Neonatal hip instability. Reason for failure of early abduction treatment.

A series of nine children with hip joint instability in 17 hips, diagnosed neonatally, is presented. Seven had bilateral idiopathic instability and two instability secondary to arthrogryposis, one of them bilateral. After reduction seven of the children (14 hips) were treated with abduction devices, which in all cases did not lead to stability in one or both hips. In these cases arthrography revealed that closed reduction was impossible due to narrowing of the joint capsule (hour-glass shape) and the interposition of a capsular fold including the acetabular labrum. The same types of changes were seen within 1 or 2 months after birth in three hips which had had no abduction treatment before arthrography. At open reduction of 11 hips it was found that the narrowing of the capsule was caused by the tendons of the iliopsoas and rectus femoris muscles. Excision of the capsular fold (labrum) was not necessary. The femoral head was deformed and anteverted. Failure of conservative treatment can be due either to incomplete reduction or to inadequate immobilization. Our analysis has shown that the most probable reason is incomplete reduction due to interposition. An obstacle to reduction should be suspected if abduction is restricted at birth, if primary reduction is difficult and the position difficult to maintain or if instability persists after 8 weeks of treatment. On the basis of our material the incidence of such an impediment to reduction was 0.08 per thousand births in the region studied during a 5-year period.


Long term results of surgery for non-acute anteromedial rotatory instability of the knee.

Seventy-eight patients treated by extraarticular reconstruction including pes anserinus transfer for anteromedial rotatory instability of the knee were reinvestigated 16--47 months (mean 28) after operation. Function before and after operation was assessed by means of a knee rating score. Of these patients, 94 per cent showed a higher score after operation. Twenty per cent showed full recovery with no limitation of knee function whatsoever. The follow-up score was higher with preserved medial meniscus function than when this structure had been removed. When not initially torn, the medial meniscus tended to become involved with time. Mild laxity in extension, possibly indicative of a posterior cruciate injury previously underestimated or not observed, was found in 15 per cent of the patients. No correlation was found between late knee function and the interval between injury and operation or the interval between operation and follow-up examination. The long term results were good. Extraarticular reconstruction is thus indicated in cases of chronic rotatory instability of the anteromedial type. Routine meniscectomy is not recommended in these patients, however. Signs possibly indicating posterior cruciate ligament involvement should be carefully looked for, as even minor posterior cruciate injury, easily overlooked, may influence the late results.


Recurrent instability of the ankle joint. Surgical repair by the Watson-Jones method.

Twenty-one ankle joints with recurrent lateral instability, treated with surgical repair by the Watson-Jones method, were included in a follow-up study 1--5 years after operation. Good results were achieved in 80 per cent. However, the results were not better than those after free dissection and direct suture of the ligamentous ruptures. It is therefore recommended that the more extensive Watson-Jones procedure be reserved for selected cases.


Morphological alteration of the stria vascularis after administration of the diuretic bumetanide.

Chinchillas were given either a single injection of the diuretic bumetanide (18 mg/kg body weight) or saline-sodium hydroxide and sacrificed at 10 min, 1 hr and 24 hr after the injection. Slight stria edema was present at 10 min, marked edema at 1 hr and no edema 24 h after bumetanide. The edema began in the first cochlear turn at 10 min and spread to the second turn by 1 hr. Along with edema, marginal cell bulging, potential capillary constriction and the formation of marginal cell membranous structures occurred after bumetanide treatment.


The influence of pneumatization of mastoid bone on caloric nystagmus response. A clinical study and a mathematical model.

Pursuing the problem whether and why the pneumatization of mastoid bone has any influence on caloric nystagmus, we examined 15 large or extensively (L.P.) and 15 poorly (P.P.) pneumatized subjects. Following water irrigation (44 degrees and 30 degrees C, 30 sec) we checked the parameters maximum SPV, max. frequency, latency, duration and time of max. response by ENG recordings. Both groups differed significantly for all parameters except duration (p less than 0.001). On comparing these findings with an earlier proposed model (Bock & Bromm, 1977) we could show a good correspondence for the P.P. group by doubling the parameter 'thermal diffusivity of mastoid bone'. An even better correspondence could be found by diminishing the parameter 'coefficient of temperature changes by perfusion'. The theoretical and practical implications and conclusions of our findings are discussed.


The significance of the target frequency and the target speed in optokinetic nystagmus (OKN).

The significance of the frequency of the stimuli (target frequency) and the angular velocity of the stimuli (target speed) on horizontal optokinetic nystagmus (OKN) was investigated in 6 normal human subjects using target frequencies from 1/3 Hz to 24 Hz and target speeds from 5 degrees/sec to 120 degrees/sec. Regularity and reproductiveness of the OKN were obtained only in test conditions where each transit of targets was followed by an optokinetic response either as one beat or as a sequence of beats. This is called synchronous response and was found when the target frequency was below 3 Hz and the target speeds below 20--30 degrees/sec, depending on the actual frequency. At higher target frequencies and target speeds, the eyes were unable to take up every target, resulting in uneven responses (hyposynchronous response). Very low target frequencies and target speeds were likewise unsuitable due to drifting of the eyes from one target to another. A target frequency and a target speed close to the upper limit for synchronous response is advocated in clinical tests of OKN. 2 Hz and 20 degrees/sec is proposed as a suitable combination of frequency and target speed.


Myringotomy in the treatment of acute otitis media in children.

The treatment of acute otitis media was studied in 158 children. All children (mean age 4 years) received penicillin orally 80 000--100 000 IU per day for 10 days. Myringotomy was performed on 68 children at the time of the diagnosis. The other 90 children were treated with penicillin and ear drops. The bacteriological findings from the nasopharynx at the time of diagnosis were equivalent in both groups. After 2 weeks, 42% of the children without myringotomy and 71% of the children with myringotomy were cured. The children who were not cured were treated with amoxicillin for 10 days. Four weeks after diagnosis 71% and 90% of the children respectively were cured. The differences between the two groups are significant. The observations indicate that myringotomy clearly accelerates the recovery from acute otitis media.


Non-traumatic cerebrospinal rhinorrhea and chondrodystrophy.

Two chondrodystrophic males have developed a non-traumatic cerebrospinal rhinorrhea within their second decade. Hydrocephalus was the cause of cerebrospinal fluid leakage in both cases. To lower the intracranial pressure the neurosurgeon performed a ventriculocardiostomy. The fistula was closed by the rhinosurgical extradural route. With respect to the atrophic brain in cases of hydrocephalus, the fronto-nasal approach appeared to be the best and less traumatic way of exposing the frontal base of the skull.


Physiological activation of the stapedius muscle in Gallus gallus.

The function of the avian middle ear muscle was investigated in the chicken, Gallus gallus (domesticus). The avian species offers excellent conditions for study of middle ear muscle function since it possesses a single middle ear muscle, the stapedius, which is located extracranially. Electromyograms (EMG), measurements of impedance change, and volume change in the middle ear cavity were used to assess the muscle's activity. The results showed that the middle ear muscle of Gallus does not exhibit an acoustic reflex. However, the stapedius is regularly activated during the animal's own vocalization. Measurements of the EMG and volume change showed the stapedial activity to increase systematically with increases in the vocal sound level. The use of volume change as a measure of stapedius function was found to be highly suitable in the present experiments in that it allows for measurements of the magnitude of the stapedius contraction without altering the intact physiological state of the middle ear, and is insensitive to the ambient noise and vocal sounds, that hamper the impedance technique.


Embryonal rhabdomyosarcoma of the middle ear.

An embryonic sarcoma of the middle ear occurring in a child has been described. The mainstay of treatment has been triple therapy. The child is well 4 years and 3 months after diagnosis.


Role of the tensor veli palatini muscle in movement of the soft palate.

To examine the role of the tensor veli palatini muscle in palatal movement, we conducted 1) quantitative measurement of palatal movement by selective stimulation of the tensor and levator muscles, and 2) EMG recording of the two muscles during phonation. The results were: 1) negligible palatal movement upon tensor stimulation, despite a marked velar elevation by levator stimulation; and 2) little EMG activity of the tensor and marked EMG activity of the levator during phonation. It was concluded that the tensor plays no role in the palatal function.


Laryngeal chondrosarcoma in Sweden.

Between 1958 and 1972, 5 cases of posterior cricoid chondrosarcoma were reported to the Swedish Cancer Registry. These cases, and one recently observed case of laryngeal chondrosarcoma, are presented in this study of one female and five male patients. The tumours grow slowly and recur locally, but have not metastasized, and none of the patients has died from tumour disease. The clinical and morphological findings indicate that these tumours represent secondary chondrosarcomas developing from pre-existing benign ecchondromas. The reason for the uniformity as to localization is not known. The microscopic appearance varied in different parts of the same tumour. The presently obtained data and review of the literature indicate that laryngeal chondrosarcomas are extremely rare, locally invasive, but usually not metastasizing tumours. Conservative laryngeal operation is suggested as primary treatment. Total laryngectomy is necessary only after local recurrences involving a major portion of the cricoid cartilage.


Work of nasal breathing: measurement of each nostril independently using a split mask.

The work of nasal breathing was determined in human subjects as a measure of impedance to respiratory airflow. The nasal cavities were examined separately and simultaneously with a split mask; flow and pressure signals were fed to a microprocessor for on-line computation and printout of respired volumes and work of nasal breathing. An alternating resistive nasal cycle of 3--4 hours' duration was demonstrated in the majority of normal, resting subjects. Reciprocity of the resistive changes in each nasal cavity maintained a constant total nasal respiratory work load of about 0.2 Joules/litre. Moderate changes in breathing rate and tidal volume had little influence on work. Inspiratory work was 1.6 times that of expiration. Increases in resistance of the dependent nostril were seen when the lateral decubitus position was adopted. Increase in cephalic venous pressure and pathological nasal obstruction increased the work of nasal breathing.


Ultrastructural changes of the nerve elements following disruption of the organ of Corti. II. Nerve elements outside the organ of Corti.

