Technique for accurate localization with the CT scanner. A method for accurate localization of intracranial lesions on CT scans is described, using a marker wire and a radiograph exposed by the CT scanner.


A brief trial of phenytoin therapy for thalamic pain. Phenytoin was given in full dosage to eight patients with thalamic pain and two others with intractable pain resistant to other forms of treatment. Serum levels were monitored and correlated with dosage levels. Three patients improved markedly, two improved only minimally, two were unchanged, and three were worse. Those patients who had improved noted return of original pain on stopping phenytoin. The results indicate the need for a further study of the drug in thalamic and other chronic pain states.


Respiratory function of infants in relation to subsequent respiratory disease: an epidemiological study. Crying ventilatory function was measured in 487 infants shortly after birth. Over the following five years 129 infants suffered attacks of pneumonia or bronchitis. Their initial crying ventilatory function was compared with that of the 358 infants who escaped these illnesses. No statistically significant differences were found in crying ventilatory function between these two groups of infants. This has been interpreted as indicating that newborn infants who subsequently suffer attacks of pneumonia or bronchitis do not start life with deficits in their ventilatory function. In the same study crying ventilatory function was measured in 550 infants at their first birthday; 70 had suffered attacks of pneumonia or bronchitis by that age and made a clinical recovery. Their crying ventilatory function showed no consistent difference from the 480 infants who escaped their illnesses. The reasons for the lack of a difference in crying ventilatory function is discussed.


Diurnal variations and reproducibility of the N2 closing volume test in healthy subjects. To assess the diurnal variation of closing volume measurements, 11 non-smokers and 10 somkers, all healthy, were tested with the single-breath nitrogen test. In each subject, 3 satisfactory tracings were recorded at 9:a.m., 11:a.m., 1:p.m., 3:p.m. and 5:p.m. on each of two consecutive days. Duplicate copies of the tracings were read in radom order by two independent observers. The "best+ and the mean values of closing volume to vital capacity ratio (CV/VC or phase 4/VC) and of the slppe of phase 3 were calculated. The study shows that: (1) the time of the day may be a source of variation of the closing volume measurements. Meals and cigarette smoke did not appear to be responsible for this diurnal variation, (2) values obtained with the "best" tracing method can, at least in some readers, give systematic differences with the mean of several traces, (3) individual variations in CV/VC and in the slope of phase 3 are the highest with the "best" trace analysis, and (4) the vlaues obtained by two independent readers may significantly differ. The differences observed between hours, although significant, were nevertheless small in magnitude and did not explain most of the variation of the measurements. Variations in trace aspect were small in some subjects. The reproducibility of the test was remarkable in them, at least when the junction of phase 4 with phase 3 was well defined. In other subjects, the coefficient of variation was high mainly because of varying curve shape and/or poorly defined departure of phase 4. This explains for a great part the intra-and interreader variations observed in this study.


Ventilatory impairment and hypoxemia in chronic non-specific lung disease. The relation between arterial oxygen tension at rest (Pao2) and ventilatory performance (VC and FEV1.0) was studied (198 determinations) in a group of 156 patients (11 females) aged 31 to 76 (mean 52.1) years, with chronic non-specific lung disease (asthmatics non included). The average results were 72.7 mmHg for Pao2, 2.87 1 for VC, 1.32 1 for FEV1.0 and 44.9 % for the FEV1.0/VC ratio. Ninety per cent of the patients had ventilatory impairment (FEV1.0 less than 81 % predicted) and 2/3 had hypoxemia (Pao2 less than 75 mmHg). The Pao2 - spirometric variables linear correlation coefficients were of medium value (0.35 to 0.51), but highly significant due to the large number of observations. The correlation was high in patients with severe ventilatory defect (FEV1.0 less than 40% pred.), weak in those with moderate (FEV1.0 41-60 % pred.) and absent in those with minor or absent ventilatory impairment. In respect to the clinical type of obstructive disease, Pao2 and FEV1.0 showed a high correlation (r=0.69) in "bronchitics", a looser one (r=0.45) in "intermediate" patients, and no correlation for "emphysema" patients. The regression equation relating Pao2 and FEV1.0 (Pao2=64.4 + 5.9 X litres) had too high a standard error of estimate (20 % of the mean) to be of practical value.


The management of the patient with calcium stones. Results of investigation of 800 patients with renal calculi are presented. The high incidence of medullary sponge kidneys (tubular ectasia) in patients of either sex is stressed as is the low incidence of idiopathic hypercalciuria in the female. Hydrochlorothiazide has been found to be highly effective in preventing recurrence of calcium stones in our personal experience with over 300 patients who have been treated for as long as 14 years with this agent. The efficacy and mode of action of other measures advocated for stone prevention is reviewed.


