Synthesis of rabbit beta-globin in cultured monkey kidney cells following infection with a SV40 beta-globin recombinant genome.

Rabbit beta-globin complementary DNA (cDNA) has been inserted into SV40 DNA in place of the gene coding for the virus' major capsid protein, VP1. The recombinant genome, SVGT5-RabetaG, multiplies efficiently in CV1 monkey kidney cell cultures and is transcribed to yield cytoplasmic, polyadenylated hybrid mRNAs containing the beta-globin coding sequence. Cells propagating SVGT5-RabetaG produce substantial quantities of rabbit beta-globin polypeptide.


On spare beta-adrenoceptors of inotropic effect of catecholamines in kitten ventricle.

Beta-Adrenoceptors of ventricular membranes of kitten heart were labelled reversibly with (--)-3H-propranolol (binding constant 6nM). Bound (--)-3H-propranolol was displaced with beta-adrenoceptor blocking agents and catecholamines. Displacement constants KD(M) of the blockers were of the same of magnitude as their constants KB obtained from the antagonism of inotropic effects of catecholamines in papillary muscles. KD's of catecholamines were, however, 2 orders of magnitude larger than concentrations causing half maximal inotropic effects, indicating large spare beta-adrenoceptor capacity.


[Immunocytochemical localization of the GFAP in heterotransplanted human gliomas (author's transl)].

Three cell lines derived in our laboratory from human malignant gliomas (SA 130, SA 132, SA 134) were injected subcutaneously into pathogen-free nude thymus less mice. These three cell lines gave origine to malignant tumors which, as original tumors, were positive for the glial fibrillary acidic protein (GFAP) revealed by immunoperoxidase method.


[Study of the relationship between intracrânial pressure and paradoxal sleep in the cat (author's transl].

The present study reports on the modification of the intracranial pressure (ICP) during rapid eye movements (REM) sleep in seven chronic cats. 1. REM sleep episodes were characterized by a succession of short lasting (9 +/- 4 seconds) oscillations of the ICP. Peaks amplitude represented a hundred percent increase of the pressure as compared to its resting level. 2. These oscillations either arose from an ICP level similar to that recorded during the preceding slow wave sleep period or were seen to overide a wave of raised ICP that lasted throughout the REM period. 3. Eighty eight percent of the phasic oscillation coincided with a burt of eye movement characteristic of REM sleep. 4. Cerebral pulse wave amplitude can vary for identical ICP mean value in the course of a same REM period.


[Significance of computed tomography in therapeutic diagnosis of brain tumors (author's transl)].

Because of its noninvasive property of direct imaging of the size and shape of the lesion, CT scan is significant not only for the diagnosis of the brain tumors, but also for the assessment of its chronological and/or therapeutic change in size. Contrary to the conventional cerebral angiography and contrast encephalography, CT scan is feasible to detect the tumor repeatedly at short intervals. From March 1976 to October 1977, 197 cases of brain tumors were examined by CT, 6 tumors (1 pineal tumor, 2 cerebellar vermian tumors and 3 supratentorial tumors) of which were radiated after the initial CT scan and re-examined by CT at every 400-1,000 rads radiation, and their grade of radiosensitivity could be evaluated. Immediately after the radiation of 400 rads for five days to the large pineal tumor of a 16-year-old boy, CT exactly showed the markedly diminished size of the tumor, and the tumor disappeared on CT after the 4,000 rads radiation. Cerebellar vermian tumors suspected of medulloblastoma were also diminished in size on CT after the 600 rads radiation. One supratentorial tumor was radiosensitive and disappeared at the end of radiation therapy. Other supratentorial tumors were not changed on CT during the radiation. Procedures for the therapeutic diagnosis, when combined with CT, can easily indicate whether the tumor is radiosensitive or not, without any invasive examination and/or operation.


[Surgical treatment of hemifacial spasm associated with tortuous vertebrobasilar system (author's transl)].

Surgical treatment of hemifacial spasm associated with tortuous vertebrobasilar system was reported. A patient was 63-year-old female, who first experienced mild and intermittent muscle twitching around her left eye twenty years prior to admission. Five years later, the twitching extended to all the facial muscles on the left side. She was treated with facial nerve block, which resulted in facial palsy for about one year. Because of recurrence of the hemifacial spasm, she was admitted to the Neurosurgical Department of Bokuto Municipal Hospital on October 12, 1977. Neurological examination revealed no abnormalities except for left hemifacial spasm with slight muscular weakness. Electromyogram showed severe twitching and synkinesis of all the muscles of facial expression. Vertebral angiogram on the left side disclosed pronounced elongation of the vertebral and basilar arteries, which extended into the left cerebellopontine angle. Compression of the facial nerve root exit zone at the brainstem by the vertebral artery was considered to be the cause of the hemifacial spasm. Suboccipital craniectomy was carried out on November 29, 1977. The vertebral artery extended into the cerebellopontine angle, and adhered to the facial nerve. After mobilization of the vertebral artery from the facial nerve, a small prosthesis of non-absorbable spongy material (Teflon felt) was interposed between the vertebral artery and brainstem. Postoperatively, the hemifacial spasm disappeared, but the facial palsy, which had been observed preoperatively probably due to previous facial nerve block and long-standing hemifacial spasm, remained. The function of the acoustic nerve was preserved. Recently vascular compression of the facial nerve root exit zone has been reported as a major cause of hemifacial spasm, but such abnormal vessels are rarely demonstrated angiographically.


Effect of norepinephrine on renin release and the cyclic AMP content of rat kidney slices: modification by sodium deficiency and alpha-adrenergic blockade.

The effect of L-norepinephrine (NE) on renin release by slices of kidney cortex from sodium-replete and sodium-deficient rats was studied in vitro. The rate of renin release by slices from sodium-deficient rats in the absence of added NE increased in proportion to the length of dietary sodium restriction and was significantly greater at all times than release by slices from sodium-replete animals. NE added to slices from the sodium-replete animals in concentrations ranging from 2 X 10(-9) to 2 X 10(-4)M caused a significant renin release only at a concentration of 2 X 10(-7)M. In contrast, the rate of renin release by slices from the sodium-deficient rats increased in a dose-related fashion when the NE concentration ranged from 2 X 10(-12) to 2 X 10(-7)M. NE in a concentration of 2 X 10(-5) had a lesser stimulatory effect, and 2 X 10(-4)M caused a significant inhibition of renin release. This inhibition was converted to stimulation by addition of the alpha-adrenergic blocking drug phentolamine. Phentolamine by itself was ineffective. The increases and decreases in renin release produced by NE were, in general, accompanied by increases and decreases in the cyclic AMP content of the slices. The changes in renin release were linear for 60 min, but the changes in cyclic AMP content were greater at 5 and 20 min than at 60 min. A dose-response relationship between the changes in renin release and cyclic AMP content was not observed. These data indicate that sodium deprivation enhances the sensitivity of the renin-secreting cells to catecholamine stimulation, and are consistent with the hypothesis that the increase in renin secretion produced by NE is mediated via cyclic AMP. The data also indicated that in high concentrations, NE exerts an inhibitory effect on renin release, and that this effect is mediated via stimulation of alpha-adrenergic receptors.


In vitro release of ACTH from dispersed rat pars intermedia cells. III. Multiple forms of ACTH biological activity.

We have reported that both an extract of rat hypothalamus-stalk-median eminence (HE) and 5-hydroxytryptamine (5-HT) will stimulate the release of ACTH biological activity from acutely, non-enzymically dispersed rat pars intermedia (PI) cells. We have also found that the ACTH activity within the PI cells is composed of 4 chromatographically separable entities, but only a small proportion of the total ACTH activity co-elutes with ACTH1-39. In the present study we subjected the media, after incubation of PI cells with either HE or 5-HT, to sequential chromatography on Sephadex G-50 F and G-100 SF. We found the same 4 ACTH-like moieties as in the PI cell extracts. Only the release of the 2 earliest eluting components, presumably of much larger molecular dimensions than ACTH1-39, was enhanced by either HE or 5-HT. There was no augmented release of the ACTH component having molecular dimensions similar to ACTH1-39. Thus, in our in vitro system, the ACTH biological activity released from PI cells is not the size of ACTH1-39, but is composed of at least 2 much larger molecules which possess ACTH (as well as some MSH) biological activity.


ACTH release after tuberal electrical stimulation in rats with various cuts around the medial basal hypothalamus.

After the combined treatment with dexamethasone, morphine and pentobarbitone, the electrical stimulation in the rat tuber cinereum induces a rise in plasma corticosterone (CS) level, probably by direct stimulation of the corticoliberin-producing neural elements and the consecutive ACTH release. We have attempted to locate these corticoliberin-containing neural elements by electrical stimulation in rats with various surgical cuts (deafferentations) around the medial basal hypothalamus (MBH). Seven to eight days after the complete circumsection of the MBH, the electrical stimulation of the isolated region did not affect plasma CS level. Also, the electrical excitation proved to be ineffective after antero-lateral or only lateral sections that interrupted the fibers running through the lateral region of the retrochiasmatic area. In contrast, a rise in CS level followed electrical stimulation of rats with anterolateral transections, provided the basal part of the lateral retrochiasmatic area stayed intact. We suggest that fibers traversing the basal region of the lateral retrochiasmatic area have a major role in the release of corticoliberin from the median eminence (ME).


Corticotropin responsiveness in the neonatal rat.

Plasma ACTH concentrations were determined in neonatal rats 1, 7, 14, and 21 days old, subjected to treatment with either a median eminence extract with corticotropin releasing factor (CRF) activity or to ether exposure. 'CRF' injection elevated plasma ACTH levels on all days tested. Ether exposure elevated ACTH levels on days 14 and 21, but not on days 1 or 7. These results indicate: (1) that there is no diminution of responsiveness of the pituitary to direct stimulation by CRF as a function of age, and (2) that the mediators of the stress response above the level of the pituitary are not functionally mature until approximately day 14. Correlations with previous studies also indicate that there is a delay in the return of adrenal responsiveness until some time after these mediators attain maturity.


The influence of diurnal rhythms in patients with intracranial hypertension: implications for management.

Decompensation of brain injured patients during the night is common and has been attributed to the retention of CO2 during sleep. When CO2 is controlled, such nocturnal decompensation needs another explanation; consequently, the records of 21 consecutive patients with acute closed head injuries and increased intracranial pressure were reviewed. There were 185 separate episodes of intracranial hypertension (30 mm Hg or more for 10 minutes or more) in the 21 patients, 124 of which (67%) occurred between 4:00 a.m. and 9:00 a.m. (p less than 0.01). Intravenous pentobarbital (3 to 5 mg/kg) was effective in reducing the intracranial pressure (ICP) to normal levels during 104 of the 124 early morning episodes (84%), whereas mannitol was less effective (7 of 17; 41%). This suggests that an increase in brain blood volume directly related to diurnal rhythm is responsible for the increase in ICP. Severe bradycardia and systemic arterial hypertension were unreliable predictors of elevation in ICP. They preceded or accompanied less than one-fourth of the episodes.