Various stages of changes in the nerve fibers, spiral ganglion cells, and satellite cells from the guinea pig cochlea 3 to 137 days after perilymphatic perfusion with streptomycin solution (2 and 20%) were observed electron microscopically. Initially, the axoplasms of the cochlear nerve fibers became swollen or pyknotic. Then, the axons disappeared and myelin lamellae disrupted. The Schwann cells shrank and degenerated, though their basement membranes survived for a time. Regeneration of the cochlear nerve fibers began with extension of axonal sprouts into the tube of the basement membrane and surviving Schwann cells, which still contained myelin debris. Only one of the axonal sprouts matured for myelination. These regenerating cochlear nerve fibers were found in the osseous spiral lamina, modiolus and internal auditory meatus, but these fibers atrophied and disappeared afterward. Retrograde degeneration occurred in the olivo-cochlear bundle. Some of the efferent myelinated fibers also showed temporary regeneration.


Long-term electrode implantation for recording cochlear electrical activity in guinea pigs.

Comparative measurements of the cochlear electrical activity over prolonged periods require long-term implantation of electrodes. During this time, changes in the electrode recording ability and/or impairment of the sound-conducting system, could erroneously be attributed to the experiment. To avoid this risk, an easy and reliable technique is described. The procedure uses the Fallopian canal as a route by which to approach the cochlear potentials' generators, while leaving the middle ear untouched.


Effects of local application of ototoxic antibiotics on cochlear potentials in guinea pigs.

The effects of neomycin, kanamycin and dihydrostreptomycin on the cochlear microphonic, the action potential of the auditory nerve and the endocochlear potential were studied in guinea pigs in which these drugs were locally administered by perfusion. These drugs suppressed the cochlear responses markedly when applied to the endolymph but were less effective when applied to the perilymph. The mechanisms of action of antibiotics on the hair cells of the organ of Corti are discussed.


Incorporation of radioactive calcium into otolithic membranes of the guinea pig after aminoglycoside treatment.

The influence of neomycin and streptomycin on the calcium metabolism of the otolithic membranes was investigated in the guinea pig. After chronic treatment with either drug, animals were injected intraperitoneally with radioactive calcium. Retention of calcium in the serum was unaffected by drug treatment, as was the incorporation of radioactivity into bone (femur and otic capsule). Both drugs inhibited the calcium uptake into saccular and utricular otolithic membranes by 30 to 40%.


Melanin capacity to accumulate drugs in the internal ear. A study on lidocaine, bupivacaine and chlorpromazine.

The distribution and retention of labelled lidocaine, bupivacaine, and chlorpromazine to melanin in the internal ear after intravenous and intraperitoneal injection were examined by whole-body autoradiography. Both young pigmented hooded rats and albino rats were studied. In the pigmented rats chlorpromazine showed the greatest accumulation, which was more pronounced in the cochlea than in the vestibular portion. The other two substances were evenly distributed in the internal ear. After a single injection of chlorpromazine and of bupivacaine these substances were still bound to the melanin of the internal ear after 14 days, which was the longest survival time. Lidocaine, on the other hand, had disappeared after only 4 days. Strong uptake and retention of the three substances were observed in the eyes of pigmented animals. In albino animals there was very weak, transient uptake in the internal ear of chlorpromazine and bupivacaine, but not of lidocaine. In studies in vitro on isolated bovine eye melanin there was considerably greater adsorption of chlorpromazine than of lidocaine and bupivacaine. An uptake was noted in the human eye in experiments in vitro. Clinical tests revealed no acute or late damage to hearing or sight after large doses of lidocaine. The participation of melanin in different basal labyrinthine functions such as the energy transfer mechanism and the sound protective mechanism is discussed in the light of the results obtained. Further, the theory is put forward that the melanin affinity of certain substances can be of both therapeutic and ototoxic importance.


Vestibular neurectomy and saccus decompression surgery in Meniere's disease.

Results of vestibular neurectomy, total eighth nerve section, and saccus decompression in 42 patients with Meniere's disease are reported. Vestibular nerve section was found in isolated cases to be a very effective method of abolishing the symptom of vertigo. Hearing is not affected but may be lost owing to opening of the vertical canal or disruption of blood supply. Saccus surgery might be the surgical treatment of choice in early cases with good hearing but in patients with fixed non-fluctuating hearing loss, rehabilitation can be effected only by vestibular neurectomy. In bilateral cases either sac surgery or the use of vestibulotoxic drugs is advised.


Cervical and vestibular afferent control of oculomotor response in man.

Oculomotor response in the absence of vision has been compared in a group of 12 normal humans in two experimental conditions testing (a) the vestibulocular reflex by whole-body oscillation on a turntable, and (b) the cervico-ocular reflex by oscillation of the body with the head held stationary. The stimulus was a sinusoidal oscillation (peak angular velocity +/- 50 degrees/sec) at frequencies between 0.2 and 1.3 Hz. The slow-phase eye movements of the vestibulo-ocular response were compensatory for head movement and showed a mean gain of 0.54--0.90, increasing with frequency. The cervicoocular response was found to be very variable. The slow-phase eye movements were of low velocity (mean gain 0.05) and did not generally compensate for body movement. During neck torsion, some subjects exhibited large overall eye deviations composed of both slow and fast phase eye movements.


Caloric pattern test with special reference to failure of fixation-suppression.

Fixation-suppression of caloric nystagmus was studied in 1230 consecutive cases. An analysis of caloric nystagmus with failure of fixation-suppression (FFS) made it possible to classify patterns of FFS into three types: Type I: FFS was observed bilaterally in caloric nystagmus; Type II: FFS was recognized unilaterally on either side; Type III: FFS was seen in either direction of nystagmus. On the basis of these three types, the underlying neuroanatomical substrate responsible for FFS is discussed.


A retrospective histological study of 669 cases of primary cutaneous malignant melanoma in clinical stage I. The consequences of a reclassification of the original group of lentigo maligna melanomas.

A selected series of primary malignant melanoma of the skin, clinical stage I, was originally classified according to Clark's system. The consistency of this classification was tested by two Brisbane pathologists who indicated that we had misinterpreted some cases of superficial spreading malignant melanoma as lentigo maligna melanoma. We have therefore reclassified the original group of 86 lentigo maligna melanomas. This resulted in a total series of 37 (5.5%) lentigo maligna melanomas, 301 (45%) superficial spreading malignant melanomas, 194 (29%) nodular malignant melanomas (unchanged) and 137 (20.5%) unclassifiable malignant melanomas. The diagnosis of lentigo maligna melanoma was not made unless the epidermis was atrophic and dermal solar elastosis was present. The new group of lentigo maligna melanomas is dominated by cases on the head among patients over 50 years of age (especially women). This is in better agreement with other studies than our previous findings. The relationship with tumour cell type, pigmentation, mitotic count, atypia, transsectional profile, level of invasion, ulceration, vascular invasion, lymphocyte infiltration and prognosis shown by the new groups of lentigo maligna melanoma and superficial spreading malignant melanoma indicates that the cases by which the diagnosis has been changed are relatively benign. Our previous conclusions are still valid. The lentigo maligna melanoma is still the most benign type and nodular malignant melanoma still the most malignant type of melanoma. The superficial spreading malignant melanoma still represents an intermediate tumour type, although it has deviated in the benign direction.


Ochratoxin A-induced mycotoxic porcine nephropathy: alterations in enzyme activity in tubular cells.

Mycotoxic porcine nephropathy was induced by p.o. administration of crystalline ochratoxin A for periods of 5 days, 3 months and 2 years. Enzyme activities of the renal tissue were studied histochemically. These were NADH-tetrazolium reductase, NADPH-tetrazolium reductase, lactate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, glucose-6-phosphate dehydrogenase, alpha-glycerophosphate dehydrogenase, unspecific acid phosphatase and unspecific alkaline phosphatase. The activity of NADH-tetrazolium reductase and succinate dehydrogenase was reduced in the proximal tubule of all nephrons after 5 days ochratoxin A exposure and remained reduced after 3 months and 2 years exposure. The effect of ochratoxin A on these enzymes would appear to cause the impairment of proximal tubular function and the morphological changes observed in the proximal tubule in ochratoxin A-induced mycotoxic porcine nephropathy. The localization of alterations in enzyme activity corresponds to the localization of ochratoxin A previously demonstrated in the kidney. The activities of NADPH-tetrazolium reductase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase and unspecific alkaline phosphatase were reduced focally corresponding to the areas with focal tubular atrophy and the degree of reduction was roughly parallel to the degree of atrophy.


Teratogenicity of intrauterine copper wire in mice. A histopathological study.

Immediately after the implantation of the fertilized ovum, on the 6th day of pregnancy a copperwire was placed in the right hand uterine section on pregnant C3H mice. The left section was similarly surgically traumatized in order to serve as a control. The mice were killed with chloroform on the 19th day of pregnancy and by means of a special histological screening technique the fetuses were examined with special reference to growth reduction, intrauterine fetal death and microscopic malformations. Differences in intrauterine fetal death were shown not to exist, nor was there any significant growth retardation in the copperwire containing uterine section. Certain microscopic defects were found with slightly increased incidence in the copper containing section, but the differences were not statistically significant.


Repair in arterial tissue. Endothelial regrowth, subendothelial tissue changes and permeability in the healing rabbit thoracic aorta.

The role of the endothelium and subendothelial connective tissue in the permeability of a healing intima was studied by vital staining with Evans blue and transmission electron microscopy after severe mechanical lesion of the rabbit aorta. Reendothelialization, decreasing permeability, and organization of neointimal connective tissue were concomitant events in the healing processes. The determinant factor in decreasing permeability was reendothelialization with the formation of endothelial flaps and junctions. Changes in the subendothelial connective tissue seemed also to be factors that influenced the permeability.


Repair in arterial tissue. 2. Connective tissue changes following an embolectomy catheter lesion. The importance of the endothelial cells to repair and regeneration.

The neointimal hyperplasia following a severe mechanical lesion of the rabbit thoracic aorta was studied by vital staining with Evans blue and transmission electron microscopy. Neointimal tissue covered with endothelium contained organized laminated elastin-rich commective tissue. On the contrary neointimal connective tissue covered with pseudoendothelium was disorganized, with a tendency to fibrosis. Reendothelialization, re-establishment of intimal barrier function and formation of lamellated neointimal connective were parallel events. The importance of a intact subendothelial zone controlling healing processes is discussed. Interaction of endothelium and smooth muscle cells seems to be essential in the regulation of neointimal tissue formation and is probably implicated in a general vascular reactive pattern.


