day of implantation (day 1) or on days 4-7, exhibited a weak, dose-related inhibition of subsequent granuloma formation. With the later treatment period, prostaglandin (PG)-like material in day 8 exudates was increased at all doses, but with MK-447 treatment on day 1, levels of PG-like material after 24 h were unaffected. Thus, inhibition of granuloma formation was unrelated to local levels of PG-like material. Following treatment with low doses of MK-447 on implantation, mononuclear cell counts in 24 h exudates were reduced. Similar results were obtained with PGE1. Higher doses of MK-447 did not alter monuclear cell counts, but both high and low doses of MK-447 markedly increased polymorphonuclear cell counts in 24-h exudates. The results do not permit the conclusion that the anti-granuloma action of MK-447 is necessarily related to alteration of stable PG level at the inflamed site. Therefore, MK-447 cannot be used unequivocably as a tool to investigate the role of endogenous stable PGs during granulomatous inflammation.


A comparison of coumarin and levamisole on parameters of the inflammatory response. Three experimental animal models have been used in the studies on the stimulatory effect of coumarin and levamisole. Both coumarin and levamisole increases cell coverage on subcutaneous implanted glass coverslip in mice. An increase in intracellular phosphatase activity was also observed. Stimulated mouse peritoneal cells when treated in vivo with coumarin or levamisole and then cultured in vitro showed increases acid phosphatase secretion (both extracellular and intracellular) as compared to control. Coumarin reduced the primary lesion of adjuvant-induced arthritis in rats. However, it potentiates the secondary lesions. Levamisole has no effect on the primary lesion but potentiates the secondary lesions. There was an increase in spleen and adrenal weights which correlate well with the severity of the secondary lesions. Increase in liver weight was only observed in coumarin-treated animals, an observation which suggests that coumarin may be a powerful mononuclear phagocytes system stimulant. The similarities and differences between coumarin and levamisole in their mode of action will be discussed.


Relationships between inhibition of rat polymorphonuclear chemotaxis and various inflammatory reactions. An extension has been made of previous studies which linked the induction of inflammatory responses by carrageenan with the production or release of a factor which could be detected in the serum and which was capable of inhibiting leucocyte chemotaxis. Thus an inhibition of chemotaxis has been shown to be related also to inflammatory reactions provoked by calcium pyrophosphate and complete Freund's adjuvant and in the latter case the chemotaxis inhibition showed some correlation with the progress of the inflammatory reaction.


[Methods of identifying carcinogenic factors in medication, food and cosmetics]. The removal of carconogenic factors would be a most efficient measure to prevent cancer. As far as known chemicals are concerned, every effort is made to avert them, or at least to reduce the exposure to such compounds, but is necessary to detect unknown chemicals, especially those, drugs and foodstuffs for example, to which large populations are exposed. Giving suspected chemicals to laboratory animals is a standard carcinogenicity test. Studies of the carcinogenicity of unknown chemicals in animals are time consuming, expensive and cumbersome. This is why other means of establishing carcinogenicity are sought for. Several rapid tests are available to-day to select suspected carcinogens. These methods aim primarily at determining with chemicals--at the cell or tissue level--certain changes that would appear essential to trigger the carcinogenic process, such as somatic mutations. Studies are used on the mutagenicity of chemicals for bacteria of the Salmonella type, for yeast and cultured mammalian cells, together with the induction of recessive lethal mutations in Drosophila and of the unscheduled repair synthesis of DNA and the transformation of mammalian cells in vitro. Although there is an unequivocal correlation between the activity of chemicals in such tests and their carcinogenicity, discrepancies are found. Thus, the in vivo tests on laboratory animals remain the most reliable method to determine carcinogenicity. Whereas direct extrapolation of experimental data to human pathology is impossible, the experimental evidence of the carcinogenicity of any chemical should allow us to draw constructive conclusions. We shall never be able to reject drugs which produce the expected results and cannot be replaced by other drugs. But we can must the drugs whose beneficial effects are not exceptional and which can be replaced by other chemicals. As for the chemicals used in food additives and cosmetics, and recognized as carcinogenic in animals, they should be totally given up. Any decision made should be based on animal studies.