Fluorometric monitoring of NADH levels in cerebral cortex: preliminary observations in human epilepsy.

In 14 patients operated upon for focal cerebral seizures under local anesthesia, cortical electrical activity was compared with the levels of nicotinamide adenine dinucleotide (NADH) observed fluorometrically. NADH levels fell 3 to 15% in response to 5-second intervals of cortical stimulation in 42 of 70 observations. Although a rough correlation was seen between the quantity of current delivered (milliamperes X seconds) and the NADH decrease, this varied from case to case. The presence of cortical afterdischarge often, but not invariably, corresponded to a greater percentage of change in the NADH levels. Averaging the NADH response to sporadic interictal epileptiform discharges failed to demonstrate concomitant NADH reductions. A similar lack of change was seen in four patients in whom low frequency spike foci were induced by topically applied penicillin in cortex destined for excision. Preliminary studies of the topography of spread of NADH change after cortical stimulation indicate that this is usually asymmetrical in human epileptogenic cortex. Under experimental conditions in cats, it seemed possible to differentiate primary from projected epileptiform activity, in that the projected activity had little or no concomitant fall in the NADH level after the electrographic spike. Pathological examination of the excised sites of NADH recording showed, with one exception, fibrous astrocytic transformation of the central cortex layers.


Growth-inhibitory effects of diphenylhydantoin on human brain tumor cells in culture.

Diphenylhydantoin (DPH, phenytoin sodium, Dilantin) inhibited the growth of cultured human astrocytoma cells in 7 of the 10 cell lines studied. This inhibition, determined by a microtiter assay, was dose-dependent; DPH levels of 20 micrograms/ml and above produced significant depression of growth in astrocytoma cultured cells. However, normal cultured human astrocytes were not affected until DPH levels of 60 micrograms/ml and above were added to the cells; normal fibroblasts also showed no growth inhibition up to 100 micrograms/ml. We have confirmed that DPH is 1.5 times as concentrated in tumor tissue as it is in normal tissue and serum. These findings suggest that DPH has properties that inhibit the growth of human astrocytoma cells in tissue culture at levels that are achievable clinically.


Effect of denervation on coxsackie A virus myositis in mice: an electronmicroscopic study.

Myositis induced by Coxsackie A4 and A9 viruses was investigated in the gastrocnemius muscles of suckling mice and adult mice with denervation. Denervation markedly increased the susceptibility of adult mice to Coxsackie A virus infection, and this effect was initiated as early as 1 day after denervation. Light microscopy demonstrated inflammation and necrosis in the denervated gastrocnemius muscle of adult mice, whereas muscle from the contralateral leg showed only infrequent, mild, focal myositis. Ultrastructually, crystalline arrays of virus particles were seen in the infected muscle fibers and in the phagocytes of both suckling and adult mice. Nuclear alterations, especially in the myotubes, and a characteristic compound membrane-vesicle complex (CMVC) in the sarcoplasm, developed simultaneously. Replicating and fusing myoblasts, activated as part of the regenerative process after denervation, appeared to be closely associated with the susceptibility of muscle to Coxsackie A virus infection.


Stereotactic localization (with computerized tomographic scanning), biopsy, and radiofrequency treatment of deep brain lesions.

In eight patients stereotactic biopsy of deep brain lesions was performed. Adequate tissue was obtained, and the information helped considerably in planning further therapy. No significant complications occurred in these patients. In three of the cases, the stereotactic coordinates were determined from the computerized tomographic (CT) scan. In one patient, after biopsy, stereotactic radiofrequency (RF) lesions in the tumor resulted in temporary improvement.


Firing rates of human motor units in partially denervated muscle.

Single motor unit firing rates were measured from the first dorsal interosseous muscle (FDI) of normal subjects and patients with partial denervation of that muscle. Motor unit discharges were recorded at various levels of voluntary, stationary, isometric contraction of the FDI. The mean increase in firing rate associated with an increased muscle tension of 100 gm was significantly greater in severely weak muscle. However, when an "adjustment" was made for the degree of weakness, reduced firing rate responses were observed which correlated with the degree of muscle weakness.


Isolated trigeminal sensory neuropathy: early manifestation of mixed connective tissue disease.

A young woman with mixed connective tissue disease (MCTD) had an isolated trigeminal sensory neuropathy as an early manifestation of the disease. Raynaud phenomenon occurred almost synchronously with the onset of trigeminal neuropathy and was followed by myositis, diffuse hand swelling, synovitis, and increased ribonucleoprotein antibody. Mixed connective tissue disease has overlapping features of systemic lupus erythematosus, scleroderma, and polymyositis, and is differentiated from them by high-titer antibody to ribonucleoprotein.


[Behavior of plasma cortisol, ACTH and STH in subjects performing controlled work on the bicycle ergometer].

A new method for the psychological and physical selection of aircrew is described. Data from the literature are cited in support of the proposition that, in muscular work tests, the response of the body to fatigue cannot only be measured by means of the usual spirometric and ECG methods, but also via the plasma cortisol, ACTH and STH response. It is shown that changes in the concentration of these hormones are mainly attributable to fatigue and its accompanying hypoglycaemia. Hitherto overlooked due to the lack of standardisation of its methods, endocrinological examination could, it is suggested, be of considerable assistance in the selection of aircrew, in the interests of greater safety in the air.


Peripheral and adrenal venous levels of steroids in a patient with virilizing adrenal adenoma.

The peripheral levels of 17-hydroxypregnenolone (17delta5P), progesterone (P), 17-hydroxyprogesterone (17P), testosterone (T), 5alpha-dihydrotestosterone (DHT), androstenedione (A), androst-5-ene-3beta,17beta-diol (delts5diol), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), estradiol-17beta (E2), and cortisol (F) were measured in peripheral and right adrenal venous blood of an amenorrheic patient with a right virilizing adrenal adenoma. Urinary 17-ketosteroids were markedly elevated and were not suppressed on a low dose of dexamethasone (Dex) for 7 days. Peripheral T level was 1.2 ng/ml and DHEA-S was 13,500 ng/ml. Calculations of the ratios of adrenal venous gradients for delta5 and delta4 steroids suggest that the predominant pathway of steroid secretion used by the tumor was as follows: pregnenolone (delta5P) leads to 17delta5P leads to DHEA leads to A leads to T. Following removal of the adenoma, T returned to normal levels but DHEA-S was still above normal at 4100 ng/ml. The patient became eumenorrheic with marked improvement at her hirsutism and virilization.


Peripheral and ovarian venous concentrations of various steroid hormones in virilizing ovarian tumors.

The ovarian-peripheral gradients of various delta4 and delta5 steroids were determined for a patient with virilizing arrhenoblastoma. The high peripheral testosterone level accompanying this tumor results from increased precursor supply from both the delta4 and delta5 pathways, with the delta5 pathway predominating, and from negligible aromatase activity. A review of 45 cases of androgen-producing ovarian tumors with measurement of peripheral venous testosterone, and of 24 cases with measurement of ovarian venous testosterone, and a comparison with findings in 159 patients with hirsutism of functional origin reveal the following 1) An androgen-producing tumor must be ruled out when peripheral testosterone exceeds 2 ng/ml; 2) an ovarian venous testosterone level exceeding 20 ng/ml generally accompanies a tumor, particularly when the tumor is less than 5 cm in diameter; and 3) virtually all (98%) of the tumors reviewed were accompanied by virilization, regardless of the peripheral concentration of testosterone.


[IgA-immunoglobulins and HLA-A1 antigen in Wilms' tumor. Significance for the prognosis of the disease].

In 45 patients with Wilms' tumor of the kidney the IgG, IgA, and IgM serum immunoglobulin levels were quantitated and 23 antigens of HLA-A and HLA-B locues were typed on the same patients' lymphocytes. In 22 individuals with increased IgA immunoglobulin level a more frequent incidence of HLA-A 1 antigen was found. This antigen was established in 62.5% of patients with IgA levels higher than 200 IU/ml. Considering the fact that 86.35% of the patients survive two years, and 16 of 22 patients (= 72.72%) are practically cured, it is suggested that the simultaneous occurrence of increased levels of IgA immunoglobulin and of HLA antigen A 1, is a favourable prognostic sign.


[Collagenolytic activity of cervix carcinoma].

We estimated collagenolytic activity of 10 invasive carcinomas of the cervix by means of a biological assay. Collagenolysis was found in 7 specimens. In order to detect the origin of the collagenolytic enzyme additional inhibition studies with ethylendiaminetetraacetate and normal human serum were performed. Normal human serum inhibited the enzymatic process by a mean percentage of 14.9%, EDTA up to 9.1%. D-penicillamine and 1.10-o-phenanthroline which inhibit collagenase specifically stopped the enzymatic activity of the tumor completely. According to our results it can be suggested that the collagenolytic activity of carcinoma of the cervix uteri is not derived from serum or from polymorphonuclear cells but is created by the tumor itself.


[Ratio of cyclo-3':5'-adenosinemonophosphate to cyclo-3':5'-guanosine-monophosphate in human tumor tissue].

In human tumor tissues of different degrees of differentiation--nevus-cell-nevus, basalioma, malign melanoma--the cAMP and cGMP content was determined and compared with the corresponding normal values. It is demonstrated that the quotient of the cAMP to the cGMP values is of importance rather than the latter values for themselves. For the benign tumor, this quotient differs only slightly from that of the adjacent normal, sound tissue. On the other hand, for the two malign tumors a drastic decrease of the quotient as compared to that of the normal tissue was found to occur.


Ultrastructural studies of intraoral verruca vulgaris.

The literature offers conflicting views regarding the existence of verruca vulgaris in the oral cavity. In an attempt to clarify this issue, a series of ten oral lesions which had been diagnosed as verruca vulgaris and ten oral lesions diagnosed as squamous-cell papilloma were examined ultrastructurally. Six of the lesions diagnosed as verruca vulgaris contained the characteristic intranuclear viral particles which are normally found in that lesion. None of the lesions diagnosed as squamous-cell papilloma exhibited this type of intranuclear viral inclusions.


Asymptomatic viral hepatitis types A and B in an adolescent population.

Sera from 95 adolescents were examined for markers of hepatitis B virus (HBV) infection and hepatitis A virus (HAV) infection. HBV markers were found in eight adolescents (8%) and evidence of previous HAV infection was found in 18 adolescents (19%); none had a history of clinically recognizable hepatitis. These findings support the growing evidence that HBV and HAV infections are diseases of the pediatric age group, and that testing of HBV vaccines when they become available for patient use will have to include a pediatric population.