Seroepidemiology of H1N1 influenza: striking differences in the attack rate among young people.

The H1N1 influenza outbreak in winter 1977-78 covered the whole of Finland in a uniform fashion, whereas striking differences emerged between various population segments in the susceptible age group. The attack rate was 68 per cent among young servicemen who had been in the armed forces during the epidemic and 33 per cent among those who had entered the service after the epidemic, but only 6 per cent among pregnant women of the same age. Based on routine specimens sent to the laboratory for reasons unrelated to influenza, the attack rate was 4 per cent among children born in 1973-76 and increased by age up to 45 per cent among subjects born in 1957-62. The findings on pregnant women and small children suggest a novel mechanism of innate resistance operating specifically against H1N1 influenza.


Quantification of tetanus antitoxin in human sera. I. Counter-immunoelectrophoresis.

An extensive sero-epidemiological survey of immunity to tetanus is to be performed in Norway during 1978 and 1979 and thus a simple and reliable method for screening sera for content of tetanus antitoxin is needed. An improved counter-immunoelectrophoretic method for quantification of tetanus antitoxin is described. The toxin neutralization test in mice is considered to correlate well with protection in humans. Counter-immunoelectrophoresis has the advantage of using tetanus toxoid instead of toxin as well as being more rapid and less expensive. Specific antibodies of the IgG, IgM, and IgA classes could be read simultaneously for many sera. This may be of importance, since it is reported in the literature that only antibody of the IgG class is capable of neutralizing tetanus toxin in mice. Counter-immunoelectrophoresis is limited by being less sensitive than the toxin neutralization test in mice.


Quantification of tetanus antitoxin in human sera. II. Comparison of counter-immunoelectrophoresis and passive haemagglutination with toxin neutralization in mice.

We described recently an improved counter-immunoelectrophoretic method for quantification of tetanus antitoxin. The toxin neutralization test in mice is considered to correlate well with protection in humans. In the present study, the correlation coefficient between the two methods was 0.89. Sera containing more than 7.0 I.U./ml could be quantified directly by counter-immunoelectrophoresis, while sera containing less tetanus antitoxin had to be concentrated prior to quantification. The passive haemagglutination test was also compared with the toxin neutralization test in mice. The correlation coefficient between the two methods was 0.76.


The distribution of soluble copper- and zinc-binding proteins in goat liver.

The distribution of copper and zinc in the soluble proteins from goat liver after gel filtration were determined. Samples from normal slaughtered animals as well as from experimentally copper-loaded goats were tested. The copper- and zinc-binding proteins were mainly separated into 3 different fractions. The approximate molecular weights were greater than 65,000, 35,000 and 10,000. Varying amounts of zinc were eluted in a fourth fraction of molecular weight less than 2000. The results indicate that the distribution of copper and zinc among soluble metal-binding proteins are highly dependent on the total liver zinc concentration. In the majority of samples, with zinc levels within 20 to 45 microgram/g wet weight, the dominating copper- and zinc-binding protein fraction was the high-molecular weight fraction. This did not seem to be influenced by the total liver copper level. In the samples with high total zinc levels (greater than 60 microgram/g w.w.) there was a shift in protein distribution of both metals toward the low-molecular weight fractions.


The loss of creatine phosphokinase (CK) from intramuscular injection sites in rabbits. A predictive tool for local toxicity.

The CK activity was measured in muscle tissue taken from the injected area (dorsal longissimus muscle) and the contralateral side of the injection site 72 hours after intramuscular injection into rabbits of 1 ml of different dilutions of propylene glycol or glycerol formal in distilled water or 0.9% saline. The total loss of CK activity from the injection site was calculated as the difference between the CK concentration in the normal muscle tissue and that of the injection site from the same animal. From the results the arbitrary amount of muscle tissue depleted of CK activity was further calculated and compared with the severity of the gross pathological findings. A large necrotic area at the injection site was present in all samples with more than 1 g of muscle tissue depleted of CK activity. Minor and probably acceptable pathological changes were found in samples with less than 1 g of muscle tissue depleted of CK activity. The local damaging effect of drug preparations for intramuscular use can thus be evaluated from the calculated amount of muscle tissue depleted of CK activity.


Inhibition of 3H-dopamine accumulation in reserpinized and normal rat striatum.

The inhibitory potencies of 27 compounds on the accumulation of 3H-dopamine (DA) in synaptosome-rich striatal homogenates of normal and reserpinized rats were determined. It was found that some compounds, e.g. amphetamine derivatives, phenmetrazine, phenethylamine derivatives and tryptamine derivatives were considerably more potent in the reserpinized preparation than in the normal one. Other compounds, e.g. amfonelic acid, mazindol, EXP 561, benztropine, pipradrol, nomifensine, methylphenidate and cocaine had similar potencies in the two preparations. It is suggested that the compounds enhanced by reserpine are more potent as DA releasing agents than as inhibitors of the DA uptake, whereas the compounds in the other group are most potent as uptake inhibitors. Interestingly, these two groups completely agree with the two groups of central stimulatory agents, viz. the amphetamine-like and the methylphenidate-like drugs.


Fluoride and energy metabolism in LS cells.

Six mM fluoride had no effect on lactate production in LS cells incubated in Eagle's minimum essential medium. In Krebs-Ringer phosphate buffer with 10 mM glucose inhibition was found with 3mM fluoride. The fluoride effect was similar in aerobic and anaerobic conditions. Twelve mM fluoride had no inhibitory effect on ATP levels in LS cells.


Effect of sodium fluoride on protein and DNA synthesis, ornithine decarboxylase activity, and polyamine content in LS cells.

Sodium fluoride exhibited a dose dependent inhibitory effect on protein and DNA synthesis at concentrations from 1.3 mM in growing LS cells. The activity of ornithine decarboxylase (ODC) was slightly stimulated by 0.5 mM-NAF, but inhibited at 1.3 mM and above. The reduced enzyme activity seemed to be due to a reduced de novo formation of the enzyme caused by an inhibition of the protein synthesis. In spite of a reduction of ODC-activity, fluoride had no effect on the cellular polyamine content during the experimental period (10 hours).


The effect of fluoride on the cellular uptake and pool of amino acids.

Fluoride decreased the initial uptake of 2-aminoisobutyric acid (AIB) in LS cells only in high (supralethal) concentrations and after several hours of exposure. The steady state level of AIB seemed somewhat more sensitive as it was halved after 23 hours exposure to 6 mM-NaF. The cellular levels of some natural amino acids were also reduced by fluoride. However, cells resistant to fluoride showed equally lowered levels of amino acids, indicating that the observed effect of fluoride on cellular amino acid levels may be of little importance.


Effects of tetraethyl lead on the activities of drug metabolizing enzymes in different tissues of the rat.

The present study describes the effects of tetraethyl lead on various drug metabolizing enzymes in different tissues of the rat. Tetraethyl lead was administered intraperitoneally to rats (250 mumol/kg) on two consecutive days. The animals were killed on day 3. Tetraethyl lead-treatment decreased the concentration of hepatic cytochrome P-450 (to 45 per cent of the control), the hepatic activity of aryl hydrocarbon hydroxylase (to 41 per cent of the control) and ethoxycoumarin deethylase (to 45 per cent of the control). Epoxide hydratase activity was enhanced in the liver (1.3-fold), kidney (3.3-fold), and small intestinal mucosa (4.7-fold). The activity of glutathione S-transferase decreased in the liver (to 69 per cent of the control) but increased in the kidney (1.5-fold) and small intestinal mucosa (1.7-fold). The glucuronidation of o-aminophenol was enhanced (2.2-fold) in the kidney of tetraethyl lead treated rats. It is concluded that exposure to tetraethyl lead brings about widespread changes in the ability of mammals to detoxify foreign compounds.


Study of thioridazine cardiotoxic effects by means of His bundle activity recording.

The effect of thioridazine on sinusal automaticity, myocardial excitability and auriculoventricular conduction have been studied in dogs by measuring the spontaneous heart rate, the effective refractory period of the atrial contractile tissue, the time of auriculonodal and infrahisian conduction. Chloralose anaesthetized dogs were administered 10 mg/kg thioridazine hydrochloride via intravenous route. While sinusal automaticity was not altered, conduction times were prolonged in the suprahisian and mainly the infrahisian part and the atrial refractory period increased. These effects are related to quinidine-like properties and consistent with cardiotoxic effects previously reported in clinical practice.


Supersensitivity of the rat urinary bladder following "chemical sympathectomy".

6-hydroxydopamine (100 mg/kg injected intravenously twice with a weekly interval) was used for the destruction of the adrenergic nerves in the rat detrusor muscle. Two to three weeks after the first injection of this substance the sensitivity of the detrusor muscle to parasympathomimetic and sympathomimetic drugs was tested by recording the intravesical pressure in situ. The sensitivity to methacholine was found to be unchanged, whereas a supersensitivity to noradrenaline, adrenaline, phenylephrine and isoprenaline was found to have developed, thus involving both alpha-adrenoceptor mediated contraction and beta-adrenoceptor mediated relaxation. The supersensitivity was of the postjunctional type.


Sensitization of the submaxillary gland of the rat after sympathetic denervation.

The sensitivity of the submaxillary gland of the rat to chemical stimuli was examined 1, 4 and 6 weeks after sympathetic denervation. The gland was found to have developed a supersensitivity not only to noradrenaline but also, in contrast to previous reports, to adrenaline and methacholine. The supersensitivity remained unaltered throughout the period of observation.


Pharmacokinetics of dipyridamole.