[The LOUVAIN rat and its importance in cancerology]. The LOUVAIN rat model is characterized by a high incidence of spontaneous tumors which is extremely rare in animals. Presently, the spectrum of monoclonal immunoglobulins synthetized by these tumors is the largest ever discovered in animals. Particularly, the LOUVAIN rat tumors produced the only IgD and IgE monoclonal immunoglobuling discovered in an animal species up to now. The contributions of this model to experimental cancerology were multiple: some of them originate in its high incidence, its anatomopathological type or its production of homogenous proteins, others, in the antigenic properties of the monoclonal immunoglobulins synthetized by these tumors, allowing the study of their natural analogues in absolutely new experimental conditions.


[Utilization of chromosomal markers in cancer research]. The mouse is an unsuitable species for cytogenetical studies to the extent that it has 40 acrocentric chromosomes and the only criterion which could be used to differentiate them is size. We envisaged using in the case of cell grafts donors or recipients of different sex. This technique has, however, been used to a limited extent. Among the other markers which have been utilized, T6T6 of CBA mice must be mentioned. The discovery in 1966 by Léonard and Dekundt of the presence in AKR mice of fusions of the Robertson type (between chromosomes 6 and 15) has generated new interest in experimental work based on the utilisation of chromosome markers. Being interested in the mechanisms of radio-induced leukemia, the authors described how they have introduced the chromosome marker of AKR mice into the C57B1 strain which is very sensitive to the induction of radio-induced leukemias.


Types and quality of animals in cancer research. In addition to studies in man, animal models may serve as important tools in the detection of the etiology, biology and treatment of certain types of human cancers. Various models have become available by performing life span studies on 2 rat strains, viz WAG/Rij, BN/Bi and (WAG x BN) F1 hybrid and on Praomys natalensis. Several of these models are described. A basic prerequisite for these types of studies is the availability of animals of good quality. After a general description of the quality of laboratory animals the desirable health status of animals in cancer research is discussed.


[An animal model for tumors of the large intestine]. Dimethylhydrazine (DMH) and its derivatives induced in many animal species tumors of the large intestine with a great specificity and reproductibility. Oour personal observations using rats BD IX injected weekly with DMH are summarized in this presentation. The induced tumors appear as invaded tumors already at the microscopic stade. Their growth is best described by a Gompertz function. The number of induced tumors increases with time as a non linear function. This model is very useful for the study of the biology of human tumors with a low development.


[Transplantable carcinoma of the large intestine in BD IX rats: a new model for study of metastatic dissemination and experimental therapeutics]. Using cells in culture of a large intestine carcinoma by the rat BD IX, the authors have produced 5 experimental models of metastases: subcutane, of the lung, the liver and the peritoneum. These metastases have the same properties as the primitive tumor. These four models have the originality to be metastases of a large intestine carcinoma chemically induced in the rat representing situations frequently encountered in human cancerology in the case of generalised cancer. These models allow immunotherapy, immunoprophylaxis, chimotherapy, angiotherapy and biochemical studies and to test the effects of certain substances such as the anticoagulants.


Induction of malignant and benign tumors with embryonic tissues. The inoculation of viruses into the placenta of fetectomized rats induces the development of malignant tumors from extraembryonic fetal membranes. The same membrane--visceral yolk sac--gives rise to benign teratomas if displaced outside the uterus after fetectomy. Moreover, the transplantation of 3 to 7 day old embroys under the kidney capsule of adult mice gives rise of malignant teratocarcinoma. The methods to induction of these tumors are described.


Family: a systems approach.