Acid hydrolase activity in red and white skeletal muscle of mice during a two-week period following exhausting exercise.

The activities of beta-glucuronidase, beta-N-acetylglucosaminidase, arylsulphatase, ribonuclease, p-nitrophenylphosphatase, and malate dehydrogenase together with protein content were assayed from representative mixed (m. rectus femoris), predominantly red (proximal heads of m. vastus lateralis, m.v. medius and m. v. intermedius), and predominantly white (distal head of m. vastus lateralis) muscle homogenates of mice during a two-week period following one single exposure to exhausting intermittent running on a treadmill. The activities of cathepsin D and beta-glycerophosphatase were assayed from mixed muscle only. In all three muscle types, particularly in red muscle, the activities of beta-glucuronidase, beta-N-acetylglucosaminidase, arylsulphatase, and ribonuclease progressively increased between one to five days after the exercise; thereafter the activities began to decrease, being near the conrol values 15 days after the exercise. In mixed muscle, cathepsin D activity increased. No corresponding changes were observed in the activities of acid phosphatases. The time course of the activity changes closely resembled that earlier found to be caused by ischaemia in rabbit muscles. It is tentatively concluded that the two treatments, exhaustive exercise and temporary ischaemia, cause similar cell injuries, and that the lysosomal system involved seems to function similarly in the post-stress recovery of the fibres from these injuries.


[Epstein-Barr virus and infectious mononucleosis. A clinical study of Epstein-Barr antibodies (author's transl)].

Thirty-seven patients--aged 2 to 58--with clinical and hematological signs of infectious mononucleosis were studied. Thirty patients gave serologic evidence of Epstein-Barr virus infections; antibodies to viral capsid antigen (VCA) appeared very early (only two seroconversions and 4 cases of increased titer were detected); antibodies to early antigen (EA) occured in 25 patients, but only 9 had high titers; antibodies to nuclear antigen (EBNA) appeared late in the course of the disease. VCA-specific IgM antibodies occurred in 25 cases (they usually disappeared during the 2nd month). The transforming EB virus was found in the saliva of the 2 patients where we looked for it. Heterophile antibody responses occured in only 17 patients; among children about half of them had a positive Paul-Bunnell-Davidsohn test. After the age of 40 (3 cases) heterophile antibodies were no longer found. Three patients had another recent viral infection at the same time as the primary EBV infection (two cases of rubella, one case of adenovirus infection). Of the remaining 7 patients (having either no antibodies to EBV or antibodies of past infection), 2 had cytomegalovirus infections and one rubella.


Mental health patient assessment record: interobserver reliability.

To determine interobserver reliability of the Mental Health Patient Assessment Record, two independent observers, a visiting nurse and the investigator who was a constant second observer throughout the study, made home visit observations at two specified times: the initial assessment (time I), and approximately two months later (time II). The stratified random sample consisted of 26 discharged psychiatric patients who comprised approximately 75 percent of the new admissions to the agency during a four-week period. At time I, 26 visits were completed and values were obtained, using the Pearson product moment correlation for the scores on the MHPAR: 1) overall behavior, r = .96; 2) physical behavior, r = .91; 3) psychological behavior, r = .93; 4) social behavior, r = .83; and 5) medical behavior, r = .98. The sign test applied to total and category scores revealed that only one category, social behaviors, demonstrated a significant systematic bias of the constant second observer. Of the 26 patients observed at time I, 20 were visited at time II. The following values were obtained using the Pearson product moment correlation for MHPAR scores: 1) overall behavior, r = .98; 2) physical behavior, r = .91; 3) psychological behavior, r = .91; 4) social behavior, r = .94; and 5) medical behavior, r = .99. The sign test applied to total and category scores showed no systematic bias of the constant second observer.


Fibrous histiocytoma: a histological and statistical analysis of 155 cases.

Various salient histological features were rated from + to +++ in a semiquantitative evaluation of a series of 155 cases of fibrous histiocytoma. Relations between individual histological features, as well as between histological findings, localisation and size of lesions, and age or sex of the patient were tested statistically. Most impressive was an inverse proportional relationship between cellular and fibrillar densities: highly cellular fibrous histiocytomas chiefly showed little fiber formation. Accordingly, cases with marked fiber formation were distinguished by low cellularity. Based on this statistically significant relation, 3 subtypes could be classified on a scale of increasing fiber formation and decreasing cellular density. The majority of cases showed medium cellularity and fibrillar density, with distinct storiform (spokewheel or "whirlygig") pattern which is compatible with typical storiform histocytoma, including clincally progressive, recurrant FH and/or "dermatofibrosarcoma protuberans". The typical patient was more frequently female than male, 40 years of age with a 0.5 to 1.0 cm size tumor node in the lower extremities located in the corium, often with beginning infiltration of the subcutaneous fat tissue.


Infectious mononucleosis and Epstein-Barr virus. 1. Epidemiology, pathogenesis, immune response.

The evidence linking Epstein-Barr virus causally with infectious mononucleosis is compelling. The disease occurs only in persons who lack antibody to this virus, and serologic findings during the acute illness provide almost certain evidence for its etiologic association. Additional evidence is derived from transformation studies using lymphocytes from persons infected with Epstein-Barr virus. Epidemiologic studies have related the need for close contact with salivary secretions to the low communicability of infectious mononucleosis. The clinically relevant antibodies which develop during the disease, other than heterophile antibody, are those against the viral capsid antigen. Part 2 of this article considers the clinical picture, diagnosis, and management and begins on page 95.


Infectious mononucleosis and Epstein-Barr virus. 2. Clinical picture, diagnosis, management.

The diagnosis of infectious mononucleosis is confirmed by hematologic, biochemical, and serologic data. An absolute increase in peripheral mononuclear cells to at least 4,500/cu mm is an essential feature. The serologic hallmark of the disease is the presence of heterophile antibody. The age of the patient may affect the clinical presentation and laboratory findings. Therapy is largely supportive, with steroids being used only in the presence of certain severe complications.


Pathophysiology of lipid transport disorders.

Over the past decade considerable insight into the mechanisms involved in normal and abnormal transport as well as the mode of action of hypolipidaemic drugs has been achieved. This progress has made the approach to the hyperlipidaemic patient increasingly more precise and effective.


Inheritance of endogenous hypertriglyceridaemia type IIB or IV.

The genetic background of endogenous hypertriglyceridaemia was evaluated in 239 first-degree relatives of 48 probands with serum triglyceride level in excess of 30.0 mM and with either normal (type IV) or elevated (type IIB) serum cholesterol concentration. In one quarter of the families, all examined first-degree relatives of the proband were normolipidaemic and, thus, the disorder was classified as non-genetic. Nine of 26 probands with IV in contrast to only three of 22 probands with type IIB abnormality fell into this category. In 75% of the families the hyperlipoproteinaemia was caused by one or several abnormal genes. A multiple-type (combined) familial hyperlipidaemia could be demonstrated in 30 families and a single-type IIB or IV familial disease was found in 6 instances. Thus, the multiple-type hyperlipoproteinaemia seems to be responsible for the elevated serum triglyceride level in more than one-half of the cases with moderate to severe hyperglyceridaemia while a pure familial endogenous hypertriglyceridaemia is relatively rare. Exactly 50% of the members of families with the multiple-type lipid disorder were affected but the distribution of individual cholesterol and triglycerides values did not show a definite bimodality. It is possible that the abnormality is heterogeneous and includes several disease entities, which are indistinguishable by a conventional lipid or lipoprotein analysis but can be separated by kinetic or enzyme  studies.


Serum lipoprotein abnormalities in ischaemic heart disease.

Quantitative lipoprotein level data was obtained from healthy subjects and patients with ischaemic heart disease or peripheral vascular disease in four European communities. Hypertriglyceridaemia, due mainly to an increase in VLDL triglyceride, was commoner in London and Uppsala than in Naples and Geneva. In three communities there were significant increases in total serum cholesterol due to both increases in LDL and in VLDL cholesterol. Hypercholesterolaemic and hypertriglyceridaemic status were over-represented in both ischaemic heart disease and peripheral vascular disease patients.


Effects of dietary treatment on lipoprotein levels in hyperlipoproteinaemia.

Diet constitutes the basis of all lipid lowering therapy. The mechanisms responsible for the effects of the different dietary measures are not yet fully understood. Dietary treatment 'normalized' the lipid levels in over 50% of the mild to moderate hyperlipoproteinaemic states encountered in a middle-aged population with clinical manifestations of atherosclerotic cardiovascular disease. Triglyceride and cholesterol determinations in isolated lipoprotein fractions supplied additional information on the character and extent of the lipoprotein changes induced by diet.


The prevalence of hyperlipoproteinaemia in vascular disease.

Surveys of the apparently healthy working population of the West of Scotland have revealed a high prevalence of hyperlipoproteinaemia (HIP). In males, type IV occurred more frequently (12%) than in females (3.3%), although obesity played an important part in this finding. HLP also occurred frequently (61%) in survivors of myocardial infarction (type II 39%, type IV 22%) but less frequently in peripheral vascular disease (38%), although there was a higher prevalence in females (47%) than males (32%) largely due to an increased prevalence of type IIa (29.5% cf 7.5%). HLP did not appear to play a significant role in cerebrovascular disease.


Treatment of severe and mild hypercholesterolaemia with probucol and neomycin.

Administration of probucol to 23 patients with familial xanthomatotic hypercholesterolaemia reduced the serum cholesterol level during the 9-month study by 9%, while in 15 patients with less severe hypercholesterolaemia the decrease was on an average 15%. A reduction of more than 10% was obtained in 57% of the former and 80% of the latter subjects. In a double blind trial a greater reduction was obtained in serum cholesterol by probucol than by placebo. Neomycin lowered the serum cholesterol more effectively than probucol in subjects with severe type II abnormality and was at least equally effective in less severe type II patients. Probucol increased transiently the faecal bile acid and dietary cholesterol excretion, while neomycin enhanced the faecal elimination of cholesterol as neutral sterols.


Cholestyramine, clofibrate and nicotinic acid as single or combined treatment of type IIa and IIb hyperlipoproteinaemia.

1. In type IIa and IIb hyperlipoproteinaemia, treatment with 16 g cholestyramine daily reduced the cholesterol concentration 23%. By adding clofibrate this effect was enhanced to a 29% reduction and at the same time clofibrate reduced the triglyceride (TG) concentration 33%. 2. The optimal cholesterol reduction with clofibrate in type II was 17% and was found after treatment with 1.5 g clofibrate/day. The optimal TG reduction appeared to be achieved with a daily dose of 2 g.3. Nicotinic acid in the form of niceritrol had another type of dose-response in type II with doses from 3 to 6 g/day. It appeared as if the optimal dose probably was above 6 g daily. The 6 g dose produced a cholesterol reduction of 22% and in type IIb there was at the same time a 50% reduction of the TG concentration. 4. By combining 3 g niceritrol with 2 g clofibrate almost the same effect on serum lipids was obtained as with 6 g niceritrol. When choosing a drug for treatment of hyperlipoproteinaemia it is necessary to consider not only the lipid lowering effect but also the side effects which are not discussed here. By combining clofibrate with either cholestyramine or niceritrol it was possible to improve the lipid lowering effect. There were no side effects which were not seen when the drugs were used alone. A more frequent use of combinations to improve the treatment of hyperlipoproteinaemia is recommended.