Primary hyperparathyroidism---a review of cases in the Sheffield area. 73 patients with primary hyperparathyroidism are reviewed. The elevated serum calcium was the main diagnostic index but estimation of the parathyroid hormone was useful confirmatory evidence when raised. A normal level does not exclude the diagnosis being found in 32% of patients. Intravenous methylene blue was a useful adjunct to surgery. 95% of the patients had relief of their hypercalcaemia after a single operation. 78% of patients had stones and there was a marked reduction in further stone formation after surgery.


Size of renal calculi, recurrence rate and follow-up. Stones smaller than 5 mm in diameter seldom need any operation other than the use of the stone-basket. Stones larger than 10 mm in diameter usually need an operation, are more often accompanied by infection, and have a higher recurrence rate. The size of the stone is unrelated to the level of urinary calcium or to body surface area. In planning the follow-up of patients with calculi the size of the first stone is a useful guide.


Recurrence of infected calculi following postoperative renal irrigation with stone solvent. Renacidin has been shown to dissolve small fragments of infected renal calculi in vitro. 34 patients with infected calculi have undergone pyelolithotomy and postoperative renal irrigation with Renacidin. 30 patients were women and Proteus was the commonest infecting organism. Renal irrigation appears to be safe if closely monitored and covered by antibiotic therapy. 24.4% of calculi had recurred at a mean follow-up of 42 months. The rate of recurrence or unilateral calculi was much less than that of bilateral calculi (15% vs. 40%). Persistent postoperative urinary tract infections later led to recurrent stone formation.


Reflux induced pelvi-ureteric obstruction. The phenomenon of pelvi-ureteric obstruction which is induced by vesico-ureteric reflux is well documented but ill understood. The radiographic findings can be impressive to an extent that obstruction is probably often over-diagnosed. Before considering a pyeloplasty it is essential to confirm the true obstructive nature of the problem. Where the urogram is not suggestive of an obstruction a re-implantation of the ureter will usually stop the gross pelvic dilatation. It is suggested that the obstruction is at least partially an active process.


Rebreathing and single breath pulmonary CO diffusing capacity in man at rest and exercise studied by C18O isotope. The pulmonary diffusing capacity for carbon monoxide, Dco, was estimated in normal subjects, using both a single breath technique (DcoSB) and a rebreathing technique (DcoRB). In order to measure CO by mass spectrometry, the stable isotope C(18)O was used. In three normal subjects Dco was measured at different lung volumes at rest, and at different levels of bicycle exercise. DcoRB was found on the average 30% higher than DcoSB when compared at the same mean lung volume, and both increased slightly during exercise. The advantages and drawbacks of the rebreathing method are critically discussed.


Occupational bladder tumour cases identified during ten years' interviewing of patients. All patients attending the Royal Marsden Hospital with urothelial tumours have their occupational histories taken. About 10% of histories suggest a possibility of past exposure to urinary carcinogens, and on examination 4% indicate definite exposures justifying claims for Prescribed Industrial Disease benefit.


Inverted papilloma of the lower urinary tract. A study of 35 cases of inverted papilloma of urothelium confirms that it is a distinctive entity and typically benign. These lesions occur mainly in males, may be multiple, and are sometimes situated elsewhere than in or near the trigone, which is their characteristic site. Their precise histogenesis remains uncertain. It must be stressed that not all transitional cell tumours of inverted pattern are of this type; some will have the appearance of and behave as malignant tumours. The same diagnostic criteria of malignancy established for the more common exophytic papillary neoplasms must be applied also to the inverted papillary tumours herein described.


Radiotherapy in the treatment of recurrent bladder cancer. A retrospective review of 1,518 cases of transitional cell carcinoma treated by supervoltage irradiation is presented. The majority of patients had recurrent disease after previous treatment. An appreciable salvage rate has been achieved. A "high risk" group for distant metastases has been identified (T3) and the suggestion is made that adjunctive therapy be employed to deal with occult metastases. The place of preoperative irradiation in Stage T2 tumours has been referred to. It is recognised that this is an ageing population. Many die not of their cancer but from other causes. It is difficult to compare these results with others published because of problems in selection and differences in staging the tumours.


The value of lymphography in the management of bladder cancer. 228 bilateral pedal lymphograms in patients with bladder cancer have been correlated with the features of the primary bladder tumour and patient survival. In 70 cases, radiographic findings were correlated with operative node histology. The results show that it is not possible to predict accurately which cases have lymphatic spread without this investigation. Positive lymphograms were found in 91 cases, and were associated with a very poor prognosis. Only 6% of patients with unilaterally involved iliac nodes survived 5 years, and all patients with bilateral iliac or para-aortic disease died within 3 years. Histological correlation was found in 90% of cases, and the results indicate that this investigation slightly underestimates the incidence and extent of microscopic lymphatic metastases. It is concluded that this investigation is essential in planning the treatment of infiltrating bladder tumours.