Family: a systems approach. The family is a social system with elements of structure, bonding, boundaries and function. The person and the dyad are the building blocks (subsystems) of the family. A systems approach allows the family physician to elucidate specific areas of disruption, describe problems in terms of family elements and intervene at the appropriate hierarchic level to promote optimum health to family members.


Muscle contraction headache.

Muscle contraction headache. This is the common "tension" or "nervous" headache. It is extracranial in origin, and is often precipitated by anxiety or depression. The headache is usually bilateral, nonpulsatile and of longer duration than migraine, with no focal signs or symptoms. While aspirin remains the most practical and useful analgesic for head pain of low intensity, combination agents are useful and drugs to control anxiety associated with headache are appropriate.


Depression in late life.

Depression in late life. The depressed elderly have the highest suicide risk of any group in our society. Thus, depression in late life is a serious mental health problem. The essential goal of the diagnostic work-up is to distinguish a major depressive episode from less severe dysphoric symptoms. The major treatment modalities are properly selected pharmacologic agents, electroconvulsive therapy, psychotherapy and counseling, increased physical and social activity, and attention to underlying medical problems.


Plasma catecholamines in acute myocardial infarction. Plasma catecholamine levels were determined in 26 cases of uncomplicated myocardial infarction within 24 hours of onset of acute chest pain. Blood samples were collected at time of entry and at 4-hour intervals during the 48 hours following admission. Average values of plasma catecholamines within 1 hour of onset of pain were 0.87 ng./ml +/- 0.21 and remained elevated during the first 24 hours period. A gradual fall in catecholamine values was observed during the second 24-hour period. Catecholamines were higher in patients with sinus tachycardia and lower in patients with sinus bradycardia, and were higher in patients with anterior or anterolateral infarction. Catecholamine values were significantly higher when determined while patients presented ventricular ectopic beats or ventricular tachycardia. Sinus tachycardia, ventricular arrhythmias, and elevated plasma catecholamine values may be considered indicators of pain, anxiety, and/or left ventricular dysfunction without necessarily being causally related between themselves.


Progression of mild mitral stenosis and incidence of restenosis after open commissurotomy: a study using echocardiography. Thirteen patients with mild mitral stenosis and 21 asymptomatic patients after commissurotomy were studied by echocardiography in order to assess the rate of progression of mitral stenosis and the incidence of restenosis after successful open mitral commissurotomy. In the group with mitral stenosis there was a decrease of the diastolic closing velocity (E-F slope) from 35.7 to 29.5 mm./sec. (p less than 0.0005) over a period of 37 months. In 23% of the patients the stenosis increased significantly (p less than 0.0005) by echocardiographic parameters. Forty-eight months after commissurotomy we noted a significant over-all slowing of the diastolic closing velocity (from 52.6 to 44.8 mm./sec., p less than 0.0005) and a decrease of the mitral valve closure index DE/MAIC (from 1.7 to 1.5, p less than 0.0025). Five of 21 patients (24%) showed a change in one or both of these parameters which was greater than 2 standard deviations of the mean change. Based on echocardiographic criteria, we conclude that patients with mild mitral stenosis and asymptomatic patients following successful commissurotomy need only be checked approximately every 3 years.


Isolated ultrafiltration in the therapy of volume overload accompanying oliguric vascular shock states. Isolated ultrafiltration (removal of plasma water and solute without dialysis) was used as a "last resort" therapy in three patients with diuretic and pressor resistant oliguria complicating severe volume overload and vascular shock. The improvement in clinical and hemodynamic parameters is reported and the possible mechanisms of action (decreased pulmonary capillary wedge pressure and increased colloid osmotic pressure) are discussed.