Neonatal diagnosis of Fredrickson type II hyperlipoproteinaemia.

Cord-serum beta-lipoprotein was measured by an immunological method in 303 children. The blood lipids were studied at 7-9 and 14-19 months after birth. The lipids of both parents were measured. Six children were found to have a greater than 2 SD elevation of beta-lipoprotein at birth. Three of these had hypertriglyceridaemia and 3 had type II hyperlipoproteinaemia. The rapid and quantitative measurement of beta-lipoprotein looks promising for screening of type II hyperlipoproteinaemia at birth.


Cyclical release of vasoactive intestinal polypeptide (VIP) from a pancreatic islet cell apudoma.

A patient is described who presented with the classical symptomatology and profound electrolyte disturbance of the Verner-Morrison syndrome due to a pancreatic apudoma secreting vasoactive intestinal polypeptide (VIP). Diagnosis was confirmed by plasma VIP as measured by a radio-immunoassay technique now available. It is suggested that the cyclical nature of the symptoms in this case was due to cyclical release of VIP from the tumour in response to an unknown stimulus. Perfusion studies confirmed the excess secretory state of water, sodium and chloride in the small intestine. Symptoms were completely abolished by surgery and the progress is being monitored by means of serial plasma VIP estimations to detect any early recurrence of metastatic disease.


Epidermal growth factor: biological activity requires persistent occupation of high-affinity cell surface receptors.

The enhancement of DNA synthesis by epidermal growth factor (EGF) in cultured human fibroblasts is demonstrable 24 hr after incubation of the cells at 37 degrees C with very low concentrations (0.83 nM) of the hormone for very short periods (30 min) followed by thorough washing of the cells to remove the free hormone in the medium. This effect must result from persistent, extraordinarily tight binding of the hormone to surface receptors, because the addition of specific, purified anti-EGF IgG as late as 8 hr after initial hormone exposure can completely reverse the biological effects of the hormone. This causes only a slight (but significant) increase in the rate of dissociation at 37 degrees C of the cell-bound (125)I-labeled EGF at low occupancy. Together with the fact that in the presence or absence of antibody virtually all of the demonstrable cell-bound (125)I-labeled EGF can be shown to dissociate from the cell during a period as short as 2-3 hr, the data suggest the possibility that the biological effects of this hormone may be mediated by occupation of only a negligible fraction of very high affinity binding sites. Thus, the processes of hormone internalization, degradation, and "down regulation" may be irrelevant to the effects of the hormone on DNA synthesis. For this effect the crucial and limiting processes appear to be strictly related to the continuous and persistent occupation of cell surface receptors.


Cell-free synthesis and processing of the proteins of poliovirus.

Poliovirus RNA can be translated completely and accurately in rabbit reticulocyte lysates; the nascent poly-protein is processed to give primary products 1a, X, and 1b indistinguishable from those made in poliovirus-infected HeLa cells. The capsid precursor protein 1a is processed to form the capsid proteins VP0, VP1, and VP3, while the noncapsid precursor 1b is processed to form protein 2.


Recombination between viral and cellular sequences generates transforming sarcoma virus.

A series of sarcoma viruses has been obtained from tumors induced by transformation-defective (td) mutants of the Schmidt-Ruppin strain of Rous sarcoma virus, subgroup A (SR-A). The RNA sequences of these "recovered avian sarcoma viruses" (rASVs) were compared with those of td mutants and of SR-A by oligonucleotide fingerprinting. Of six sarcoma-specific oligonucleotides present in SR-A RNA, three to six were missing in the RNAs of the four td mutants examined. All six isolates of rASV examined have regained these six oligonucleotides. In addition, most rASV RNAs have three new oligonucleotides not present in the RNA either of td mutants or of SR-A. The newly obtained oligonucleotides are located between 800 and 2600 nucleotides from the 3' end of rASV RNA, which corresponds to the src region of SR-A RNA mapped previously. Furthermore, viral RNAs of two td mutants isolated from a clone of rASV lack most src-specific oligonucleotides, including the three new ones. No differences were found among RNAs of td, SR-A, and rASV in the regions outside of src. Our results indicate that RNA sequences that rASVs have acquired from cells in the process of conversion from td virus to transforming virus are mapped within the src region and segregate with the transforming function. Some of the sequences are new and some are identical with those in SR-A RNA.


Specific RNA sequences and gene products of MC29 avian acute leukemia virus.

The 28S RNA of the defective avian acute leukemia virus MC29 contains two sets of sequences: 60% are hybridized by DNA complementary to other avian tumor virus RNAs (group-specific cDNA) and 40% are hybridized only by MC29-specific cDNA. Specific and group-specific sequences of viral RNA, defined in terms of their large RNase T(1)-resistant oligonucleotides, were located on a map of all large T(1) oligonucleotides of viral RNA. Oligonucleotides representing MC29-specific sequences of viral RNA mapped between 0.4 and 0.7 unit from the 3'-poly(A) end. Oligonucleotides of group-specific sequences mapped between 0 and 0.4 and between 0.7 and 1 map unit. Cell-free translation of viral RNA yielded three proteins with approximate molecular weights of 120,000, 56,000, and 37,000, termed P120(mc), P56(mc), and P37(mc). P120(mc) contained both MC29-specific peptides and serological determinants and peptides of the conserved, internal group-specific antigens of avian tumor viruses. P120(mc) is translated only from full-length 28S RNA. Furthermore, MC29 RNA contains sequences related to the group-specific antigen gene (gag), near the 5' end, which are followed by MC29-specific sequences. We conclude that this protein is translated from the 5' 60% of the RNA, and that it includes a segment translated from the specific sequences. It is suggested that the transforming (onc) gene of MC29 may consists of the specific and some group-specific RNA sequences and that P120(mc), which is also found in transformed cells, may be the onc gene product.


Resolution of cytochrome oxidase into two component complexes.

Cytochrome c oxidase (ferrocytochrome c: oxygen oxidoreductase, EC 1.9.3.1) has been resolved into a pair of complexes of unequal molecular weight. The larger complex (electron transfer complex) contains exclusively the oxidation-reduction proteins characteristic of cytochrome oxidase; the smaller complex (ion transfer complex) shows exclusively the capability for cation-dependent induction of the fluorescence of 8-anilino-1-naphthalenesulfonic acid--a capability demonstrable in preparations of cytochrome oxidase. The duplex nature of cytochrome oxidase has important implications for the mechanism of energy coupling.


Translation of polyoma virus T antigens in vitro.

Polyoma virus-specific RNA isolated from the cytoplasm of lytically infected cells can be translated in vitro to yield three T antigens, of Mrs approximately 90,000, 60,000, and 22,000. The tryptic peptide patterns of the T antigens synthesized in vitro are similar or identical to the patterns of the corresponding proteins in polyoma-infected cells. All three proteins incorporate methionine donated from initiator tRNA in vitro. Polyoma cRNA codes for a protein that is slightly larger than the 22,000 T antigen and that, by other criteria, is similar to the 22,000 T antigen. Translation of cRNA does not yield the 90,000 and 60,000 T antigens, suggesting that the generation of the mRNAs for these T antigens requires the removal of intervening sequences. The mRNA for the 90,000 T antigen is smaller than the mRNAs for the 22,000 and 60,000 proteins. All three proteins share common NH2-terminal sequences, and the 60,000 T antigen may be translated partially in a different reading frame from sequences also coding for the 90,000 T antigen. The demonstration that polyoma virus codes for three different T antigens raises the possibility that all three proteins may be involved in cell transformation.


Compartmentalization of cyclic AMP-dependent protein kinases in human erythrocytes.

The human erythrocyte contains two types of cyclic AMP-dependent protein kinase. The membrane-associated protein kinase holoenzyme can be released intact by hypotonic treatment at alkaline pH. Chromatography on DEAE-cellulose and molecular weight determinations demonstrate that this enzyme is a type I cyclic AMP-dependent protein kinase, while the predominant cyclic AMP-dependent protein kinase found in the cytoplasm is type II. The catalytic subunits of the two types of kinase found in the erythrocyte are identical, but the regulatory subunits, which distinguish the two types of kinase, determine their localization within the cell. It is proposed that the regulatory subunit of the type I enzyme, in addition to binding the catalytic subunit, interacts specifically with one or more membrane proteins and that this interaction may serve to position the kinase in preferential proximity to protein substrates.


Endogenous viral genes of the White Leghorn chicken: common site of residence and sites associated with specific phenotypes of viral gene expression.

The DNAs from greater than 150 individual White Leghorn chickens were digested with restriction endonucleases BamHI, EcoRI, HindIII, and Sst I, fractionated by gel electrophoresis, denatured, and transferred to nitrocellulose filters. Fragments containing the endogenous viral genes were detected by hybridization with 70S Rous associated virus type 2[32P]RNA. Embryos of several different phenotypes with respect to production of the endogenous virus and expression of viral group-specific antigen and viral envelope protein were analyzed. DNA from birds of each phenotype produced a distinctive pattern of fragments containing viral genetic information. Individual fragments were seen to segregate as genetic loci in mating experiments. From the fragment patterns and the segregation data, the following conclusions were drawn with respect to the sites of residence in the chicken chromosome of the endogenous viral genes: (i) the DNA of all chickens contains viral genetic information in at least one site, and this site of residence appears to be the same in all chickens analyzed; (ii) four other sites have been identified, and the presence of viral information at each of these sites is always accompanied by a specific phenotype of endogenous viral gene expression; (iii) in addition to the above-mentioned five sites, a small number of other sites have been identified which are not associated with a known phenotype.


Origin of DNA replication in papovavirus chromatin is recognized by endogenous endonuclease.

Isolated simian virus 40 (SV40) and polyoma nucleoprotein complexes contain endonuclease that, under in vitro conditions, converts part (up to 30%) of the covalently closed superhelical DNA to full-length linear rods. The positions of the cleavage sites within the genomes of SV40 and polyoma were determined by digestion with various single-cut restriction endonucleases and subsequent agarose gel electrophoresis of the cleavage products. Both SV40 and polyoma covalently closed superhelical DNA were cleaved open at their respective origins of DNA replication (+/- 75 base pairs). The full-length linear DNA rods whose ends map adjacent to the origin of DNA replication could also be isolated by sodium dodecyl sulfate/phenol extraction both from SV40-infected permissive cells and from purified SV40 virions. These data reveal the presence of a unique structure of the papovavirus chromatin close to the initiation site of DNA replication.