Hyperthermia in the treatment of bladder tumours. High temperature bladder irrigation was employed in 4 men as an alternative to cystectomy because of their age and frailty. Hyperthermic irrigation of the bladder from 63 degree C for 70 minutes to 82 degree C for 25 minutes caused partial, but not total, necrosis of the bladder. Transitional cell carcinoma appears to be resistant in vivo, in some cases, to heating at temperatures that destroy adjacent normal structures. Hyperthermic irrigation of the bladder at these high temperatures may be hazardous. In view of these findings we cannot recommend high temperature bladder irrigation as an alternative to cystectomy even in poor risk patients.


Treatment of advanced bladder cancer with adriamycin and 5-fluorouracil. The cytotoxic drug combination of adriamycin and 5-fluorouracil has resulted in a 35% objective response in 20 patients with advanced bladder cancer. This has been achieved with minimal toxicity and on an out-patient basis. If the survival rate of patients with invasive bladder cancer is to be improved it seems likely that some form of systemic treatment will need to be added to the local measures currently in use. Further studies of different chemotherapeutic agents should help to define an effective and safe form of adjunvant therapy.


The endemic bladder stones of Indonesia---epidemiology and clinical features. Bladder stone is a relatively common disease of childhood in West Sumatra with an incidence of 8.3/100,000 population per year. We have studied 87 cases with a peak age of onset of 2-4 years and a male/female ratio of 12:1. The majority of these are from poor families with a diet low in protein and phosphate. Diarrhoea is common. The composition of the stones is primarily ammonium acid urate. Patients with sterile urine have shown significantly higher levels of urinary ammonia than controls, and only approximately 50% of patients' urine were infected. This is consistent with excretion of a high acid load, due both to an acidogenic rice diet and diarrhoea, combined with a low level of phosphate. This condition was once endemic in Europe but is now confined to a belt of countries from the Balkans through Asia.


Distension therapy for the unstable bladder: later results including an assessment of repeat distensions. 51 patients with urgency and urge incontinence of urine and enuresis have been treated by prolonged bladder distension. At recent follow-up, 16 patients were symptom free, 25 substantially improved and 10 symptomatically unchanged, at a mean of 13 months after distension. 13 patients whose symptoms relapsed after a previous distension or who failed to obtain a satisfactory improvement have had a further distension for a more prolonged period. The early results in this group are not as good as for patients having first distensions, although 2 patients have become symptom free, and 6 have shown a substantial symptomatic improvement.


Clinical and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vitro and in vivo. Experiments on muscle strips have shown that prostaglandin is naturally produced by the detrusor, and acts to increase the tone and spontaneous activity. An intimate relation between acetylcholine and prostaglandin has been demonstrated. Therapeutic application of prostaglandins has been successful in the treatment of chronic retention in women.


Anti-reflux surgery in the congenital neuropathic bladder. 42 refluxing ureters were re-implanted into the bladder in 28 children with neuropathy. In each case other measures directed at enhancing bladder emptying were employed. Reflux was cured in 36 of 38 ureters investigated after operation. The incidence of contralateral reflux following unilateral re-implantation was 50%. 1 of 12 undilated units showed late post-operative deterioration. 22 of 28 initially hydroureteronephrotic units either improved or stabilised  at a satisfactory level. In 6 children urinary diversion was subsequently performed because of persistent reflux (2 cases), postoperative deterioration (1 case) or failure of severely dilated upper tracts to improve (3 cases). Since reflux from a high pressure bladder can rapidly cause severe renal damage, cystography is indicated when there is clinical or pyelographic suspicion of its existence. Operative cure is needed when reflux is of major degree or if, when of lesser severity, it does not stop spontaneously following improved bladder emptying resulting from therapeutic lessening of the urethral resistance.


The assessment of sphincteric activity in patients following trans-sphincteric urethral reconstruction. 12 patients who had previously undergone trans-sphincteric urethral reconstruction were studied with regard to their sphincter mechanisms. The method of study was by urethral pressure profile and urethral voluntary sphincteric pressure increment. This study showed that patients may undergo trans-sphincteric urethral reconstruction with preservation of normal profiles and voluntary pressure increases indicating preservation of the "external" sphincter mechanism.