Dipyridamole, though originally introduced as a coronary vasodilator, has lately been increasingly investigated in the treatment of thromboembolic diseases because of its inhibitory influence upon blood platelet function. The compound is eliminated from the organism by hepatic biotransformation to the monoglucuronide, which almost exclusively is subjected to biliary and faecal excretion with simultaneous partial enterohepatic circulation taking place. Only minute amounts are excreted through the kidneys. In experiments on four normal human volunteers it was found that the serum concentration curve after intravenous administration of dipyridamole rather closely fits the pharmacokinetics of an open two-compartment model with first order, linear disposition kinetics and elimination taking place from the central compartment. Experiments with oral ingestion of the compound could be described by the use of a corresponding pharmacokinetic model with two consecutive first order input steps, representing the dissolution and absorption processes. The disposition rate constants (beta) were within the range of 0.0051--0.0083 min.-1 corresponding to biological half-lives of 84--145 min. The absorption rate constant was about 0.07 min.-1, and the systemic availability of an oral dose of 100 mg dipyridamole in tablets varied from 37 to 66%.


Effects of various in vitro--inhibitors of benzo(a)pyrene metabolism in isolated rat lung perfusion.

Various in vitro-inhibitors were added with 3H-benzo(a)pyrene (BP) into the perfusion fluids in isolated rat lung perfusions to see whether their effects are dependent on the integrity of tissue. 3H-BP and its metabolites were measured by thin-layer chromatography and radiometry from both samples of perfusion medium and homogenates of lung tissue. The total covalent binding to lung tissue was used as a measure of the formation of reactive metabolites. In methylcholanthrene-induced rat lung, the metabolism of BP was inhibited by alpha-naphthoflavone, an inhibitor of monooxygenase, and less with diethylmaleate, a depletor of glutathione, with salicylamide, an inhibitor of conjugases, and, astonishingly, with D-saccharo-1,4-lactone, an inhibitor of beta-glucuronidase. With trichloropropene oxide, which inhibits epoxide hydratase, the metabolism was either decreased or unchanged. Nicotine had no effect on BP-metabolism. Nicotine and diethylmaleate increased statistically significantly and alpha-naphthoflavone and salicylamide decreased the covalent binding of radioactivity to lung tissue. In most cases, the changes in BP metabolism observed during perfusion can be explained on the basis of effects of modifiers on the enzyme systems.


Urinary elimination of nitrazepam and its main metabolites.

Nitrazepam and its main metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjugated, were determined in the human urine after a single oral dose of 5 mg. The determinations were performed by GLC method using 63Ni-EC-detector for unchanged nitrazepam and nitrogen selective detector for the metabolites. Unchanged nitrazepam was poorly eliminated through the kidneys (about 1% of the dose). The interindividual variation of total excreted urinary metabolites was large ranging between 848-4933 microgram (17-99% of the dose during 7 days). Of this amount conjugated metabolites made up 57%. The urinary half-lives of free and conjugated-7-aminonitrazepam were (mean and ranges) 44 (23-65) and 46 (25-69) hrs, and of 7-acetamidonitrazepam 12 (5-31) and 18 (5-46) hrs, respectively. The half-lives of the excreted amounts of the metabolites did not correlate with any pharmacokinetic parameter of unchanged nitrazepam in serum.


Pharmacokinetics of nitrazepam in saliva and serum after a single oral dose.

The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r = 0.472, P less than 0.001, n = 97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P less than 0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P less than 0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nitrazepam in serum was 30.5 hrs and in saliva 39.9 hrs, the difference being significant at P less than 0.05. The distribution phase parameters, poorly described before, were calculated. The clinical value of nitrazepam analysis in saliva seems to be negligible.


Effects of digoxin on islated human mesenteric vessels.

Digoxin had contractant effects on isolated, human mesenteric arteries and veins. Veins were more sensitive to this action of the glycoside than arteries. The contractions were not affected by phentolamine or by washing with a digoxin-free solution. However, they were abolished by the calcium antagonist nifedipine, and by washing with a calcium-free medium. In the presence of digoxin, the maximum response to noradrenaline (1.8 x 10(-5) M) increased markedly in both arteries and veins, and the concentration-response curve for the amine was displaced to the left. Immersion of vein preparations in calcium-free solution for 30 min. abolished the digoxin contracture; an increase in extracellular calcium restored the response. Changes in extracellular potassium concentration caused changes in tension in tension of the mesenteric veins similar to those previously demonstrated in peripheral veins--both in the presence and in the absence of digoxin. It is concluded that digoxin contracts mesenteric vessels by a direct action on the muscle cells, and potentiates the contractant effects of noradrenaline. These effects are dependent on the availability of extracellular calcium. Mesenteric vascular reactions caused by changes in extracellular potassium are influenced by digoxin.


Ornithine decarboxylase activity and polyamine content of normal and fluoride resistant LS cells.

The activity of ornithine decarboxylase (ODC) in suspension cultures of mouse fibroblasts, LS cells, varied in a characteristic cyclic pattern after dilution of the cultures. Two strains of fluoride resistant LS cells, FR6 and LSFR6 cells, exhibited the same cyclic pattern, but with markedly higher ODC activities. These fluoride resistant cells, however, contained less putrescine, the product of the ODC reaction. Possible reasons for this finding are discussed.


Ascitic fluid modifying the distribution of sulphafurazole in rats with intestinal occlusion.

In order to confirm our previous findings of increased sulphafurazole (sulfisoxazole, SF) inactivation by intestinal occlusion, SF was given intravenously 20 mg/kg to rats with a low small intestinal occlusion and to sham-operated controls 40-45 hours after the operation. Occlusion did not cause major changes in the distribution of SF to various tissues, but there were some indications of increased SF acetylation after occlusion. The occlusion rats produced ascitic fluid into the abdominal cavity and the total SF levels in the ascitic fluid were almost identical to those in blood, also after oral administration of SF, 50 mg/kg. After intraperitoneal administration of 2 ml of SF (60 microgram/ml) more SF accumulated into the small intestinal wall in occlusion rats than in controls, and the acetyl SF levels were increased in the small and large intestine. So, our previous suggestion of an increased excretory function of the large intestine in occlusion states may not be the only explanation for increased drug levels in the large intestine found after oral administration of SF. Part of the SF in the intestinal wall can also result from ascitic fluid SF, and ascites must be taken into account when considering drug pharmacokinetics.


Glutathione depletion in isolated hepatocytes: its relation to lipid peroxidation and cell damage.

The effects of glutathione depletion in isolated hepatocytes have been studied. A list of compounds which depleted glutathione and induced lipid peroxidation and cell lysis is given. The effects of halogenated acetamides were studied in more detail and results of studies on the interaction of iodoacetamide with cellular constituents are presented. A single metabolite of iodoacetamide, tentatively identified as the glutathione conjugate, was excreted from the cells while less than one percent of the "parent compound" was retained, tightly bound to macromolecules. This bound component could not be associated with the cellular damage. Methionine, cysteine and alpha-tocopherol, as wellas paracetamol and ethylmorphine, were found to prevent lipid peroxidation and lysis. It is concluded that GSH deficiency per se can lead to lipid peroxidation and that this reaction caused the observed hepatocellular lysis.


Sotalol intoxication, two patients with concentration-effect relationships.

Two adult patients ingested an overdose of 2.4 g and 8.0 g of sotalol hydrochloride, respectively, i.e. 7-25 times the mean daily dose. Certain signs as bradycardia and hypotension were similar to those described for other beta-blocking agents. In addition to these, however, both patients had severe cardiac tachyarrhythmias and a considerably prolonged QT-interval in their electrocardiogram. The decline of serum sotalol concentrations followed first-order kinetics with the elimination half-life of 13-15 hours. There was a good correlation between the serum sotalol concentration and the prolongation of the QT-interval. Sotalol differs from other beta-blocking agents in its effects on the action potential of the ventricular muscle and Purkinje fibers of the heart. This is likely to explain the different symptoms and findings of sotalol intoxication compared to those seen in connection with other beta-blocking agents.


Penetration enhancers and other factors governing percutaneous local anaesthesia with lidocaine.

The percutaneous penetration of the local anaestetic lidocaine was investigated in the guinea-pig. Three different types of composition were employed: lidocaine hydrochloride in aqueous solution, lidocaine base in an aqueous alcoholic solvent mixture and lidocaine base in aqueous solutions of dipolar aprotic solvents. The latter solvents included simple tertiary aliphatic amides, amides related to dimethylacetamide, some cyclic amides as well as a number of miscellaneous compounds. The degree of dermal anaesthesia was noted in each case. In addition, the uptake and distribution of lidocaine in the skin and its absorption into the blood were studied using tritium-labelled drug. The results show that the percutaneous penetration of lidocaine is dependent on the concentration of the agent, the time of epicutaneous application of the composition, whether the agent was used as salt or free base, and the nature of the solvent medium. Lidocaine base in aqueous dimethylacetamide was most effective in producing percutaneous local anaesthesia.


Inter and intra laboratory variation of digoxin radioimmunoassay in Sweden.

Samples from two pools were sent 10 times to 27 laboratories for assay of digoxin. One pool contained digoxin 2.60 nmol/l in normal plasma (SP); the other was pooled plasma from patients treated with digoxin (PP). Ten radioimmunoassay (RIA) methods were used. The mean of SP assays was 2.59 nmol/l, not significantly different from 2.60 nmol/l. The mean of PP determinations was 2.46 nmol/l. Within each of the 10 assay rounds, the concentrations showed an almost twofold variation and S.D. averaged 0.33 nmol/l and 0.31 nmol/l for SP and PP respectively. Significant differences (P less than 0.001) were found between mean concentrations obtained for the pools at various laboratories (SP range 2.15-2.85 nmol/l; PP range 2.12-2.72 nmol/l). The laboratory means obtained for SP and PP correlated significantly (P less than 0.001). Nevertheless, significant (P less than 0.01) variations between laboratories were found also concerning the mean difference between SP and PP concentrations. The interassay SD of the assays differed significantly between laboratories (range 0.05-0.61 nmol/l. Between and within groups of laboratories using the same RIA method and between various types of laboratories, differences were also found concerning both accuracy and precision of the assays. It is concluded that a better control of digoxin assay is needed.


Studies on the distribution and metabolism of 14C-dimethylnitrosamine in foetal and young mice.