Refolding of a bifunctional enzyme and its monofunctional fragment.

The renaturation of the bifunctional enzyme aspartokinase II-homoserine dehydrogenase II has been studied by using the reappearance of its two activities. The same kinetics of renaturation are obtained for the dehydrogenase (EC 1.1.1.3) and the kinase activity (EC 2.7.2.4). The mechanism of refolding of the enzyme apparently involves two steps, a folding step occurring within a monomer and a subsequent dimerization step. The reappearance of the two activities depends on this dimerization step, suggesting that monomeric species are inactive. A proteolytic fragment possessing full dehydrogenase activity is shown to be able to renature, as judged by the recovery of its activity. In this case also, the refolding depends on the formation of dimeric species. However, the refolding of this fragment is much faster than that of the dehydrogenase region in the intact enzyme. These results suggest that, although the dehydrogenase region can refold by itself when isolated as a fragment, refolding of this same region in the whole protein involves interactions with the remainder of the protein.


Escherichia coli mutants defective in dipeptidyl carboxypeptidase.

Two independent mutants of Escherichia coli deficient in dipeptidyl carboxypeptidase activity (Dep-) were isolated after mutagenesis with ethyl methanesulfonate. Mating experiments and introduction of specific episomes indicated that the responsible gene was located at approximately 27--31 min on the E. coli chromosome. The Dep- mutants differed from the parental strain in their inability to grow with N-acetylalanylalanylalanine as the sole nitrogen source. Revertants selected for growth on this substrate of the enzyme were found to have reacquired the activity. Enzyme activity was highly sensitive to inhibition by 1-(D-3-mercapto-2-methylpropanoyl)-L-proline (SQ 14225), a potent inhibitor of mammalian dipeptidyl carboxypeptidase (angiotensin-converting enzyme, peptidyl dipeptidase, EC 3.4.15.1). This compound also reduced the rate of growth of the wild type with N-acetylalanylalanylalanine but not with ammonium sulfate. A fraction of the enzyme was released into the medium by osmotic shock, indicating that its presence in the periplasmic space may account for growth with N-acetylated peptides that cannot be taken up by E. coli. In addition to providing information about the specific role of this exopeptidase in E. coli, the Dep- mutants may prove useful for delineating the regulation and cellular function of dipeptidyl carboxypeptidases in higher organisms.


Construction of bacterial plasmids that contain the nucleotide sequence for bovine corticotropin-beta-lipotropin precursor.

mRNA that encodes the common peptide precursor for the hormones corticotropin and beta-lipotropin was purified from the neurointermediate lobe of bovine pituitaries, and double-stranded cDNA species synthesized from this template were cloned in Escherichia coli X1776 by inserting them into the Pst I endonuclease cleavage site of the pBR322 plasmid using poly(dG)poly(dC) homopolymeric extensions. Certain of the cloned cDNA inserts contain nucleotides corresponding to the complete amino acid sequence of bovine corticotropin and a coding sequence that corresponds to at least the first portion of bovine beta-lipotropin. The nucleotide sequences coding for corticotropin and beta-lipotropin are separated on the cDNA by a 6-base-pair sequence encoding lysine and arginine, indicating that the carboxyl terminus of corticotropin is connected on the precursor peptide with the amino terminus of beta-lipotropin by these two amino acids. In addition, the cloned cDNA insert is characterized by an unusually high C+G nucleotide base content as well as by a number of DNA sequence duplications.


Demonstration of an ecdysteroid receptor in a cultured cell line of Drosophila melanogaster.

Incubation of the high-speed supernatant from the Kc cell line of Drosophila melanogaster with [3H]ponasterone A results in significant binding of the ligand as determined by gel filtration and dextran-coated charcoal binding assays. In vivo exposure of the Kc line to [3H]ponasterone A for 30 min results in a marked binding of the ligand by a KCl-soluble nuclear extract. With both the cytosol and nuclear preparations the binding has specificity and a low dissociation constant (3 X 10(-9) M). In addition the labeling of the nuclear preparation exhibits a saturation at approximately 7 X 10(-10) M which probably reflects the molar concentration of cytoplasmic receptors.


Ecdysteroid receptors in imaginal discs of Drosophila melanogaster.

[3H]Ponasterone A (PNA) of high specific activity has been used to identify and begin characterization of ecdysteroid (formerly called ecdysone) receptors in cytoplasmic and nuclear fractions of imaginal discs of Drosophila melanogaster. The equilibrium Kd of the observed macromolecular binding, 3--4 X 10(-9) M PNA, is in good agreement with the minimal concentration required for induction of complete morphogenesis in vitro, 4.2 X 10(-9) M PNA. Binding is analog specific and has kinetics consistent with a role in hormone response. On gentle homogenization, less than 5% of the binding capacity of the cell is released as soluble receptor; the other 95% remains with the nuclear fraction. This nuclear fraction specifically binds [3H]PNA in vitro. Greater than 95% of nuclear PNA receptors are released by extraction with 0.3 M KCl. The binding properties of the nuclear receptors are indistinguishable from those of the cytosol fraction or of the whole cell.


Monovalent antibodies directed to transformation-sensitive membrane components inhibit the process of viral transformation.

Monovalent antibodies (Fab) directed to two classes of transformation-sensitive cell surface components, ganglioside and galactoprotein a (Gap a), inhibit the process of oncogenic viral transformation of cells. Mouse 3T3 cells infected with murine sarcoma virus were not transformed in terms of morphology change and enhancement of sugar uptake when the infected cells were cultured in the presence of monovalent antibodies directed to GM(1) ganglioside or to Gap a. Transformation inhibitory activity of these cell surface ligands was not related to cell growth inhibition because the monovalent antibodies to globoside and divalent Con A were growth inhibitory but did not inhibit oncogenic transformation. Neither anti-GM(1) Fab nor anti-Gap a Fab inhibited virus production. The transformation inhibitory activity of antiganglioside and anti-Gap a Fab was additionally assessed by inhibiting the transformed phenotype in NRK cell lines with mutants of avian sarcoma virus that are temperature sensitive for expression of the transformation phenotype (NRK/LA25). In this cell line, the GM(3) ganglioside (not GM(1)) and Gap a were transformation-sensitive cell surface components. The expression at permissive temperature of transformed phenotypes, such as morphology change and capability of growth in 0.3% agar, was inhibited by preincubation of the cells with anti-GM(3) Fab or anti-Gap a Fab.GM(3) labeling of NRK/LA25 cells decreased at permissive temperature, whereas preincubation of cells with anti-Gap a, which induces the inhibition of transformation after a temperature shift, prevented the decline of GM(3) label on the cell surface. The data suggest a possible correlation between GM(3) and Gap a expression. Application of monovalent antibodies to these transformation-sensitive components may prevent changes of these components on cell surfaces, and thus may result in abortion of phenotypic expression of transformation, although the transforming gene (src) has been set active. These results indicate that pericellular structures influence gene expression.


Establishment of preadipocyte clonal line from epididymal fat pad of ob/ob mouse that responds to insulin and to lipolytic hormones.

A clonal cell line that responds to insulin and to lipolytic hormones has been established from the epididymal fat pad of the C57BL/6J ob/ob mouse. This line, designated ob 17, has a doubling time of 12.5 or 19 hr in 10% or 1% fetal calf serum, respectively. It presents a heterogeneous chromosome number with 40% of the cells containing 35-44 chromosomes and expresses the characteristic H2-LA antigen. After cessation of growth, ob 17 cells accumulate droplets of triglycerides; this accumulation occurs to a significant extent even in the absence of insulin normally added after confluence. Lipoprotein lipase activity is negligible in exponentially growing cells but appears at its maximal level just after confluence with or without insulin. Acid:CoA ligase and acylCoA:diglyceride acyltransferase develop later than lipoprotein lipase. The appearance of lipolytic and lipogenic enzymes, but not of triglycerides, seems to be independent of the presence of lipoproteins or of unesterified fatty acids in the culture medium. Therefore, the differentiation program becomes operative when growth is arrested, and differentiation occurs, providing a source of exogenous lipids. Differentiated ob 17 cells in which endogenous triglycerides have been prelabeled on the fatty acid moiety do respond to epinephrine and corticotropin by release of radioactive fatty acid. This lipolytic response is counteracted by prior addition of insulin. The ob 17 cell line appears to be a useful model for study of growth and differentiation of adipose cells as compared to preadipocyte cell lines from the nongenetically obese mouse.


DNAs of simian virus 40 and polyoma direct the synthesis of viral tumor antigens and capsid proteins in Xenopus oocytes.

Purified simian virus 40 and polyoma DNAs injected into nuclei of Xenopus oocytes were transcribed and subsequently translated into virus-specific tumor antigens and capsid proteins. Simian virus 40 large and small tumor antigens synthesized in the oocytes were indistinguishable, by gel electrophoresis and [35S]methionine-labeled tryptic peptide mapping, from the corresponding polypeptides synthesized in CV-1 African green monkey cells. The synthesis of large simian virus 40 tumor antigen implies the correct splicing of its mRNA, which is complementary to nonadjacent nucleotide sequences in the early region of the viral genome. Polyoma DNA directed synthesis of two polyoma tumor antigen polypeptides, 57,000 Mr and small tumor antigen, and of the main capsid protein.


Infection with paramyxoviruses stimulates synthesis of cellular polypeptides that are also stimulated in cells transformed by Rous sarcoma virus or deprived of glucose.

Infection of several types of cultured cells with the paramyxoviruses simian virus 5 and Sendai virus stimulates synthesis of four polypeptides (I-IV) with molecular weights of approximately 99,000, 97,000, 86,000, and 78,000, respectively. That these are host polypeptides encoded in cellular mRNAs has been shown by the inhibition of their synthesis by actinomycin D and by the similarity of the peptide maps of them and of polypeptides with the same electrophoretic mobility from uninfected cells. Peptide mapping as well as identical migration in polyacrylamide gels has also indicated that polypeptides I, II, and IV are the same as plasma membrane polypeptides whose synthesis is enhanced in cells transformed by Rous sarcoma virus and in normal cells by glucose deprivation or treatment with 2-deoxyglucose. Polypeptides I and II appear to be the same polypeptides, with the observed differences in migration reflecting the glycosylation of polypeptide I, a relationship previously shown to exist between polypeptides in glucose-deprived and glucose-fed cells. Infection with paramyxoviruses does not significantly increase the transport of glucose by cells, and the maintenance of a high concentration of glucose in the medium does not prevent the enhanced synthesis of these polypeptides. This is in contrast to the situation in transformed cells in which stimulation of synthesis of these polypeptides is secondary to depletion of glucose in the medium due to increased glucose uptake by the cells. Thus, although paramyxovirus infection and transformation by Rous sarcoma virus result in stimulation of the synthesis of the same membrane polypeptides, the mechanism of stimulation differs.