An assessment of surgical treatment of vesical outlet obstruction in spinal cord injury: a review of 471 cases. An assessment of 139 cases of outlet obstruction following spinal cord injury, in a consecutive series of 471 patients, is presented. The figures in relation to the level and extent of the spinal lesion and the type of operation (transurethral resection and external sphincterotomy), are reviewed. The incidence of repeat operation is recorded and assessed. It is concluded that transurethral resection and external sphincterotomy, either alone or combined, will relieve outlet obstruction in most cases of neuropathic bladder following spinal cord injury.


A simple artificial implantable sphincter. A device is presented for the cure of urinary incontinence in males. 16 cases have been operated on, 10 have been cured, 1 improved and 5 failed. Most of the failures were due to sepsis. Despite this small number of cases the results are extremely encouraging. The device, because of its simplicity, both in construction and ease of insertion, is considered worthy of extensive trials.


Excretion urography in the investigation of prostatism. The excretion urogram and urodynamic studies of 201 patients presenting with prostatism were reviewed. The urographic features of trabeculation and diverticula were found to be associated with bladder instability as shown on inflow cystometry but not to be associated with outflow obstruction as shown by the pressure-flow analysis of micturition. The bladder shadow on the preliminary film and the bladder size on the post-evacuation film were associated with the measured residual urine and with outflow obstruction. The basal prostatic filling defect was also associated with outflow obstruction.


Urethroplasty in context.

Urethroplasty in context.


Lymphography and pelvic lymphadenectomy in carcinoma of the prostate. 20 of 45 new patients with prostatic carcinoma have undergone lymphography and lymphadenectomy to determine the N-category. The overall accuracy of lymphography was 75%. Lymphadenectomy was a safe procedure with minimal morbidity. Although it would be premature to recommend its universal adoption in the management of this disease, its further application and study seems desirable. Full TNM classification has proved to be of considerable value in the management of these patients. This study confirms that 50% of T3 MO tumours are free of lymph node metastases.


Hypospadias--problems of postoperative fistulae formation and a modified 2-stage procedure to reduce these. A retrospective review of hypospadias repair reveals a high incidence of postoperative fistula nad stenosis. Further studies using Silicone casts have revealed a potential cause for the occurrence of these complications. The close co-operation between urologists and plastic surgeons has resulted in a grea er awareness of the surgical problems and the development of a simplified 2-stage technique which it is hoped will reduce these.


Plasma gonadotrophic hormones, testicular biopsy and seminal analysis in the men of infertile marriages. The first step in the investigation of infertile men is to obtain 2 seminal analyses 3 days after the previous ejaculation. Clinical assessment of testicular size is an unreliable means of assessing spermatogenesis and is best done by performing bilateral testicular biopsies. Azoospermic men with grossly elevated FSH levels should be advised to consider AID or adoption. Those with normal or mildly elevated FSH levels should undergo testicular exploration in an attempt to correct an obstructive lesion. Azoospermic men with subnormal FSH levels may have an isolated hormone defect which will respond to treatment with Pergonal. Different treatment programmes for oligozoospermic men depending on the results of the FSH and LH assays may lead to a more rational approach to therapy. Infertility associated with varicocele may possibly be associated with a local disturbance of "inhibin" and FSH concentrations. Testicular size, levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in plasma, and testicular biopsy were determined in 261 men of infertile marriages and the results were clinically interpreted. Analysis of the  findings in azoospermic and oligospermic men and men with varicocele led to the following conclusions: 1) assessment of testicular size is not a reliable indicator of spermatogenic function;  2) azoospermic men with markedly elevated FSH levels should be advised to consider artificial insemination donors or adoption, while those with normal or slightly elevated FSH levels should undergo testicular exploration to correct what may  be an obstructive testicular lesion;  3) Pergonal is of therapeutic value in azoospermic patients with subnormal FSH levels who may have an isolated hormone defect;  4) different treatment programs based on the results of LH and FSH assays of oligozoospermic are recommended;  and 5) men with varicocele may possibly have a local disturbance of ''inhibin'' and FSH concentrations.


The development of the isthmo-optic nucleus. The nucleus of origin of centrifugal fibers to the retina (the so-called isthmo-optic nucleus - ION) has been used as a model for the study of the major features of neural development, from the period of cell proliferation until after the formation of its afferent and efferent connections. 3H-thymidine autoradiography has established that in the chick cells of the ION are generated (i.e., become post-mitotic) between the middle of the 5th and the end of the 7th days of incubation. The first-formed cells are found in the ventrolateral part of the nucleus, while those that are generated at successively later stages come to occupy progressively more medial and dorsal positions within the nucleus. The anlage of the ION can be identified on the 8th day of incubation, and by the 11th day, when it is numerically complete, it occupies a prominent position in the caudo-dorsal part of the midbrain tegmentum at the level of the IVth nerve nucleus. At this stage the nucleus contains about 22,000 neurons, and shows no signs of cytoarchitectonic differentiation. Between the 13th and 17th days of incubation, about 60% of the neurons in the nucleus degenerate; as a result of this degeneration, the arrival of afferent fibers, and the growth of the cells' processes, the nucleus comes to have its characteristic adult form of a complex, folded, bilaminar sheet, in which each part of the retina is precisely represented. Experiments based on the retrograde transport of horseradish peroxidase (HRP) from the eye indicate that the first centrifugal fibers, in the isthmo-optic tract (IOT), reach the retina on the 10 day of incubation, and by the 12th day all but about 5% of the neurons in the ION can be retrogradely labeled in this way...