In pregnant mice injected with 14C-dimethylnitrosamine, whole-body autoradiography was performed with hemisections at -80 degrees (to prevent evaporation of the volatile dimethylnitrosamine) and with dry tape sections (to localize the non-volatile metabolites). The results indicated that the non-metabolized substance passed to the foetal tissues with a uniform distribution and without formation or accumulation of non-volatile metabolites. Autoradiography in young (1-10 days old) and adult mice showed a high level of metabolites in the liver already 5 min. after the administration of 14C-dimethylnitrosamine. No metabolism of the substance could be detected at in vitro incubations of liver tissue obtained from foetuses on the last day of gestation (14CO2-production and incorporation of radioactivity in acid-insoluble macromolecules were used as metabolic indices). However, in vitro experiments with livers of 1-5 days old mice indicated a rapid increase in enzymatic activity after birth. Studies in vivo showed an increased incorporation of radioactivity in the acid-insoluble macromolecules of the liver and a decreased exhalation of 14CO2 in 10 and 14 days old mice as compared with 21 and 60 days old mice. This indicates a difference in the fate of dimethylnitrosamine in vivo between the young and older mice.


Bimodal distribution of serum trypotphan level.

Serum levels of total L-tryptophan (L-TP) were determined before and during treatment in patients suffering from endogenous depression, who were treated with L-TP, 6 g daily, and unilateral electroconvulsive therapy (ECT). The gaussian curve of initial L-TP concentrations changed into a bimodal distribution during treatment. The patients with initially lower L-TP levels also had lower L-TP levels during the treatment, thus forming the low-concentration group within the bimodal distribution. In the patients with higher initial concentrations, the L-TP levels increased to a much greater degree, forming the high-concentration group. Patients in this group needed a larger number of ECT's, probably owing to L-TP's property of shortening the seizure duration. No other background data or clinical variables showed significant differences between the groups. It is suggested that the bimodality of L-TP levels is genetically determined.


Psychiatric illness among adults adopted as infants.

In an epidemiological study of 2,323 adopted adults, the registrations about sick-leave, diagnoses and hospitalization (F-cards) from the National Health Insurance were studied. There was a significantly higher frequency of psychiatric illness among the adoptees compared with non-adopted controls. A classification into different diagnostic groups from the records of psychiatric hospitals showed an over-representation due to alcohol and drug abuse and personality disorders in both male and female adoptee groups compared with non-adopted controls. There was also an over-representation in the male adoptee group due to neuroses.


Parental contact in male and female transsexuals.

The parental contact reported by 12 biologically male and 12 biologically female transsexuals was compared with that reported by control subjects (109 conscripts in the Swedish Army; 101 pregnant nulliparous women). Parental contact was estimated for three different periods: 1) childhood, 2) adolescence, 3) the year before investigation. Transsexual patients generally reported less satisfactory relations to both parents than same-sexed control subjects. A pattern characterized by warm and intense contact with the cross-sexed parent and poor contact with the same-sexed one was observed in about half of the male transsexuals, but not in the female ones. Our findings suggest that disturbed emotional relations to the parents may be one contributory cause in the development of transsexualism and are in accordance with the hypothesis that gender identity grows out of an interaction of biological and environmental factors.


Family-size and birth-order in obsessional neurosis.

Family size and birth-order of 156 British-born patients diagnosed as having obsessive-compulsive neurosis were determined from case-notes; these were compared with matched controls. Separate consideration was given to male and female patients. Mean family size of obsessionals was found to be smaller than that of controls. An excess of first-born was found among male obsessional patients.


Monoamines and monoamine metabolites in brains from demented schizophrenics.

The brains from 12 schizophrenic patients were investigated post-mortem for their content of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA). Six of the schizophrenics had been lobotomized 25--30 years prior to death. A control group matched for age was collected in the autopsy room. The concentrations of NA, DA, and HVA in different parts of the brain from the schizophrenic group did not differ from those of the controls. 5-HT was determined in 11 nuclei or areas of the brain. The schizophrenic group had lower mean values compared with the controls, and in the hypothalamus, medulla oblongata, and hippocampus the difference was at a significant level. 5-HIAA was determined in six areas of the brain but only in a few cases. There was a trend towards lower means of 5-HIAA in the schizophrenics. Cause of death, medication, food intake, age, time between death and autopsy, time the corpses have lain in room temperature, and dissection technique are discussed in relation to these findings. These variables have to be kept under careful control before changes can be claimed as having pathogenetic importance for schizophrenia or for the progressing dementia in this disease.


Dissimulation function in some functional psychoses.

Dissimulation function as estimated by means of Lie-Scale scores can be used as a pointer towards the impaired self-appraising ability of the individuals in relation to others. Sixty non-psychiatric normal persons and 133 psychiatric cases, representing two major psychotic groups, were investigated for the dissimulation function. The results show a significant difference between the two groups of normal and abnormal individuals, the abnormal group dissimulating distinctively more than the other. However, this impaired self-appraising ability does not seem to relate to the chronicity of the illness but only partly with the typology of illness.


Neurasthenic symptoms in workers occupationally exposed to jet fuel.

Long-term exposure to petroleum distillation products (e.g. jet fuel) has been suggested to cause chronic mental and neurological symptoms. In the present "cross-sectional epidemiological study" the extent of neuropsychiatric ill-health in 30 workers exposed to jet fuel was compared with that in 60 non-exposed matched controls. Standardized medical interviews showed a higher occurrence of neurasthenic symptoms in exposed subjects (P less than 0.001). The result was confirmed by examination of the medical records kept by the factory physician (P less than 0.01). The prevalence of psychiatric symptoms was assessed with a rating scale of 37 items (a modified CPRS). Again, the exposed workers scored higher than the controls (P less than 0.001), particularly regarding the neurasthenic symptoms, i.e. fatigue, anxiety, mood changes, memory difficulties, and various psychosomatic symptoms (P less than 0.01). The results could neither be explained by observer's bias, nor by a greater susceptibility for mental disorders in the exposed subjects. We therefore conclude that occupational exposure to jet fuel vapours around the present threshold limit values may induce a neurasthenic syndrome.


Validity of some neuropsychological tests in the assessment of mental deterioration.

Eighty-three control subjects and 200 patients suspected of diffuse cerebral damage were submitted to the Mental Deterioration Battery. Three independent judges evaluated each patient on the basis of all available data. Only 103 patients, unanimously classed as demented by the three judges were retained. On the basis of controls' performances, the scores obtained by each demented patient in the various tests were corrected for age and educational level. Both single tests and the Battery as a whole discriminated normal controls from demented patients at a very satisfactory level.


Intra- and interhemispheric EEG differences quantified by spectral analysis. Comparative study of two groups of schizophrenics and a control group.

In this work we have studied comparatively the relationships between alpha intensity, alpha frequency, root-mean-square amplitude and their standard deviations, versus the location of the four recorded EEG channels: left and right rolando-parietal, left and right parieto-occipital. Twenty-four spectral parameters were computed for each 5-min EEG recording, in the eyes closed situation. The hebephrenic group (36 EEGs from six patients) presented higher values of alpha intensity and RMS amplitudes with low coefficient of variation when compared with the other groups. The left/right rolando-parietal amplitude ratio was 0.73 versus 1.52 for the parieto-occipital ratio. An amplitude hypovariability in the central regions, probably associated with hyperarousal, especially in the left hemisphere, can then be observed in hebephrenics, together with high alpha intensity on the left parieto-occipital area. The two groups of schizophrenics differ from the control group (27 EEGs from 12 subjects) in terms of spectral parameters, the hebephrenic group presenting a possible interhemispheric dysfunction.


Attempted suicide. An Egyptian investigation.

This study comprises 200 cases from a total of 1,155 patients who attempted suicide in 1975 and were admitted to the casualty department of Ain Shams University Hospital in Cairo, which has a catchment area comprising approximately 3 million people. A crude rate of suicide attempts in Cairo would be 38.5/100,000. There was a high percentage among the age group 15--44 years with no major differences between the two sexes. Single patients represented 53% of the total, with students showing the highest risk (40%). Depressive illnesses, hysterical reactions, and situational disorders, in that order of frequency, were the main causes of the attempt. Overdose by tablet ingestion was the most common method used (80%). Official government records are misleading and do not represent the true rate.


Angiotensin II in primary hypertension, relationship to plasma renin activity, aldosterone and urinary electrolytes.

Plasma concentrations of angiotensin II (AII) were studied in 36 patients with primary (essential) hypertension and 15 normotensive control subjects during basal (1 h supine rest), upright and frusemide-stimulated (80 mg orally) conditions. Plasma renin activity (PRA) and plasma aldosterone (PA) were determined on the same occasions. AII was then correlated statistically to PRA, PA and 24-hour urinary excretions of aldosterone (Aldo-U), sodium and potassium and to the blood pressure (BP) levels. The AII values in the hypertensive patients were not statistically significantly different from those in the normotensive subjects. A close relationship was found between the AII values and the corresponding PRA values in the hypertensive patients (r=0.65--0.76, p less than 0.001 for all). Correlations between AII and PA, and AII and Aldo-U were not consistently significant. No correlation was found between AII and BP or between AII and 24-hour urinary electrolytes. The findings point to an intact function between PRA and AII but a disturbed AII-aldosterone interrelation in primary hypertension.


Heart and kidney involvement and prognosis in hypertension. A study concerning referred hypertensive patients and hypertensive patients found by blood pressure screening.

Severity of hypertension, frequency of secondary hypertension and prognosis have been compared in two groups of hypertensive men. The first group (n=686) was taken from a blood pressure screening of a total population sample. The other group (n=154) consisted of hypertensive men, referred to a hypertension clinic by physicians. The mean age of the groups was the same, (X=52 years, range 46--59 years). All went through the same investigations and were followed up and treated in a similar way at the hypertension clinic. The referred men had more severe hypertension, as shown by significantly more heart and kidney involvements. They also had a higher incidence of myocardial infarction, implying a poorer prognosis with regard to cardiovascular disease. The analysis shows the importance of a detailed description of studied groups, not only in terms of blood pressure, age and sex, but also with respect to the frequency and degree of present and previous signs of heart and kidney involvement. With such a description it is possible to compare results from different studies regarding pathophysiological mechanisms and the effect of treatment in hypertension.


A follow-up study of hypertensive patients after operative treatment of unilateral renovascular or renal disease.