Exercise testing: a prospective study of complication rates. Twenty departments of clinical physiology in Sweden, doing annually 30,000 exercise stress tests, mainly of patients, completed a questionnaire regarding how they carried out exercise testing. Bicycle ergometry was predominantely used. The criteria for inclusion of patients for exercise testing and for interruption of the test were generally wide, allowing the patient to work until symptoms limited the test. In a second part of the investigation, the departments continuously reported all complications that occurred during an 18-month period which included 50,000 exercise tests. The complication rate was 18.4, the morbidity rate was 5.2, and the mortality rate was 0.4 per 10,000 tests. The number of complications leading to permanent damage was low and it could not be proved that the exercise test had induced a higher complication rate than otherwise would have occurred during the observation period. Patients with aortic stenosis had a high risk for complications. With adequate safety measures and a well-trained staff, exercise stress testing can be regarded as a safe method to be used in the evaluation of even very ill patients.


Complications with retained transvenous pacemaker electrodes. Out of a series of 1,734 pacemaker patients, the clinical course of 46 patients was reviewed in whom a functionless endocardial electrode was retained. Non-infected electrodes (25 patients) were generally well tolerated without complications, except in one patient who experienced fatal catheter embolism into the pulmonary artery. In cases of infected electrodes (21 patients) a mortality rate of 25% was encountered due to septic complications. Catheter migration was fatal in two out of three patients. It is concluded that entrapped electrode catheters should be removed by thoracotomy if persisting infection is present or if catheter migration has occurred.


Evaluation of the beta-blocking drug acebutolol in angina pectoris. The effects of the beta-adernergic blocking drug acebutolol were studied in 23 patients with angina pectoris and angiographically documented coronary artery disease. Patients were evaluated clinically, by graded treadmill testing and by 24-hour Holter monitoring in the control state, after 2 weeks treatment with placebo, and after 2 weeks treatment with 600 mg. and then 1,200 mg. of acebutolol. Acebutolol (in a daily dose of 600 mg.) was an effective antianginal drug: the number of clinical attacks of angina pectoris (p less than 0.001) and the consumption of sublingual nitrate decreased (p less than 0.01), there was a significant increase in the treadmill effort tolerance as measured by the time to appearance of ischemic ECG changes (p less than 0.001) and the total work performed (p less than 0.001), and there was also a significant decrease in ischemic ST segment depression on 24-hour Holter monitoring. Treatment with 1,200 mg. acebutolol was associated with a further decrease in heart rate and a further improvement in effort tolerance on treadmill testing (p less than 0.05). On the large dose of the drug, however, there was no further clinical improvement, and no further improvement on 24-hour ECG monitoring; several patients complained of weakness and fatigue. Graded treadmill testing was an excellent objective method for assessing physical effort tolerance and its improvement after treatment with the beta-blocking drug. Twenty-four-hour Holter monitoring was a useful and complementary test, especially in patients who stopped exercising on the treadmill because of fatigue or weakness, and especially for assessing the efficacy of beta-blockade in controlling emotionally induced tachycardia and ischemia in the patient's own daily environment.


Low output syndrome in right ventricular infarction. In this paper we describe clinical and hemodynamic data in ten patients with right ventricular infarction and low output syndrome. Atrioventricular block and supraventricular arrhythmias were a common finding. All of them had a right atrial pressure disproportionately increased (average 16.3 +/- 5.2 mm. Hg) in relation to left ventricular filling pressure (average 15 +/- 4.5 mm. Hg), and a very low cardiac index (average 1.42 +/- 0.45 liters/min./m.2). The right atrial pulse tracings were similar to those of constrictive pericarditis, showing a deep "y" descent in every patient. We made the differential diagnosis between similar hemodynamic entities and constructed function curves of right and left ventricles. Right ventricular diastolic work index was always increased (average 6.26 +/- 3.63 gm./beat/M.2), being higher than net work index (average 3.28 +/- 1.87 gm./beat/M.2). While all function curves of the right ventricle were flat or depressed, those of the left ventricle were very different. Treatment consisted mainly of fluid overload and, in some cases, of vasodilators or dopamine. Mortality rate was 40%. We think that coexisting left ventricular damage may account in part for the bad prognosis of these patients.