Detection of viral sequences of low reiteration frequency by in situ hybridization.

The sensitivity of in situ hybridization has been increased at least 10-fold by hybridizing in cDNA excess, by increasing the diffusion of the cDNA through the cells, by hybridizing at optimum temperature, and by stabilizing hybrids during autoradiography. Saturation of intracellular RNA with [3H]cDNA has been achieved. The assay is quantitative. In situ hybridization has been used to detect and quantitate visna virus RNA in infected cells. By using [3H]cDNA with specific activity of 2 X 10(8) dpm/micrograms and conditions that reduce background to negligible levels, 10--20 copies of viral RNA per cell can be detected and quantitated after 2 days of autoradiographic exposure.


Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells.

We have prepared (125)I-labeled [Tyr(4)]bombesin and have examined the kinetics, stoichiometry, and chemical specificity with which the labeled peptide binds to dispersed acini from guinea pig pancreas. Binding of (125)I-labeled [Tyr(4)]-bombesin was saturable, temperature-dependent, and reversible and reflected interaction of the labeled peptide with a single class of binding sites on the plasma membrane of pancreatic acinar cells. Each acinar cell possessed approximately 5000 binding sites, and binding of the tracer to these sites could be inhibited by [Tyr(4)]bombesin [concentration for half-maximal effect (Kd), 2 nM], bombesin (Kd, 4 nM), or litorin (Kd, 40 nM) but not by eledoisin, physalemin, somatostatin, carbachol, atropine, secretin, vasocative intestinal peptide, neurotensin, or bovine pancreatic polypeptide. At high concentrations (>0.1 muM), cholecystokinin and caerulein each caused a small (15-20%) reduction in binding of lableled [Tyr(4)]bombesin. With bombesin, litorin, and [Tyr(4)]bombesin, there was a close correlation between the relative potency for inhibition of binding of labeled [Tyr(4)]bombesin and that for stimulation of amylase secretion. For a given peptide, however, a 10-fold higher concentration was required for half-maximal inhibition of binding than for half-maximal stimulation of amylase secretion, calcium outflux, or cyclic GMP accumulation. These results indicate that dispersed acini from guinea pig pancreas possess a single class of receptors that interact with [Tyr(4)]bombesin, bombesin, and litorin and that occupation of 25% of these receptors will cause a maximal biological response.


Time-dependent resistance or susceptibility of tumor cells to cytotoxic antibody after exposure to a chemotherapeutic agent.

We report that a chemotherapeutic agent (melphalan) can affect the sensitivity of tumor cells to cytotoxic antibody. Depending on the time interval between drug treatment and subsequent exposure to antibody and complement, the tumor cells can be either more resistant or more susceptible to antibody when compared to control cells. The number of tumor cells surviving the combined treatment was determined by a colony inhibition assay. The two antisera used in this study were directed against either virus-specific or myeloma protein-specific antigens on the surface of S107 murine myeloma cells; identical results were obtained with both sera. Twenty-four hours after exposure to the drug, the number of tumor cells surviving the antibody treatment increased. During this period of increased resistance, the tumor cells were temporarily arrested in the G(2) phase of the cell cycle. After this period of maximal resistance, the effect of cytotoxic antibody on the cells changed such that 4 days after melphalan treatment the cells were significantly more susceptible to the antibody than were the sham-treated control cells. The period of increased susceptibility correlated with an increased density of S107 myeloma protein and viral antigens on the surface of the tumor cells. Eight days after the drug treatment, the susceptibility of the tumor cells and the density of surface antigens both returned to normal levels. This study shows that the correct time interval between exposure to a drug and subsequent treatment with antibody is critical for maximal killing of the tumor cells. The basis for the differential sensitivity of the tumor cells to anti-body may be related to the drug-induced changes in the cell cycle and in antigen expression on the cell surface.


Inhibition of lymphocyte-mediated cytolysis by 3-deazaadenosine: evidence for a methylation reaction essential to cytolysis.

3-Deazaadenosine (deazaAdo) inhibits lymphocyte-mediated cytolysis in vitro at micromolar concentrations and is potentiated markedly in this activity by L-homocysteine thiolactone. DeazaAdo alone causes a rapid, dose-dependent buildup of S-[(3)H]adenosylhomocysteine (AdoHcy) and S-[(3)H]adenosylmethionine in cytolytic lymphocytes labeled with L-[2-(3)H]methionine; smaller amounts of S-3-[(3)H]deazaadenosylhomocysteine (deazaAdoHcy) are also formed in these cells. The simultaneous addition of deazaAdo and L-homocysteine thiolactone to the lymphocytes results in a massive intracellular accumulation of deazaAdoHcy. Both the inhibition of lymphocyte-mediated cytolysis and the cellular accumulation of [(3)H]AdoHcy caused by deazaAdo alone are reversed rapidly by removal of drug from the medium. However, the inhibition of cytolysis and the large cellular buildup of deazaAdoHcy resulting from treatment of the lymphocytes with deazaAdo plus L-homocysteine thiolactone are dissipated more slowly under these same conditions. Unlike adenosine, deazaAdo is not potentiated in its inhibition of lymphocyte-mediated cytolysis by Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone], an inhibitor of cyclic AMP phosphodiesterase, and has little or no effect upon the level of lymphocytic cyclic AMP. DeazaAdo is not metabolized detectably to 5'-nucleotides in the lymphocytes and does not cause a decrease in the pool sizes of CTP, UTP, ATP, or GTP. Both AdoHcy and deazaAdoHcy have been reported to be powerful inhibitors of a variety of S-adenosylmethionine-utilizing methyltransferases. The present results, therefore, indicate that the effect of deazaAdo upon lymphocyte-mediated cytolysis is due ultimately to the inhibition of an unidentified but crucial methyltransferase within the cytolytic lymphocytes and provide an insight into the biochemical processes involved in lymphocyte-mediated cytolysis.


gamma-Aminobutyric acid receptors visualized in spinal cord cultures by [3H]muscimol autoradiography.

gamma-Aminobutyric acid (GABA) receptors were visualized in mouse spinal cord explant cultures by [3H]muscimol autoradiography over certain small neurons of the dorsal horn grey matter, in the interneuronal neuropil of dorsal and ventral horns, and (rarely) in small clusters on processes of anterior horn cells. Specificity was indicated in control experiments by inhibition of binding by [3H]muscimol after pretreatment with GABA or a GABA analogue, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, isoxazole 16), or with receptor antagonists bicuculline and picrotoxin. Unlabeled muscimol exchanged effectively with [3H]muscimol and produced autoradiographic label in locations indistinguishable from those found in experiments with [3H]muscimol alone. Pretreatment with the GABA uptake and transport inhibitors (-)-nipecotic acid and guvacine did not affect binding with [3H]muscimol. These experiments indicate that explant culture systems can be used for demonstration of functional receptors.


Biochemical evidence for presynaptic and postsynaptic alpha-adrenoceptors in rat heart membranes: positive homotropic cooperativity of presynaptic binding.

In crude rat cardiac membrane preparations, [3H]dihydroergocryptine (3H-DHE) appears to bind to two classes of sites with limited capacity, differing in their specificities and their affinities. The first class of binding sites interacts preferentially with the postsynaptic alpha-adrenoceptor blocker ARC239, as can be expected for postsynaptic alpha-adrenoceptors. The binding of 3H-DHE to these receptors follows the law of mass action, with a high affinity for 3H-DHE (Kd 25 degrees C = 1.67 +/- 0.37 nM). Postsynaptic saturating levels of 3H-DHE are necessary to occupy the second class of binding sites. These sites exhibit a preferential affinity for presynaptic ligands such as clonidine and yohimbine, as would be expected for presynaptic alpha-adrenergic receptors. This presynaptic binding shows a markedly positive homotropic cooperativity (Hill n = 2.88) with initial and final apparent Kds of 23 and 0.83 nM, respectively. Free energy of interaction between sites is of the order of 2 kcal (8.36 kJ)/mol of sites. These characteristics provide a rational molecular basis for the functional role of presynaptic alpha-adrenoceptors that mediate the inhibition of norepinephrine release from nerve endings.


Voltage-sensitive calcium channels regulate guanosine 3',5'-cyclic monophosphate levels in neuroblastoma cells.

Veratridine or high potassium concentration increased guanosine 3',5'-cyclic monophosphate (cGMP) levels in neuroblastoma cells of clone N1E-115 without affecting levels of adenosine 3',5'-cyclic monophosphate (cAMP). The increases in cGMP appear to be a direct result of the depolarizing action of these agents and not due to the action of substances released from the cells upon depolarization. The increase in cGMP produced by depolarization was dependent upon extracellular calcium and could be prevented by the calcium channel blockers D600 and cobalt. Carbachol, acting on muscarinic acetylcholine receptors, also caused a calcium-dependent increase in cGMP in these cells. The carbachol and potassium effects were additive from 5 to 100 mM potassium and from 1 to 3 mM calcium. The carbachol response was nearly as sensitive as the potassium response to inhibition by D600 but was much less sensitive to inhibition by cobalt. The results suggest that depolarization increases cGMP levels in these cells by opening voltage-sensitive calcium channels and that activation of muscarinic receptors opens separate, voltage-insensitive calcium channels.


Pituitary-adrenal axis and oral morphine consumption in rats.

Removal of the pituitary gland in rats leads to suppression of oral morphine and quinine intake behavior. Experiments measuring oral intake of solutions containing graded concentrations of morphine or quinine, revealed that the detection acuity for bitter taste is changed in hypophysectomized (hypox) animals. Treatment of these rats with ACTH 1--24 restored oral morphine intake towards that on intact rats. Morphine consumption in hypox rats was not affected by administration of ACTH 4--10 or ACTH 11--24, but was normalized by treatment with corticosterone. Adrenalectomy also diminished oral morphine intake. It is concluded that hypophysectomized animals refuse a morphine solution because their threshold for bitter taste quality is altered, presumably due to a diminished release of corticosteroids.


Morphine self-administration and EEG power spectra in the rat.

Power spectral analyses were used to study changes in cortical EEG during morphine self-administration in freely-moving dependent rats prepared with chronic cortical and muscle electrodes and with permanent indwelling IV cannulae. As time progressed from a morphine self-injection toward another injection, a significant spectral shift of the EEG to lower frequencies occurred during successive REM sleep episodes. Each morphine self-injection reinstated the predominance of higher frequencies in the EEG spectra. These EEG changes which preceded lever pressing may reflect changes in morphine plasma levels and in the state of the CNS that precede drug-seeking behavior.