Brain circuits for consciousness.

Brain circuits for consciousness. The question is explored of the location of consciousness in the human brain. The author's own studies of defects of consciousness as the result of the splitting of the corpus callosum are described and disorders of consciousness associated with damage to other specific areas of the brain, are reviewed. A circuit spanning the brain is described which stretches from the parietal lobe at one side to the parietal lobe at the other and includes the splenium of the corpus callosum. The medial banks of the hemispheres, the callosal as well as the cingulate areas, are also thought to be involved.


Telencephalon of the lizard Gekko gecko (Linnaeus): some connections of the cortex and dorsal ventricular ridge. Interhemispheric connections of the telencephalon in the lizard, Gekko, were studied with anterograde degeneration methods following lesions variously placed in the medial, dorsal, and lateral cortices and/or the dorsal ventricular ridge (D.V.R.). After lesions involving dorsal cortex, the medial wall, and the DVR, the majority of degenerated fibers decussate in the hippocampal commissure and terminate in the septum, medial wall, dorsal cortex, and the lateral edge of the DVR contralaterally. Lesions confined to dorsal cortex result in a similar pattern of degeneration, while lesions confined to the lateral wall result in degeneration in the contralateral lateral cortex, DVR and striatum, mainly via the anterior commissure. Some variation has been reported on the pattern of interhemispheric projections among reptiles studied to date; two possible interpretations of the data are that (1) dorsal cortex may be homologous as a field to parts of both neocortex and the hippocampal formation of mammals or (2) only the lateral part of dorsal cortex may be homologous to neocortex.


Behavioral correlates of 'tectal compression' in goldfish. I. Intensity and pattern discrimination. Goldfish were trained to perform visual intensity and pattern discriminations. Three groups of fish had bilateral ablation of the caudal optic tectum, a fourth consisted of unoperated controls and a fifth group consisted of sham-operated controls. The fish were tested after various postoperative intervals ranging from 19 to 147 days. The lesions produced modest deficits in intensity discrimination irrespective of postoperative interval. The fish that began training on the pattern discrimination after 14-18 postoperative days showed no improvement in performance. Fish that began training after 39 postoperative days showed improvements in performance after about 65 postoperative days. The group that began training 158-160 postoperative days showed steady and persistent improvements in discrimination performance. The results suggest that improvements in pattern vision after partial tectal ablation follow the same time course as compression of the retinotectal map after partial ablation of the tectum.


Behavioral correlates of 'tectal compression' in goldfish. II. Visual acuity. Visual acuity was measured in three normal goldfish and two goldfish in which the caudal optic tectum had been ablated bilaterally. Compression of the retinotectal map was assumed to have occurred in the two operated fish, which were tested more than 200 days after surgery. The results indicated that the visual acuity of the normal fish ranged from 0.94 to 0.95 degrees of visual angle. The visual acuity of the fish with presumed compression of their retinotectal maps ranged from 1.91 to 2.07 degrees. The results suggest that compression of the retinotectal map occurs at the expense of the spatial-resolution ability of the visual system.


Human values in medicine.

Human values in medicine.


The bronchi in the fibrotic forms of the extrinsic pulmonary granulomatoses.


Plasma cell sarcoma complicating a case of multiple myeloma.


The mineral dust load of human lungs.

The mineral dust load of human lungs. Studies of the dust content of lungs from non-industrially exposed city dwellers have shown that many people build up during life a total dust load of 2 grammes or more. This dust load may include up to 17 X 10(6) mineral fibres large enough to be visible with the light microscope and 360 X 10(8) fibres visible only by electron-microscopy. All lungs examined contained a small percentage of fibres that appeared structurally similar to chrysotile asbestos. It was found that the total dust content and content of light microscope sized mineral fibres was much lower in a non-industrialised city than in one with a high level of heavy industry, but levels of electron-microscope sized fibres did not differ markedly between the two groups. It would appear that these very small fibres are part of a general mineralogical background rather than resulting from industrial atmospheric pollution. This was further indicated by the fact that many of the dust particles, including large numbers of the fibrous ones proved to be derived from diatom skeletons.