A study of 44 hypertensive patients with unilateral renovascular or renal parenchymal disease is presented. All patients underwent corrective surgery. Out of the 44 operated patients, five did not participate in the follow-up examination. The remaining 39 patients constitute the study population. The effects of surgery on the hypertensive state could be evaluated in 35 patients, whereas four died less than two months after the operation. Follow-up studies were carried out at 8-60 months after the operation. The average period of observation was 32 months; 24 patients were observed for more than two years. As a group, the patients had severe hypertension with extensive target organ damage and widespread atherosclerosis. A fairly rigorous selection process was applied, and an unsatisfactory response to medical management was considered a point of major importance. In the majority of cases, renovascular lesions were atherosclerotic, with only two cases of fibromuscular dysplasia. Unilateral nephrectomy was performed in 32 patients, whereas seven underwent reconstructive vascular surgery. Out of 35 patients, 22 (63%) were cured, 8 (23%) improved and 5 (14%) unaltered. A gratifying regression of hypertensive lesions in target organs was observed in patients who were cured or improved by surgery. The frequency and severity of postoperative complications were related to the presence of extrarenal vascular disease.


Glomerulonephritis and exposure to organic solvents. A case-control study.

Fifty patients with biopsy-proven glomerulonephritis and 100 sex- and age-matched controls (50 patients each with non-glomerular renal disease or acute appendicitis) were asked by questionnaire and a telephone interview whether they had been exposed to organic solvents. The questioning and the evaluation of the exposure, if any, was made without knowing the diagnosis of the interviewee. Fifty per cent of the patients with glomerulonephritis reported more than slight exposure, but only 20% of the controls. Exposure to organic solvents may often play a role in the causation of glomerulonephritis.


Acute glomerulonephritis and exposure to organic solvents in father and daughter.

A man and his daughter had acute glomerulonephritis, the daughter eight years after the father. Both were exposed to vapours of organic solvents shortly before the onset of nephritis.


Cellular immunity in renal diseases.

Cellular immune reactivity was studied in 78 patients with various forms of renal disease by skin testing with four recall antigens and a lymphocyte transformation test with tuberculin PPD and leucoagglutinin. Patients with S-creatine greater than or equal to 230 micromol/l as well as those with chronic pyelonephritis who had S-creatinine values below 230 micromol/l had significantly lower skin reactions than the controls to streptokinase-streptodornase, parotitis and PPD. Glomerulonephritic patients with S-creatinine values below 230 micromol/l had normal skin reactivity. Lymphocyte transformation tests showed decreased reactivity only in patients with S-creatinine level greater than or equal to 230 micromol/l. The results suggest an association of chronic pyelonephritis with a defective efferent, nonspecific arm of cellular immunity.


Renal function and plasma aldosterone during acute lithium intoxication.

Studies on plasma aldosterone, total serum protein, electrolytes, osmolal concentrations in serum and urine, creatinine, lithium and osmolal clearances were carried out on 14 patients suffering from lithium intoxication. The determinations were done on samples obtained on admission and during the following twelve days of treatment with hemodialysis, sodium chloride loading, or forced diuresis. Plasma aldosterone and total serum protein were increased; serum sodium concentrations and creatinine clearances were decreased on admission. Serum osmolality was normal; urine osmolal concentration was just above that in plasma. The results showed that the lithium intoxicated patients were moderately depleted of sodium and water on admission. Plasma aldosterone, total serum protein and serum sodium were normalized during treatment. Creatinine clearance increased but did not normalize in all patients. Renal concentrating tests were performed in five patients three to four weeks after lithium intoxication. The renal concentrating ability was reduced in all. The elevated plasma aldosterone seen in lithium intoxication might have been a result of sodium and water depletion. It is suggested that impaired renal concentrating ability induced by lithium may make some patients more susceptible to conditions which can lead to sodium and water loss, and thereby to lithium intoxication.


Mortality from chronic interstitial nephritis and phenacetin consumption in Denmark.

After 1950, a pronounced increase in the mortality from chronic interstitial nephritis among women was registered in Denmark. This was suspected to be caused by a contemporary increase in the consumption of drugs containing phenacetin. Restrictions were therefore imposed on the sale of such drugs in 1961 and consumption decreased sharply. This report, based upon death certificates from 1941--76, shows that the mortality rate from chronic interstitial nephritis has decreased gradually among women in Denmark since 1960, and has now reached the same level in younger women as in the 1940's.


1 alpha-hydroxyvitamin D3 treatment of therapy-resistant symptomatic hypocalcemia in a hypoparathyroid patient with intestinal malabsorption.

The case history of a hypoparathyroid female with short bowel syndrome and long-standing therapy-resistant symptomatic hypocalcemia is reported. During treatment with massive doses of the potent vitamin D analog, 1 alpha-hydroxyvitamin D3(1 alpha(OH)D3), normocalcemia was re-established and clinical symptoms of hypocalcemia were relieved. Furthermore, significant improvement of t of intestinal calcium absorption and bone mineral content was observed after three months of treatment with 1 alpha(OH)D3. The data suggest that 1 alpha(OH)D3 may be of therapeutical value in patients with hypoparathyroidism and intestinal malabsorption.


Serum calcitonin in patients with chronic renal disease.

The relationship between serum calcitonin, calcium-phosphorus metabolism and renal function was studied in 66 patients with chronic renal disease. Serum calcitonin was significantly elevated both in non-dialysed patients and in patients on chronic hemodialysis. In the non-dialysed patient group a highly significant inverse correlation was found between serum calcitonin and creatinine clearance. Between serum concentrations of calcitonin and phosphorus a significant positive correlation was found. In the dialysed patients a significant inverse correlation was found between serum calcium and serum calcitonin. It is concluded that the elevated serum calcitonin in patients with chronic renal disease might be explained by a reduced renal degradation of calcitonin and/or an increased production due to stimulation by serum phosphorus.


Serum levels of testosterone and luteinizing hormone in patients with chronic renal disease.

Androgen metabolism has been studied in 33 patients (17 males, 16 females) with chronic renal disease not undergoing dialysis treatment. The mean value of serum testosterone was reduced in both sexes, whereas that of serum leteinizing hormone (LH) was elevated in the males. The parameters became increasingly pathological with decreasing renal function. There was no correlation between serum testosterone and serum LH, indicating an inadequate hypothalamic-pituitary response to the testicular dysfunction. The clinical significance of this relative hypoandrogenaemia is obscure. A possible relation to the anaemia and bone disease of chronic renal failure is discussed.


Iron absorption and iron status in patients with chronic uremia on regular peritoneal dialysis.

Gastrointestinal iron absorption was measured by whole body counting in 18 patients on regular peritoneal dialysis. Ten patients received regular oral iron treatment prior to the study (iron treated group), 8 patients did not receive iron treatment (non-iron treated group). Whole body retention 14 days after oral administration of 10 microCi 59Fe together with a carrier dose of 10 mg Fe2+ was used as an estimate of absorption. The erythrocyte iron incorporation, i.e. the percentage of administered 59Fe incorporated into the total erythrocyte mass, was measured. Geometric mean iron absorption in the non-iron treated groups was 7.4+/-3.3 (S.D.) % and in the iron treated group 2.8+/-2.5% (p less than 0.01). Absorption in the non-iron treated group did not differ significantly from the value in a normal control group (p greater than 0.3). Absorption in the iron treated group was distinctly lower than in the controls (p less than 0.01), due to the high iron supplementation. Several patients in the non-iron treated group had latent or overt iron deficiency, while patients in the iron treated group had satisfactory iron status. The correlation between iron absorption and erythrocyte iron incorporation was highly significant (r=0.95, p less than 0.001). Peritoneal dialysis patients on the whole have a normally functioning iron absorption. However, due to increased iron losses and insufficient dietary iron intake, the maintenance of a satisfactory iron balance implies an adequate oral iron supplementation.


Increased red cell content of Zn2+ in essential hypertension.

The zinc content in plasma as well as in erythrocytes was studied in 61 patients with untreated essential hypertension. They displayed an intraerythrocytic mean value of Zn2+ of 128.2 micromoles/l intracellular water, which is significantly higher than the corresponding mean of 101.5 micromoles/l from 42 normal persons. In plasma, on the other hand, the mean zinc value of the hypertensive persons was 15.2 micromoles/l plasma, i.e. well within the normal range of plasma Zn2+. Possible mechanisms underlying the elevated red cell zinc level in hypertension are discussed.


Resolution of renal amyloidosis secondary to rheumatoid arthritis.

A patient with seronegative rheumatoid arthritis developed a nephrotic syndrome. Histological examination of renal biopsy disclosed moderate amyloidosis. Ultrastructurally the glomerular amyloid deposits were seen to be located both within the mesangium and subepithelially in the peripheral capillaries. The patient was treated with prednisone and cyclophosphamide for two years. The nephrotic syndrome remitted and a follow-up biopsy showed almost total disappearance of Congo red positive amyloid substance. Electron microscopy showed abundant finely granular material but only small amounts of fibrillar amyloid in the mesangial regions and intramembranous lucent areas containing few amyloid fibrils but no subepithelial deposits in the peripheral capillaries. We conclude that the mesangial amyloid substance was degraded to granular material and that the subepithelial amyloid deposits were resolved by mechanisms similar to those involved in the resolution of subepithelial immune complex deposits, i.e. through slow washing out and incorporation into the basement membrane.


Anthropometric data in middle-aged women. The population study of women in Göteborg 1968-1969.

Body weight, body height, skinfolds, circumferences and weight indices in a population sample of 1462 women in ages between 38 and 60 years are presented. Significant age differences were noted. High correlations (r) were found between body weight and triceps and subscapular skinfolds (0.62 and 0.72 respectively) and between body weight and arm, waist and buttock circumferences (0.75-0.88). Age differences were mostly noted between 46 and 50 years of age. After that age there was a comparatively greater increase of the waist circumference than of the buttock circumference, while triceps skinfold seemed to decrease after the age of 50 indicating an altered adipose tissue distribution from the extremities to the trunk with increasing age. When taking data from a previous study of body weight in the same population of women into consideration it seems that the age differences in body weight found in cross-sectional study like the present one may to a large extent depend on differences between different cohorts studied.