MSH/ACTH4-10 and task-induced increase in tendon reflexes and heart rate.

Earlier studies revealed that during a binary choice reaction task an increase of tendon reflex amplitudes and heart rate can be found, together with a suppression of heart rate variability. The results were interpreted as a task-induced increase in generalized arousal. In this study two experiments, consisting of a rest period and a binary choice reaction task, were done. In Experiment 1, twenty subjects, in a cross-over design, received 15 mg MSH/ACTH4-10 or a placebo. Only reflexes were recorded. In experiment 2, three groups of 9 subjects received either 30 or 15 mg MSH/ACTH4-10 or a placebo. Reflexes, heart rate and heart rate variability were recorded. Rest-task differences of reflexes and heart rate were enhanced by the drug. We hypothesized that MSH/ACTH4-10 intensified the arousal effect of the task.


The effects of prostaglandins on cAMP levels in subpopulations of mouse lymphocytes.

The effects of prostaglandin E2 (PGE2) on cyclic AMP levels in various mouse lymphocyte populations were studied. It was found that spleen cells and thymocytes respond comparably to PGE2. Cortisone treatment abolished the responsiveness in thymocytes. Fractionation of splenic lymphocytes on glass wool columns into subpopulations of bone-marrow derived (B) cells or thymus-derived (T) cells showed that both B and T splenic lymphocytes can respond to PGE2. Lymphocytes or spleen cells cultured for varying periods (24--96 hrs) lose their sensitivity to PGE2 stimulation of cAMP. This "refractoriness" to PGE2 is only partially reversed by incubating lymphocytes with phosphodiesterase inhibitors.


The relationship between changes in REM sleep and clinical improvement in depressed patients treated with amitriptyline.

EEG sleep recordings were obtained on consecutive nights from six hospitalized depressed patients before, during, and after treatment with amitriptyline for a total of 370 nights of data, about 85% of all nights of the study. Amitriptyline significantly reduced time spent in rapid eye movement (REM) sleep and prolonged the REM latency throughout the treatment period. Three patients who improved during treatment showed a REM rebound when amitriptyline was discontinued, whereas three patients who did not improve showed no REM rebound.


Sustained ingestion of methadone and the sleep of monkeys.

Methadone HCl was administered daily to four stump-tailed macaques. The animals' sleep was periodically examined throughtout a year of methadone maintenance and, in two animals, during eight months of withdrawal. REM sleep was substantially decreased by methadone treatment and gradually returned to predrug values over a 6- to 8-month period of maintenance. Measures of non-REM sleep and awakenings showed similar disruption with no return to predrug values. These changes were not correlated with alterations in plasma-methadone concentrations. REM sleep rebound occurred temporarily upon drug withdrawal in two animals, but no consistent sleep disruption was apparent during the subsequent eight months. Contrary to some suggestions, therefore, tolerance to the sleep-disruptive effects of the drug may be specific and incomplete, and extended REM rebound upon withdrawal is not a universal response.


[The significance of sialography in tumors of the parotid gland (author's transl)].

The significance of sialography in diagnosis of parotid gland tumors is based on the differentiation of chronic inflammatory, benign and malignant lesions. This method combined with history and physical findings will establish the diagnosis in 80% of cases with parotid gland tumors. Water-soluble contrast media are most useful for ductography. It provides good contrast, stays in the duct system for a sufficient period of time and will not cause inconvenience to the patient. Tomograms are particularly valuable in addition to the standard a.p. and lateral standard views. Chronic inflammation causes alterations with small paraductal contrast accumulations throughout the entire efferent duct system. Benign tumors may be recognized by straight ducts and interlobular paravasates. In malignant neoplasms filling defects are more characteristic than parenchymal staining. Peracute and subacute inflammations as well as tuberculosis are difficult to diagnose by sialography.


Computed tomography in the staging of testicular neoplasms.

Twenty-six patients with primary testicular tumor were evaluated by computed tomography. It was highly accurate in differentiating lymph node metastases from testicular tumors. CT scanning may reveal tumor in lymph nodes not normally opacified during bipedal lymphangiography. It can also be used in treatment planning, follow-up, and in localizing sites of recurrence when serum tumor markers become positive. Some pitfalls of CT are also discussed.


A simple model for anatomic bone scanning studies.

A simple anatomic model for studying the scintigraphic appearance of various skeletal structures is described. The technique makes use of the fact that technitium pyrophosphate uptake in bone occurs by chemisorption to the surface of crystals in the bone matrix. By soaking clean bones in solutions of technetium pyrophosphate they can be rendered radioactive and subsequently studied by various imaging techniques.


Regulation of beta-adrenergic response in human lymphocytes: agonist induced subsensitivity.

The concentration of intracellular cAMP in lymphocytes is regulated by isoproterenol and PGE1. Preincubation of lymphocytes with isoproterenol leads to a loss of the response to beta-adrenergic agents but not to PGE1. Preincubation of lymphocytes with PGE1, however, affects the sensitivities both to isoproterenol and PGE1. A decrease of beta-adrenergic receptors was found in cells preincubated with isoproterenol but not with PGE1. Part of the abnormalities associated with PGE1-preincubated cells can be restored by treating the cells with theophylline.


Influence of inhibition of angiotensin I converting enzyme with SQ-14225 on the arterial blood pressure of mongrel dogs.

Effects of SQ-14225 (0.1, 0.3, and 3.0 mg/kg, i.v.) on the pressor responses to angiotensin I (A-I) and on the arterial blood pressure were investigated in anesthetized mongrel dogs. All the three doses significantly inhibited A-I induced pressor response (70-80%), however reduction in the blood pressure was noted only with the highest dose used. Neither bilateral nephrectomy, autonomic ganglionic blockade nor pretreatment with saralasin, an angiotensin II antagonist, altered the hypotensive activity of SQ-14225 (3 mg/kg, i.v.). The results of this study indicate that significant inhibition of angiotensin converting enzyme does not result in a decrease in the blood pressure in dogs, and that the hypotension produced by SQ-14225 may involve a mechanism yet to be identified.


Reduction of methylmercury concentration in neonatal rat brains after administration of dimercaptosuccinic acid to dams while pregnant.

Sprague-Dawley rats were gavaged on day 7 of gestation with 1.62, 3.23 or 10 mg methylmercury/kg. Beginning one day later, the dams were administered 0, 20 or 40 mg 2,3-dimercaptosuccinic acid/kg/day until they delivered their pups. Concentrations of methylmercury in the brains of pups whose dams were treated with 20 mg DMSA/kg/day were reduced 50% compared with control pups. 40 mg DMSA/kg/day decreased brain concentrations 70% compared to non-chelated controls. The data indicate that DMSA might be effective in protecting the developing organism against morphological and/or behavioral teratological consequences of methylmercury poisoning in utero.


The relative effectiveness of some chelating agents as antidotes in acute cadmium poisoning.

An examination has been made of the relative effectiveness of three chelating agents in reducing lethality in acute cadmium poisoning. The chelating agents used were sodium 2,3 dimercaptosulfonate (DMPS), N-Acetyl d,1 penicillamine (NAPA), and 2,3 dimercaptosuccinic acid (DMSA). For cadmium acetate administered ip at a level of 16.9 mg/kg, the oral administration of the chelating agents at a 20:1 mole ratio in three doses subsequent to the cadmium acetate at 20 minutes, 90 minutes, and 210 minutes resulted in a significant enhancement of the survival rate for all three compounds. At this level none of the control animals survived beyond 2 days. On the basis of the experiments carried out here the survival rates decreased in the order sodium 2,3 dimercaptopropane-sulfonate greater than 2,3 dimercaptosuccinic acid greater than N-Acetyl d,l penicillamine. In a study of the effect of the mole ratio of the chelating agent sodium 2,3 dimercaptopropanesulfonate to cadmium acetate on the survival rate, it was found that the survival rate attained a maximum for values between 20 and 60 and dropped off at both higher and lower values. It was also found that for at least one set of conditions, younger animals were better able to survive the administration of cadmium acetate and the antidote than older animals.


Selective action of hypoxia on rat lung cyclic AMP.

The effect of three different levels of 24-h hypobaric hypoxia (630 mm Hg, 520 mm Hg, and 340 mm Hg) on rat lung cAMP and cGMP was studied. Liver was also examined to evaluate comparatively with lung. Lung cAMP concentration averaged 33.6 +/- 2.2 (SE) pmol/mg protein, and cGMP averaged 2.4 +/- 0.21 (SE) pmol/mg protein. Twenty-four-hour hypoxia resulted in a significant 40% decrease in lung cAMP at 520 and 340 mm Hg. The magnitude of change was the same for both hypoxic levels suggesting threshold dependency. In contrast, liver cAMP was not affected by the hypoxic exposure. Lung and liver cGMP were also relatively refractory to hypoxia. The decreased cAMP concentration seen in the hypoxic lung returned to normal level within 24 hours. These data show that acute hypoxia has a selective action on lung cAMP.


A crucial factor in community program success: the extended psychosocial kinship system.

A crucial factor in community program success is the program's capacity to foster and strengthen an extended psychosocial network of neighbors, friends, and associates at work or school, as well as the extended kinship system. The chronically hospitalized patient and the young, isolated, acutely psychotic adult are both in need of an enhanced psychosocial system when entering a community program. The experience of Berkeley House, a psychiatric halfway house, is related as an example of a program that has achieved successful community tenure for its patients through the creation of an extended psychosocial kinship system. Four principal ways in which the system was sustained through the Berkeley House program are described: (1) through the ex-resident program; (2) through housing arrangements; (3) through work; and (4) through a variety of avocational and social groupings. The extended psychosocial matrix formed by overlapping groups is illustrated.


Psychiatric rehabilitation and long-term rehospitalization rates: the findings of two research studies.

Two controlled studies at Fountain House examined the influence of psychiatric rehabilitation services on rehospitalization. Study I, initiated in 1959, followed 252 experimental and 81 control subjects for 9 years. Study II, initiated in 1964, followed 40 experimental and 34 control subjects for 5 years. Experimental subjects had Fountain House services available, while controls did not. Additionally, experimental subgroups received systematic reaching-out services: home visits, telephone or letter contact. Study II findings essentially replicated study I. Followup was 96--97 percent complete. Three quarters of controls were rehospitalized within 5 years. Experimental subjects receiving reaching-out services for 2 years had significantly lower rehospitalization rates for the first 5 years in study I and the first 2 years in study II. Rehospitalizations were delayed, not prevented. Study I experimentals receiving 2 years of reaching-out services spent twice as long in the community before rehospitalization and 40 percent fewer days in the hospital than controls. Study II experimental subjects were in the community almost three times longer than controls before rehospitalization. Half of study I experimental subjects attended less than 10 times. Experimental subjects receiving reaching-out services attended twice as often as those not receiving reaching-out services. Low or nonattending experimentals had almost identical relapse rates (77 percent) as controls (74 percent), while, of experimentals having 100 or more visits, 37 percent were rehospitalized.