Exo-ploygalacturonate lyase of Fusarium culmorum.


Effect of some lipid compounds on the development of Colorado potato beetle (Leptinotarsa decemlineata Say).


A study on the role of some protein compounds in the development of Colorado potato beetle (Leptinotarsa decemlineata Say).


A new method of intrathoracal biopsy using thoracoscope and tissue adhesive.


Resolution of chloroplast lamellar proteins by sodium tetradecyl sulphate gel electrophoresis.


Different frequencies of point mutations in barley ears after treatment with N-nitroso-N-methylurea.


The structure of the alimentary canal and the dimensions of the mucosa in the smooth newt (Triturus vulgaris L.).


Effect of Trichinella spiralis (Oven, 1835) infection on ultrastructure of epithelium of small intestines in germfree or conventional mice.


Measurements of mineral content and its crystallinity in some selected bones of rats surviving twenty days in conditions of weightlessness.


The effect of insulin or 2-deoxy-D-glucose administration of body temperature during physical exercise in dogs.


Scintillation autoradiography as a quick method for detection of radioactivity in cells and tissues.


New Siphonaptera from the fauna of Bulgaria.


Tabanus castellanus Strobl, 1906 (Diptera, Tabanidae)--a species distinct in the European fauna.


Abundances of Mn, Na, Zn, Co, Ag, U and Ba in males and females of Dioecocestus asper (Mehlis, 1831) (Cestoda: Dioecocestidae).


Effect of methoxychlor on the embryonic development and respiratory metabolism of Fasciola hepatica (Trematoda) and Triaenophorus nodulosus (Cestoda) embryos.


Effects of the insulin-secreting action of lysine on some metabolic parameters of blood and of tissues in subdiabetic rats.


Sarcoid reactions in pulmonary neoplasms.


Isoelectric points and molecular weights of salt-extractable ribosomal proteins. Rat liver ribosomes prepared in low salt buffer contain basic and acidic proteins not found on ribosomes washed in high salt buffer. Proteins extracted from liver ribosomes by 500 mM KCL were characterized by acid urea-polyacrylamide gel electrophoresis, sodium dodecyl sulfate - polyacrylamide gel electrophoresis and gel isoelectric focusing. The salt-solubilized proteins contain 12 polypeptides with a molecular weight over 67000, several polypeptides with molecular weights less than 67 000, and three polypeptides whose molecular weight exceeded 130 000. Ten to 12 of the proteins were basic, and about 24 acidic proteins were partially or wholly extracted from the ribosomes. Four of the acidic proteins have isoelectric points less than 4.5.


Purine catabolism in man: inhibition of 5'-phosphomonesterase activities from placental microsomes. The 5'-phosphomonoesterase activity of 5'-nucleotidase (EC 3.1.3.5) and alkaline phosphatase (EC 3.1.3.5) participates in the catabolism of purine ribonucleotides to uric acid in humans. Initial velocity studies of 5'-nucleotidase suggest a sequential mechanism of interaction between AMP nad MgCl2, with a Km of 14 and 3 muM, respectively. With product inhibition studies the apparent Ki's for adenosine, inosine, cytidine, and inorganic phosphate were 0.4, 3.0, 5.0, and 42 mM, respectively. A large number of nucleoside mono-, di-, and tri-phosphate compounds were inhibitors of the enzyme. Allopurinol ribonucleotide, ADP, or ATP were competitive inhititors when AMP was the substrate, with a Ki slope of 120 muM. The phosphomonoesterase activity of human placental microsomal alkaline phosphatase had a pH optimum of 10.0 and had only 18% of maximum activity at pH 7.4. Substrates and inhibitors included almost any phosphorylated compound. The Km for AMP was 0.4 mM and the apparent Ki for Pi was 0.6 mM. Activity was increased only 19% by 5 mM MgCl2. These observations suggest that 5'-nucleotidase and alkaline phosphatase may be inhibited by ATP and Pi, respectively, under normal intracellular conditions, and that AMP may be preferentially hydrolyzed by 5'-nucleotidase.


Converging evidence for automatic perceptual processing in visual search.