A scanning electron microscopy study of vascular casts from senile human brains.

A scanning electron microscope study was performed of vascular casts from 26 senile human brains. In 15 of these, three types of arterial deformities (glomerular loop formations, vascular wickerworks and bundles) were frequently encountered. They were compared with the appearance in microangiograms and histological sections.


Classification of vertebro-basilar aneurysms.

In continuation of earlier studies concerning the aneurysms of ICA and PCA a proposed detailed classification of vertebro-basilar aneurysms has been given. It has been proved that nearly all the aneurysms originate at the divisions of the main arteries or at the ends of large arteries as direct continuations of the main branches (BA as well as ICA). Aneurysms of the vertebro-basilar junction are of special aetiological interest. These last aneurysms are unique, and demonstrate that congenital defects seem to be more important for the origin of aneurysms than the direction of the blood flow. Origin and projection characterize the different types. Atypically located aneurysms away from arterial divisions exist, as in the ICA system. The relations between aneurysms and the multiplicity of variations and anomalies of the main arteries and the posterior part of the circle of Willis are still unknown, and should be checked in detail. Our studies have convinced us that the exact knowledge of microtopographic classification is the key to correct preoperative diagnosis, access, and treatment.


Aneurysm surgery above the eighth decade.

A series of nine patients over 70 years of age with saccular aneurysms, operated on by direct surgery, is reviewed in order to discuss aneurysm surgery in older patients. The median age of the patients was 74 years, and the median interval from haemorrhage to surgery was 18 days. Operative mortality was 11%, and morbidity was 33%. Because of arteriosclerosis round the aneurysm neck and parent artery, special considerations for surgical treatment on the older patients are required.


Value of electroencephalography (EEG) before and after surgery of intracranial aneurysms.

Electroencephalographic (EEG) investigations were done in 36 patients with intracranial aneurysms, before and after surgery. Thirty five of them suffered from subarachnoid hemorrhage (SAH). Pre-operatively, there was no correlation between patients' age or sex and localisation of the aneurysm or degree of EEG disturbances. The most frequent finding was a generalised slowing, the degree of which depended on the time from bleeding to EEG. Focal abnormalities were due to spasms of the vessels or intracerebral haematomas. There was a high correlation with neurological deficits. Post-operatively, EEG disturbances became worse in 21 cases. Generalised and focal abnormalities increased. These were due to focal oedema and the operative approach. The EEG could be correlated very well with the findings from other investigative methods (CT scanning, angiography). The EEG, as a functional method, showed very well the whole state of the brain after bleeding and after operation.


Persistent embryonic veins in the arteriovenous malformation of the diencephalon.

The diencephalic arteriovenous malformation is produced by the posterior cerebral, posterior choroidal, and anterior choroidal arteries. The abnormal arterialised vessels seen in these malformation represent dorsal and ventral diencephalic veins. The drainage of the shunted blood is primarily into the transverse sinus. This is later diverted medially into the great cerebral vein, with the formation of the basal vein. The medial drainage, in keeping with the normal developmental pattern, is seen frequently. The presence and locations of angiomas are very variable and do not follow any predictable pattern.


Acquired hydrocephalus. III. A pathophysiological study correlated with neuropathological findings and clinical manifestations.

On the basis of the laws of Pascal and Laplace, it is shown that the ventricular dilatation in acquired hydrocephalus is due to a primary increase in the intraventricular pressure (IVP), and that a new steady state can be reached, whether the IVP is increased or normal. The pressure increase is due to a disproportion between the production and reabsorption of cerebrospinal fluid (CSF). As water and salts pass freely across the ependyma and the choroid plexus in hydrocephalus, the pressure increase is caused by an increased protein concentration in the ventricular CSF, leading to increased fluid contents according to the Gibbs-Donnan equilibrium. During the ventricular dilatation, the ependyma is destroyed, and the protein molecules penetrate into the subependymal part of the white matter. This results in a reduction in the colloid osmotic pressure of the ventricular CSF, and a new steady state can be reached, with a normal protein concentration in an increased volume. The attendant microscopic changes in the ventricular wall were demonstrated in a patient with acquired hydrocephalus, and the observations made were in conformity with the results of a number of animal experiments. The symptomatology of acquired hydrocephalus is in agreement with a primary affection of the axons running in the juxtaventricular part of the white matter.


A new surgical approach to the third ventricle with interruption of the striothalamic vein.

In the removal of tumours that develop within the third ventricle, most approaches are not entirely satisfactory. Therefore, a new approach has been devised: transfrontal exposure of the anterior portion of the frontal horn; coagulation and section of the striothalamic vein in order to open up the roof of the third ventricle; use of a blunt spatula introduced in the foramen of Monro and pushed backwards under the choroïd plexus. This approach has been used in ten cases. Postoperative mortality has been nil; the surgical approach has not apparently been responsible for any sequelae. It is simple and gives a good view of the third ventricle.


Unilateral inferior temporal lobectomy with hippocampectomy for relief of incisural herniation.

1. The syndrome of incisural hippocampal herniation, accompanied by unilateral and then bilateral fixed pupils, deepening coma, respiratory irregularity (Cheyne-Stokes), contralateral hemiplegia, ipsilateral decerebrate posturing rising blood pressure, and finally renal shutdown, indicates a terminal state that requires immediate relief. 2. Accepted methods of relief by brain shrinkage, dexamethasone, subtemporal decompression, anterior temporal lobectomy, cutting of the tentorium, and even massive uncapping of the skull, have failed in the author's experience to reverse the process when once established. 3. Presentation is made of a rapid and relatively simple inferior horizontal temporal lobectomy, including the hippocampal gyrus, so as to relieve peduncle compression, blockage of cerebrospinal fluid circulation, midbrain haemorrhage, and infarction in the posterior cerebral artery distribution area. 4. Reports are given of 15 cases out of 30 cases in which operation proved lifesaving, with restoration of normal function in 13. 5. Those patients who died did so in an average of five days, and generally showed either no herniation or continuing evidence of tumour or internal bleeding. 6. Very young patients particularly have an excellent chance of survival, which is seven times better than that of adults in having good to excellent results without operation.


The management of obstructive hydrocephalus by the use of external continuous ventricular drainage.

External continuous ventricular drainage (CVD) in patients suffering from obstructive hydrocephalus is being used in many neurosurgical centers as a routine procedure for the temporary relief of intracranial pressure. The results of this treatment have been insufficiently evaluated. In the present study two groups of patients were investigated. In one, CVD was never used. In the other one it was used in all cases. It was found that the use of CVD decreased mortality rate most significantly. It is recommended that CVD should be used as a temporary measure for the treatment of the increased intracranial pressure in patients suffering from obstructive hydrocephalus.


Significance of intravascular and intracardiac movement of the cardiac catheter in ventriculo-atrial shunts (review of 655 cases).

Proper placement of ventriculo-atrial shunts can be complicated by three phenomena: 1. Movement of the cardiac catheter intravascularly into the internal jugular vein as noted on chest X-ray. 2. Movement of the cardiac catheter during intraoperative X-ray leading to blurring and hence problems in accurate localization. 3. No sign on X-ray of the catheter tip or even of the catheter itself despite previous X-ray visualization and good function, a problem to be obviated by better radiopaque markings.


Subarachnoid pouches of the posterior fossa with syringomyelia.

Three men are presented, all of whom were born with difficulty and later developed severe syringomyelia with collapsing cords on air myelography. Each had hydrocephalus and a sizable subarachnoid pouch in the posterior fossa. The clinical features and investigations are presented with a discussion of the aetiology and possible mechanisms concerned in pathogenesis and treatment. All three men had posterior fossa exploration over fifty years after birth, and the first two were also treated by valved ventriculo-atrial shunts. Each patient has improved a little since operation, but no certainty that this was due to surgery has been proved in any case; none has progressed since the last operation.


Regional cerebral blood flow in patients with subarachnoid haemorrhage.

With a multidetector scintillation camera regional cerebral blood flow, rCBF, was evaluated in 13 patients with subarachnoid haemorrhage. Mean CBF was subnormal, and there seems to be a relationship between CBF and severity of the neurological deficit. The regional pattern showed ischaemic as well as hyperaemic areas. Vasospasms mostly produced ischaemic areas, roughly corresponding to the region supplied by the involved artery. The hyperaemic areas were striking. This hyperaemia can perhaps be regarded as a reaction to initial ischaemia.


Effect of reperfusion on the uptake of [3H] uridine in the gerbil brain after prolonged ischaemia.

The uptake of labelled uridine is reduced in the whole ischaemic hemispheres of gerbils subjected to unilateral carotid artery occlusion. Following circulatory restoration, brain structures that had an ischaemic insult of moderate intensity exhibit a progressively increased uptake. However, during reperfusion there is a tendency towards a clear cut definition of dead zones. This progression of the lesions seems to be related to a maturation phenomenon occurring in areas with an irreversible damage at the end of the ischaemic period.


Persistent embryonic veins in the arteriovenous malformation of the telencephalon.

The arterial components of the telencephalic arteriovenous malformations arise from the anterior cerebral and middle cerebral arteries. The complexity of the development process in this region obscures the fundamental segmental pattern. There are three regions where the primitive pial vessels cross at right angles. They are: a) over the convexity of the cerebral hemispheres, b) in the Sylvian territory, c) in the region of the basal ganglia. The malformations over the surface drain into the superior sagittal sinus. The Sylvian and deep telencephalic malformations drain primarily into the tentorial sinus, and this is often replaced by a medial drainage into the internal cerebral vein through the tributaries of the basal vein.


Relevance of antibiotics in the treatment of brain abscesses. Report of a case with eight simultaneous brain abscesses treated and cured medically.

A case of eight simultaneous brain abscesses in the right cerebral hemisphere, treated medically after puncture of two of them, is reported. Antibiotics and hypertonic mannitol and, after seven days, dexamethasone were sufficient to cure these lesions. CT scan was of primary importance to follow the evolution under treatment. To get the best efficiency from antibiotics, identification of the microorganism and assessment of its resistance to antibiotics are necessary. It is suggested that in certain conditions medical therapy might be sufficient to treat cerebral abscess, after simple puncture to isolate the infecting agent. Corticosteroids should be avoided in the acute phase because they prevent antibiotics from penetrating the abscesses.