Intracerebral adrenocorticotropic hormone mediates novelty-induced grooming in the rat.

Intact male rats exhibited more grooming in unfamiliar testing chambers than in their home cages. Hypophysectomized rats showed a much reduced increase in grooming in these testing chambers. Intraventricular injections of antiserum to adrenocorticotropic hormone to intact rats decreased the grooming usually observed in the novel situation, whereas a similar injection of control serum did not produce this effect. Peripheral injections of the antiserum did not affect grooming. Since intraventricularly injected adrenocorticotropic hormone induces excessive grooming, these results suggest that the increased grooming observed in the novel environment may be at least partly due to the release of this hormone directly into the cerebral ventricular system.


Hepatocellular carcinoma (an approach to the study of risk factors in human cancer).

Risk factors can be used to formulate hypotheses on the aetiology and pathogenesis of site specific cancers. Persistent infection with hepatitis B virus (HBV), chronic liver disease, and maleness are associated with a greatly increased risk of developing primary hepatocellular carcinoma (PHC). A model for the pathogenesis of this tumour is proposed that does not involve integration of the HBV genome into the tumour cell. If chronic infection with HBV is necessary for the development of chronic liver disease and PHC, prevention of PHC could be accomplished by prevention of infection with HBV. A vaccine against HBV could be accomplished by prevention of infection with HBV. A vaccine against HBV has been developed; if it is effective, we can predict that its use in endemic areas will be accompanied by an eventual fall in the incidence of PHC.


Lithium: a modulator of cyclic AMP-dependent events in lymphocytes?

Theophylline, salbutamol, isoproterenol, and dibutyryl cyclic AMP inhibited E-rosette formation by human T lymphocytes and immunoglobulin M secretion from human plaque-forming B cells and augmented T-suppressor cell activity in three patients with agammaglobulinemia. Lithium chloride increased mitogen-induced lymphocyte proliferation and inhibited suppressor cell activity. In the presence of lithium, the effects of all the drugs except dibutyryl cyclic AMP could be prevented. The data suggest a role for lithium in the modulation of cyclic AMP-dependent events in lymphocytes. Its potential role as an inhibitor of suppressor cell activity warrants further attention.


Cloning of herpes simplex type 1 DNA fragments in a bacteriophage lambda vector.

DNA isolated from defective and nondefective virions of herpes simplex type 1 (HSV-1) (strain Patton) was digested with restriction endonucleases, and the resulting DNA fragments were inserted in the EK2 coliphage vector lambdagtWES . lambdaB. The recombinant DNA was encapsidated in vitro under P4 maximum containment conditions. These lambda-HSV1 hybrids were purified and amplified, and the DNA was isolated in the P4 facility. DNA, free of viable phage and bacteria, was removed from P4 conditions and analyzed. Represented among the hybrids studied to date are DNA fragments from about 50 percent of the normal HSV-1 genome. The hybrids derived from defective HSV-1 DNA fragments demonstrate the existence of many similar but not identical classes of defective genomes.


Rotaviral immunity in gnotobiotic calves: heterologous resistance to human virus induced by bovine virus.

The possibility of immunizing human infants against rotaviruses, which cause severe dehydrating diarrheal disease, may depend on the use of a related rotavirus, derived from another animal species, as a source of antigen. To test the feasibility of this approach, calves were infected in utero with a bovine rotavirus and challenged with bovine or human type 2 rotavirus shortly after birth. Infection in utero with bovine rotavirus induced resistance to diarrheal disease caused by the human virus as well as the homologous bovine virus. These data suggest that the bovine virus is sufficiently related antigenically to the human type 2 virus to warrant further evaluation of the former as a source of vaccine.


[Importance of endoscopy with biopsy in gastroduodenal amyloidosis. Apropos of 5 cases].

The authors report five cases of gastric amyloidosis in addition of the fourty three published cases. These cases was polyvisceral forms, 4 times primitive and 1 time secondary to a psoriasic rheumatism. Three times only the patients had complaints of digestive tract. Four times non specific radiologic and endoscopic signs lead to a biopsy which permits diagnosis. The biopsy of gastric mucosa must take place beside the rectal biopsy; more difficult to do, it might be more successfull because the stomach is more often infiltrated by amyloidosis than the colon.


[Intravenous nitroglycerin as vasodilator therapy in acute myocardial infarction (author's transl)].

Thirteen patients with left ventricular failure complicating acute myocardial infarction were treated with intravenous nitroglycerin. The hemodynamic criterium for admission to this study was a pulmonary capillary wedge pressure greater than 15 mm Hg. All patients received intravenous nitroglycerin at infusion rates sufficient to lower pulmonary capillary wedge pressure by an average of 15 mm Hg, corresponding to the optimal left ventricular filling pressure in acute myocardial infarction. During this study, heart rate did not vary significantly; pulmonary capillary wedge pressure decreased from 24 +/- 0,7 to 15 +/- 0,8 mm Hg (p less than 0,001), mean arterial pressure from 95 +/- 5 to 80 +/- 4 mm Hg (p less than 0,005), mean right atrium pressure from 8,7 +/- 1 to 4,6 +/- 0,8 mm Hg (p less than 0,001), systemic vascular resistance index from 36,4 +/- 2 to 29,6 +/- 2 mm Hg/mm-1/l/m2 (p less than 0,005). Cardiac index increased from 2,5 +/- 0,2 to 2,7 +/- 0,1 l/mn/m2 (p less than 0,025) and stroke work index did not vary significantly. These data indicate that nitroglycerin provides a significant improvement of cardiac performance, more through reduction of preload than through reduction of afterload, the later being however significant. This study points out that intravenous nitroglycerin is a most efficient drug in patients with left ventricular failure complicating acute myocardial infarction.


[Calcitonin and hypercalcaemia (author's transl)].

We have discussed in an earlier paper the value of estimating the circulating levels of biologically active parathyroid hormone. We consider here the importance of an evaluation of circulating calcitonin by showing the frequency of raised calcitonin secretion in hypercalcaemia of different origins. These results lead one to attribute to calcitonin a role which goes beyond the regulation of phospho-calcium metabolism and which in fact is that of a particularly sensitive indicator of tumours.


[Hypotensive effects of timolol in 86 patients (author's transl)].

Antihypertensive action of timolol (MK 950) was studied in 86 outpatients with essential, uncomplicated hypertension. Timolol is an effective hypotensive drug with significant lowering pressor effect. Timolol was given alone in 53 cases and in association with other hypotensive drugs in 33 cases: the mean dose was 20 mg daily for 8 months. At the end of treatment the mean diastolic pressure recumbert, standing, and after exercise had decreased by 10.2, 9.2 and 11 mmHg. Cardiac frequency had decreased by 13, 24 and 29 p. min lying, standing and after exercise. Side effects were rare, with cessation of treatment only in 4 cases.


[Study of rapidity of hypotensive effects of acebutolol on non hospitalized patients (author's transl)].

Acebutolol whose hypotensive properties are well established, appears as a most interesting beta-adrenergic blocking agent for simplification of treatment of moderate hypertension in man. Hypertensive patients likely to benefit from treatment with acebutolol can be identified within 5 days after administration of a single initial dose of the product. Long-term treatment with acebutolol can be considered in those patients identified as receptive. In non-responders, acebutolol can be used in combination with a diuretic agent. Such simplification of the therapeutic schedule in hypertension will certainly be helpfull both to the physician and his patient.


[Comparative study of antiarrhythmic properties of quinicine versus quinidine (author's transl)].

Quinicine, an isomer of quinidine is used for its cerebral vasodilating activity. This study was performed in order to find out if quinicine also behaves like an antiarrhythmic agent in animals. The preventive and curative actions of quinicine on the experimental ouabain induced arrhythmia have been demonstrated. The mechanism of action of this drug seems to be the same as quinidine, i.e. prolongation of refractory period, diminution of atrial and atrioventricular conduction velocities, anticholinergic and local anaesthesic properties. The quinuclidic ring is therefore not a major factor to assure the antiarrhythmic activity of quinquina alkaloids.


[Acute gastric and duodenal distress lesions. Circumstances of appearance, endoscopic detection. Treatment].

Upper digestive hemorrhages in patients in a state of distress have been known for some time whether the stress if of surgical of medical origin. Emergency gastroscopy is of great interest in the field of diagnosis and operative indications. As regards treatment one should emphasise the interest of prevention. As for the treatment of hemorrhage, it should first be medical and cimetidine gives at present the best results. Surgical treatment remains however indicated in a certain number of cases. The choice of operation is still debatable.


[Dysglobulinemic neuropathy. Apropos of IgD myeloma manifested by mononeuritis].

The authors report a case of IgD myeloma of which the initial symptom was a mononeuritis and the biological, immunological and ultrastructural study performed about this case. Then are reviewed the mechanisms, proved or hypothetical, by which are actually explained the event of neuropathies within lympho-plasmocytic disorders.


[Very severe haemorrhages of the lower digestive tract. The value of emergency arteriography (author's transl)].

The authors report six cases of massive lower gastro-intestinal tract haemorrhage, diagnosed by angiography. They emphasize the value of angiography performed on an emergency basis. It is the most reliable diagnostic modality to know before surgery the precise localization of the bleeding point and sometimes its aetiology. The interest and the problems of therapeutic angiography are discussed.


[Selective IgA deficiency, DPH-treated epilepsy and polyarthritis (author's transl)].

A selected IgA deficiency was found in a 66 years old, DPH-treated epileptic female, suffering from polyarthritis. Familial survey brings information for genetic transmission of IgA decreased concentrations in her offspring, unrelated with HLA A, B, C system.


[Is rheumatoid arthritis connected with a digestive tract parasitosis? (author's transl)].

The comparison of blood eosinophil counts and stool parasites in two groups of patients--twenty one suffering from rheumatoid arthritis and twenty one from other various diseases--did not show any significant difference in favour of a parasitological etiology in rheumatoid arthritis, an hypothesis which had to be considered because of the efficacy of levamisole in the treatment of this disease.


[Report of a case of Gaucher's disease in adult].

The authors report a case of Gaucher's disease in an adult. This is a rare disease due to the accumulation of a glucoceramide in the reticulo-endothelial cells and may remain for long clinically symptomless, as in this case. The diagnosis suggested by the biological disturbance, viz. moderate thrombopenia, hypergammaglobulinemia, increase in SGPT, was conformed by the presence of Gaucher's cells in the liver and in the bone marrow, and by the existence of an intraleukocytic glucosidase deficiency. The authors recall the clinical forms of this disease, and recent clinical trials.