Ethmozin: a new antiarrhythmic agent developed in the USSR. Efficacy and tolerance. Ethmozin, a phenothiazine derivative, was developed in the Soviet Union as a new antiarrhythmic agent. We evaluated ethmozin using a controlled single-blinded in-hospital protocol in 14 ambulatory patients with ventricular ectopy ranging from an average of 48 to 1,801 depolarizations per hour and in eight patients with atrial ectopy ranging from 63 to 693 depolarizations per hour. Placebo was administered for the first 3 days, followed by ethmozin from 2.4 to 11.2 mg./Kg./day administered orally every 8 hours for 7 days and concluding with placebo for the final 3 days. Continuous 24-hour long-term electrocardiographic monitoring for 13 days was employed to measure drug efficacy accurately. Six of eight (75 per cent) patients with atrial ectopy and 10 of 14 (71 per cent) patients with ventricular ectopy had statistically significant reductions in ectopy during ethmozin therapy. Atrial ectopy was reduced at a lower dose and plasma level of ethmozin than was ventricular ectopy. With the exception of mild nausea in one patient, no side effects of ethmozin therapy were noted. Ethmozin appears to be a well-tolerated, effective antiarrhythmic agent with a dosage regimen that can promote patient compliance for long-term use.


Re-evaluation of a possible high incidence of hypertension in hypothyroid patients. In an attempt to re-evaluate a possible high incidence of hypertension in hypothyroid patients, blood pressure was measured in 38 slightly hypothyroid patients, in 17 moderate hypothyroid patients, and in 26 severe hypothyroid patients. The data were then compared with the findings in 73 known euthyroid subjects and in 1,601 possibly euthyroid subjects. Blood pressure and incidence of hypertension increased progressively with age in known euthyroid subjects and in possibly euthyroid subjects. Similarly, blood pressure increased progressively with age in slight and moderate hypothyroid patients, but the incidence of hypertension was high in the sixth decade in slightly hypothyroid patients for some unknown reason. In contrast, blood pressure and the incidence of hypertension were low in the fifth and sixth decades in severe hypothyroid patients. This low blood pressure was elevated slightly when Sv1 + Rv5 and C/T were shifted toward normal by T4 treatment for 3 to 4 months. It is suggested that the hypothyroid state does not accelerate the development of hypertension.


Rate of progression of severity of valvular aortic stenosis in the adult. In a retrospective study, 29 patients at least 20 years of age with known aortic stenosis are reported who had the peak systolic gradient (PSG) measured on at least two occasions without an intervening surgical procedure or episode of endocarditis. In these 29 patients, there were 31 intervals available for evaluation with a mean follow-up time of 43.5 months (1 week to 120 months). In 16 of the 31 intervals, the PSG increased by 50% or more and in 15, it did not. In the group where the PSG increased, the average rate of increase was 1.3 mm. Hg/month with the most rapid gradient increase at 3.8 mm. Hg/month. Progression to high gradient was correlated with the development of angina pectoris or left ventricular hypertrophy by voltage and ST-T wave changes. In this study, other symptoms were not helpful in predicting an increase in severity. It is still recommended, however, that any patient with aortic stenosis and the development of symptoms of congestive heart failure or exertional syncope should be suspected of having progressed to severe aortic stenosis and should be restudied.


Clinical study on the right-sided Austin Flint murmur using intracardiac phonocardiography. Right heart catheterization was carried out on 14 patients with pulmonic regurgitation using intracardiac phonocardiography. All the patients showed pulmonic regurgitant murmur in the right ventricular outflow tract. In addition, seven out of the 14 patients showed mid-diastolic and presystolic murmurs maximally in the outflow tract of the right ventricle. Furthermore, inspiration increased the loudness of these diastolic murmurs in four patients. These findings were compatible with those of right-sided Austin Flint murmur due to functional tricuspid stenosis in pulmonic incompetence. Ten out of the 14 patients had pulmonary hypertension and all the subjects with a rightsided Austin Flint murmur showed elevated pulmonary arterial pressure. Thus, pulmonic regurgitation with pulmonary hypertension is thought to be closely related to the right-sided Austin Flint murmur and the turbulence resulting from antegrade flow across a closing tricuspid valve may be responsible for the genesis of the murmur.