Preparation of active run-off 80S ribosomes and their subunits from mouse liver. A method is described for the preparation of active "run-off" 80S ribosomes and 40S and 60S subunits of mouse liver. A polysome preparation was incubated at 37 degrees C for 10 min under the condition for protein synthesis (4 mM Mg2+, 100 mM KCL). Puromycin (10 mM)and 2 M KCL were added to a final concentration of 0.1 mM and 500 mM, respectively, and the reaction mixture was further incubated at 37 degrees C for 10 min. This latter treatment destabilized small polysomes and "stuck" 80S particles, which were remaining after the first incubation, leading to complete release of 40S and 60S particles. Thus, the present method minimized variations in yield of subunits due to polysome preparations and preincubation conditions. The subunits were separated by sucrose density-gradient centrifugation or recovered by precipitation following reassociation into 80S particles (run-off 80S). The reformation of 80S particles from the subunits occurred spontaneously at 5 mM Mg2+ and 100mM KCL. The isolated 40S and 60S subunits, separately, showed low phenylalanine-incorporating activity in the presence of poly(U), but when recombined, polymerized up to 10 phenylalanine residues per couple.


The Western psychiatrist and his non-western clientele. Transcultural experiences of relevance to psychotherapy with Canadian Indian patients.


Supernatural influence in psychopathology. Puerto Rican folk beliefs about mental illness.


Children of immigrants. The adjustment of Ugandan Asian primary-school children in Canada.


Psychiatry in Ethiopia.

Psychiatry in Ethiopia.


The extent of mental disorder. Beyond the layman's madness.


Psychiatric disorders among natives and non-natives in Saskatchewan.


Therapeutic abortion and psychiatric disturbance in Canadian women.


The double blind method.

The double blind method.


Youth and contemporary religious movements: psychosocial findings.


Female physicians as psychiatric patients.


Outcome of hospitalization of geriatric patients in public psychiatric wards in New York and London.


Comparison of depression inventories in a clinical population.


Depression in a university clinic population.


Psychiatry in family practice.

Psychiatry in family practice.


The effect of liquor store strike upon psychiatric hospital admissions for alcoholism.


Intravenous methylphenidate as a diagnostic and psychotherapeutic instrument in adult psychiatry.


Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT)


Decreased uptake of orotate in kidney tumors. The uptake of isotope by three transplanted kidney tumors after i.p. injection of 3H-labeled orotate was less than 5% of that in the host kidney cortex. A decrease of similar magnitude in the uptake into the acid-soluble tissue fractions from the kidney tumors was observed with very low incorporation into RNA relative to the host kidney cortex. Total uptake of orotate-3H and incorporation into RNA were several fold higher in the normal kidney cortex than in the kidney medulla and for the kidney cortex both parameters were less in young than in old rats. The uptake of uracil-3H by two kidney tumors was approximately 40% of that in the kidney cortex of host rats. Although the uptake of orotate-3H in kidney cortex was greater than that for uracil-3H the reverse situation was observed with kidney tumors, indicating that renal neoplasia in the rat is accompanied by an altered pattern of uptake of these metabolites.


Shapes of carcinogenic benz[alpha]anthracenes: an x-ray crystal structure analysis of 12-methylbenz[alpha]anthracene. The crystal structure of the moderately active carcinogen 12-methylbenz[alpha]anthracene (12-MBA) has been determined by application of direct methods to X-ray single-crystal diffraction data. Least-squares refinement to a residual R = 0.09 over 929 independent reflections enabled carbon positions to be established with apparent e.s.d.s. of atomic coordinates about 0.008 A. Deviation from planarity is exemplified by the 15.5 degrees inclination of the benz ring (A) to the anthracene nucleus and by the 0.89 A distance of the methyl carbon out of the best plane through the whole benzanthracene nucleus. Comparison with the structure of the highly carcinogenic 7,12-dimethylbenz[alpha]anthracene (7,12-DMBA), and with the recently solved structures of the weak carcinogen 1-MBA and the extremely weak carcinogen 1,12-DMBA, shows a close similarity in the anthracene parts; in 1-MBA, and 1,12-DMBA, the phenanthrenic K-region bond is close to 1.34 A and the M-region bond about 1.38 A. In 12-MBA, overcrowding in the 'bay' region causes the central anthracene ring C and the benz ring A each to be bent about 10 degrees in opposite directions from the phenanthrenic B ring, much as in 1-MBA and 7,12-DMBA, but less than in 1,12-DMBA; the 12-methyl carbon lies about the same distance (0.55 A) above the anthracene plane in 12-MBA as in 1,12-MBA and 7,12-DMBA.


Theoretical prediction of mutagenicity and carcinogenicity of chemical substances. The pseudopotential with respect to free electrons has been calculated for a series of chemical substances. These potentials are different for carcinogenic, mutagenic-carcinogenic, and mutagenic substances thus allowing the theoretical prediction of their biological activity. The reaction mechanism is discussed on the basis of the interaction potential.