The immunoendocrinology of estrophilin.

Immunoglobulin from the serum of rabbits immunized with highly purified estradiol-receptor complex from calf uterine nuclei has been shown to contain specific antibodies to estrophilin by five criteria. Antibodies to calf nuclear estrophilin cross react with nuclear estradiol-receptor complexes of rat, rabbit and sheep uterus, rat endometrial and pituitary tumor, and MCF-7 human breast cancer cell line. They also react with extranuclear receptor of calf, rat, mouse, rabbit, guinea pig, monkey and sheep uterus, rat mammary, endometrial and pituitary tumor, and human breast cancer. There is no interaction of the antibody with estradiol itself. The nuclear form of estrophilin appears to bind more immunoglobulin molecules than does the cytosol form. The antibodies do not react with either the nuclear or extranuclear dihydrotestosterone-receptor complexes of rat prostate, with the extranuclear progesterone-receptor complexes of rabbit uterus, chick oviduct or rat endometrial tumor, or with rat and mouse alpha-fetoprotein. These findings indicate an immunochemical similarity among estrophilins from several mammalian species, as well as between nuclear and extranuclear forms of the receptor, but not among receptor proteins for different steroid hormones. Immunoglobulin from the serum of a goat immunized with similar antigen shows a considerably higher titer of antibodies to estrophilin. These react with nuclear and extranuclear estradiol-receptor complexes of calf uterus to produce somewhat larger entities than those formed with the rabbit antibody. Unlike the rabbit antibody, interaction with the goat antibody causes a noticeable decrease in estradiol-binding affinity of the extranuclear estrophilin as well as an apparent decrease in the total hormone-binding capacity. Specific antibodies to estrophilin offer promise as valuable reagents for receptor analysis and purification, as well as for the elucidation of many still unresolved questions concerning receptor synthesis, localization and function.


Estrogen and antiestrogen action: studies in reproductive target tissues and tumors.

Studies are reported using unlabelled and radiolabelled antiestrogens which are aimed at elucidating the nature of interaction of antiestrogens with uterine and mammary tissue. Antiestrogens and long-acting estrogens move estrogen receptor sites to the nucleus and maintain elevated nuclear receptor levels for a prolonged period. The antagonistic action of antiestrogens in the uterus, however, appears to derive from their ability to effect a marked perturbation in the subcellular distribution of receptor whereby very little (ca. 10%) is cytoplasmic and further estrogen receptor accumulation is blocked. In DMBA-induced rat mammary tumors, the nonphototoxic antiestrogen, U-23, 469, effectively antagonizes the development and growth of tumors and elicits regression of 90% of established tumors with a time course similar to that seen after ovariectomy. Again, during antiestrogen treatment, the levels of cytoplasmic estrogen receptor are depressed with over 90% of total receptor being found in the nucleus. Two radiolabelled antiestrogens of high specific activity and purity have been prepared by us and their interaction with nuclear and cytoplasmic estrogen receptors is reported. Both 3H-CI-628 and 3H-U-23, 469 are metabolized in vivo to more polar forms which are found associated with the nuclear estrogen receptor, and which may be the true agents active in vivo.


Inhibition of cell division and stimulation of progesterone receptor synthesis in rat oestrogen target tissues by non-steroidal antioestrogens.

Recent studies from this laboratory have demonstrated oestradiol-oestrogen receptors associated with the nuclear compartment of the rat uterine cell will initiate protein synthesis, as evidenced by a rise in progesterone receptor concentrations, and cell division whereas the anti-oestrogen - oestrogen receptor complex causes protein synthesis and cellular hypertrophy rather than hyperplasia. It is probable that this separation of biological activities resides in the intrinsic activity of the respective receptor complexes. We have demonstrated that caution should be exercised in the interpretation of low affinity ligand-hormone receptor interactions undertaken in vitro. Simple tests for ligand specificity for a binding protein are clearly insufficient evidence to characterise a hormone receptor complex using a conventional 15 hr technique of sucrose density gradient analysis. Oestrogens and anti-oestrogens do not seem to disrupt the subunit integrity of the cytoplasmic oestrogen receptor and it appears likely that the ligand plays a fundamental role in confering the correct biological properties to the hormone receptor complex.


Nuclear binding of the estrogen receptor: heterogeneity of sites and uterotropic response.

Two kinds of estradiol binding sites are present in purified nuclei from the rat uterus following estradiol injection. One of these sites (type I) corresponds to the well-known estrogen receptor which undergoes translocation from the cytoplasm to the nucleus. The second site (type II) is not translocated from the cytoplasm to the nucleus, however, estradiol treatment does stimulate an increased number of these sites. Type II sites are observed in purified nuclei and chromatin isolated from the uterus but not from non-target tissues such as the spleen and diaphragm. Thus an elevation in the levels of type II sites appear to be a specific nuclear response of the rat uterus to estradiol. Saturation analysis over a wide range of [3H]-estradiol concentrations produces a binding curve for type II sites which is sigmoidal and hence no accurate estimation of the dissociation constant is possible. The binding of [3H]-estradiol to nuclear type II sites is inhibited by estradiol and diethylstilbestrol but not by progesterone, testosterone, or corticosterone. Extraction of nuclei isolated from estrogen treated rat uteri with KCl provides a complex picture. Direct labeling of nuclear estrogen receptors either by in vivo injection or in vitro incubation of intact uteri with [3H]-estradiol measures only a fraction of the specific estrogen binding sites associated with the nuclear pellet following 0.4 M KCl extraction. These sites are more accurately determined by performing saturation analysis over a wide range of [3H]-estradiol concentrations by exchange which measures specific estrogen binding sites, not [3H]-steroid. Saturation analysis of estradiol binding to KCl extracted nuclei when performed by exchange, with appropriate corrections for type II binding, reveals that approximately 1000--2000 receptors per nucleus are resistant to KCl extraction 1 hr after administration. The same numbers of type I sites display long-term nuclear retention. A single injection of estradiol results in long term (greater than 6 h) retention of type I sites, rapid and sustained elevations (1--72h) in type II sites and true uterine growth (uterine wet weight at 24--43 h). Estriol injections caused a rapid increase in nuclear type I sites which was not accompanied by an increase in type II sites and no true uterine growth occurred. Administration of estriol or estradiol as a pellet implant, which causes continuous occupancy of type I sites, increases the quantity of nuclear type II sites and stimulates true uterine growth. Therefore, we conclude that elevated levels of nuclear type II sites correlate with the long term uterotropic response to estrogenic hormones. Although we do not understand the function of this second class of binding sites it is possible that the type II sites represent a major component in the mechanism by which estrogens stimulate growth of the uterus.


Regulation and function of estrogen and progesterone receptor systems.

We have developed and validated assay methods which are appropriate for studying the subcellular distribution of estrogen receptor (Re) and progesterone receptor (Rp) in hamster uterus during the estrous cycle and pregnancy. Cytosol receptors were monitored by conventional procedures, and nuclear receptors were extracted from nuclei at 2 C using 0.5 M KCl in buffer containing glycerol and measured by ligand exchange during incubation with [3H] progesterone (P) at 2 C for 24 h or [3H] estradiol-17 beta (E2) at 30 C for 1 h. The nuclear exchange assay described herein measures total receptor and also permits estimation of unlabeled steroid in the nuclear KCl extract. Nuclear Rp translocation was shown to be target-tissue specific, hormone specific, and dependent on P dosage under in vivo conditions. The duration of nuclear Rp retention was about 6 h following exogenous P treatment. During the estrous cycle, Re and Rp levels in uterine cytosol and nuclei varied in response to the changing pattern of E2 and P secretion. Our results document a positive relationship between serum E2, nuclear Re and cytosol Rp levels during the follicular phase of the cycle. Nuclear Rp remained low on cycle days 1--3, and increased abruptly on day 4 coincident with preovulatory P secretion and cytosol Rp depletion. Nuclear Rp translocation during the preovulatory period on cycle day 4 was associated with a marked decline in nuclear Re, and the latter was demonstrated to be a rapid (2--4 h) response to P action rather than serum E2 withdrawal. The negative effect of P on nuclear Re levels may represent a fundamental mechanism for P antagonism of E action. Cytosol and nuclear Rp levels in deciduomal and myometrial tissue were responsive to experimental alteration of serum P, indicating that nuclear Rp is maintained by a continuous process of P-induced Rp translocation. Of interest was the finding in pregnant animals that Re levels declined dramatically in deciduoma as compared to myometrium. The loss of cytosol and nuclear Re from deciduomal cells cannot be attributed to changes in serum E2 or P. Thus, the intracellular regulation of Re numbers may change during differentiation of certain target cells such as those found in the deciduoma.


Effects of progestins on the progesterone receptor in guinea pig uterus.

We examined the effects of progesterone and some synthetic progestins and other steroids on the physical properties of the progesterone receptor of guinea pig uterine cytosol and on the binding of the receptor by nuclei. Progestational potency seemed to correlate with the ability to keep the receptor in the 7S form and to prevent dissociation into smaller subunits. The rate of activation prior to nuclear binding was slower with steroids of increasing progestational activity. Therefore activation in vitro may be unrelated to biological activity. Concentration of the cytosol led to a decrease in the equilibrium association constant. The extent of the decrease was less with progesterone than with its metabolite, 5 alpha-pregnanedione. When cytosol and nuclei were incubated in the absence of ligand measureable progesterone receptor was bound by the nuclei. The uncomplexed nuclear receptor bound [3H]-progesterone of [3H]-R5020 rapidly at 0 degrees, but progesterone-receptor complexes exchanged [3H]-progestin slowly at 0 degrees. Progesterone increased the amount of nuclear receptor at concentrations of 10(-9) and 10(-8)M, but decreased binding at higher concentrations. 5 alpha-Pregnanedione had the same effect as progesterone, but other metabolites of progesterone that had little affinity for the 7S progesterone receptor in cytosol had no effect on nuclear binding at any concentration. Glucocorticoids, testosterone and estradiol-17 beta increased the nuclear binding of the progesterone receptor when present at concentration of 10(-8)M and greater.