Quinidine therapy in hospitalized patients with ventricular arrhythmias. Quinidine serum levels and pharmacokinetic data were assessed during steady state therapy with oral quinidine sulfate in 19 hospitalized patients who were being treated for ventricular arrhythmias. A new high performance liquid chromatography assay was employed. Four patients were studied both after the first dose of quinidine and at steady state, and the initial dose pharmacokinetic values were found not to be predictive of steady state. The mean half-life of quinidine was 4.5 hours, but there was wide individual variation. The elimination rate constant for quinidine was significantly lower in patients with echocardiographic evidence of left ventricular dilatation than in patients with normal echocardiographic left ventricular size. The average urinary excretion of quinidine was only 11.3%. The pharmacokinetic data in seven chronic alcoholic patients without clinical or laboratory evidence of hepatic insufficiency did not differ from the data obtained in nonalcoholic patients. However, with severely impaired liver function, there may be marked prolongation of quinidine half-life predisposing to quinidine toxicity. The possible clinical implications of these findings are discussed.


An experimental study of release arrhythmia: Occlusion time-dependent changes in ventricular fibrillation threshold. There have been many reports about ventricular arrhythmias during acute coronary occlusion. Nevertheless, it is only recently that interest has been taken in the occurrence of ventricular arrhythmia after reperfusion following coronary occlusion. To investigate the mechanism of the latter kind of arrhythmia, we studied the effect of changing the duration of occlusion time on the recovery time courses of the VMRT (Ventricular Multiple Response Threshold), and of the A-V differences in the serum K+ concentration across the heart. The time course of delta K+ recovered soon after reperfusion, while changes in VMRT needed more time for recovery to the initial state. Concerning heart rate, blood pH, and the levels of Na+, Cl-, and Ca++, no significant changes were detected. There was no relation between the time courses of VMRT and those of the A-V differences in serum K+. Consequently, time courses in VMRT were dependent upon the duration of coronary occlusion time. A possible explanation for these results may be that the longer the duration of the preceding occlusion time, the more severe the myocardial damage due to myocardial ischemia.


Increased ejection fraction produced by a long-term subhypertensive infusion of norepinephrine in the conscious dog. Five mongrel dogs with chronically implanted catheters in the left atrium, mid-thoracic aorta, and right atrium were continuously infused with subhypertensive doses of norepinephrine for 3 months. Left ventricular cineangiography, determinations of aortic pressure, and cardiac output were performed in the conscious dog. After 3 months of continuous norepinephrine infusion, stroke volume increased from 38 +/- 3.0 to 67 +/- 8.0 ml. (p less than .01), the left ventricular end-diastolic volume increased from 72 +/- 6.4 to 89 +/- 12.9 ml. (p less than .05), and the ejection fraction increased from 52 +/- 3.6 to 76 +/- 3.6% (p less than .005). We postulate that norepinephrine results in an increased myocardial function by producing physiological myocardial hypertrophy.


Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients. Twenty-four post-cardiac patients had 24 hour DER at a mean time of 30.1 days post-MI and 31.5 days post-MR. All patients experienced sexual activity at least once during the 24 hours. Heart rate ranged from a mean of 74.0 to 107.8 BPM in the MI group and from 90.2 to 117.8 in the MR group. Twelve of the 24 patients recorded cardiac electrical abnormalities during sexual activity and five of these 12 had abnormalities associated only with or more frequently with sexual activity. It is concluded that sexual activity may provoke cardiac electrical events not elicited by other stimuli and this may warrant consideration for patient counseling and/or specific therapy.