Temporal changes in chromatin isolated from Friend virus-infected mouse spleens. Differences noted in enzyme II directed RNA synthesis under varying salt conditions in nuclei isolated from uninfected and Friend virus (FV)-infected spleen cells, have been attributed to chromosomal modifications (Babcock and Rich 1973). This investigation was undertaken to determine if compositional changes occur in the chromatin of FV-infected spleens, which correlate with an altered rate of synthesis by enzyme II. A quantitative study of the chromatin constituents at various times after infection indicated that they vary in the same temporal manner as the rate of RNA synthesis in isolated nuclei. Relative to DNA, RNA, histone, and nonhistone protein reached a maximum at 14 days postinfection. This was followed by a gradual decrease during the remainder of the infection. Chromatin endogenous DNA-dependent RNA polymerase activity varied in the same manner, suggesting that RNA synthesis directed by enzyme II is modulated by chromosomal proteins.


Minimizing false negatives in electron microscope searches for virus or other specific features of cancer cells. Electron microscopic searches for virus particles and other specific features of cancer cells involve exceptionally poor sampling statistics. It is probable that most searches conducted in the past were of limited value in establishing whether such viruses or special features are associated with one or more tumor types. On the other hand, in a few cases, the electron microscope has provided the first, or even the only, evidence of virus particles. A radical change in the way the electron microscope is applied to this problem is suggested whereby a high-voltage microscope is used to examine thicker sections and an image-processing arrangement is used to focus and select images and to search the images for virus particles. It is suggested that it is important to distinguish virus producers amongst oncogenic viral genome carriers since these may be in a more advanced state of tumor induction and may be capable of transmitting the virus to others.


Behavior of rat liver catalase during electrophoresis in a pH gradient. Investigations were conducted on the distribution of rat liver catalase subsequent to electrofocusing in a pH gradient. Differences were observed depending on the enzyme being extracted from the total mitochondrial fraction, from the supernatant of the homogenate or from purified peroxisomes. Catalase solubilized from the total mitochondrial fraction exhibits an apparent isoelectric point lower than that of catalase derived from the supernatant. Catalase released from purified peroxisomes shows a behavior similar to that of the supernatant catalase. It has been concluded that, in a total mitochondrial fraction, a factor is present that alters the electric charge of the catalase molecule during or after the extraction of the enzyme. This factor is probably associated with lysosomes existing together with peroxisomes and mitochondria in a total mitochondrial fraction. As a matter of fact, the addition of an extract of purified lysosomes to purified peroxisomes or to supernatant will cause a shift towards a more acid pH of catalase distribution subsequent to electrofocalization.


Transfer RNA and aminoacyl tRNA synthetases in hormone dependent and independent mammary tumors of GR mice: II. Isoacceptor tRNA's in hormone dependent and independent mammary tumors of GR mice. The chromatographic elution profiles of 15 aminoacyl tRNA's from dependent and independent mammary tumors of GR mice have been studied using the reversed phase chromatography (RPC 5). The seryl tRNA from the dependent tumor displayed three isoacceptor peaks while only two isoacceptor peaks were observed in the case of the independent tumor when the tRNA's were charged in the presence of the GR mice liver enzyme. Charging of the tRNA's with radioactive leucine by homologous and heterologous enzyme revealed major differences in the leucyl isoacceptor species. The homologous dependent tumor system charges five leucyl tRNA species while the independent system only charges four. The leucyl tRNA from the dependent tumor has a new peak which is only recognized by its own enzyme, but this peak is either suppressed or completely absent in the independent tumor.


Carcinogenic effects of different nitroso-compounds in chinese hamsters: N-dibutylnitrosamine and N-nitrosomethylurea. Three hundred and twenty Chinese hamsters (Cricetulus griseus) (CH) were subcutaneously (s.c.) treated with 1/5, 1/10 or 1/20 the mean lethal dose (LD50) of N-dibutylnitrosamine (DBN) or N-nitrosomethylurea (NMU). In several respects these two substances produced the same organotropy in the CH as in the Syrian golden (SGH) and European hamsters (EH). DBN prolonged lung tumours and neoplasms of the injection site. NMU induced tumours of the injection site only.


Polycyclic aromatic hydrocarbons in human bronchial carcinoma. A study was made to determine whether and to what extent polycyclic aromatic hydrocarbons (PAH) are present in human bronchial carcinoma. Twenty-four carcinomas, obtained from surgical operations and autopsies, were examined. The samples were tested for 12 PAH; these were determined by direct fluorescence analysis on thin-layer plates. Only 4 of the 12 PAH were detected in the cancerous tissue: benzo(a)pyrene, fluoranthene, benzo(ghi)perylene. Beno(a)pyrene was found in all carcinomas. The reasons for increased concentration of the detected PAH in cancerous tissue are discussed with respect to deposition and elimination of inhaled particles as well as the metabolism of these compounds.


A further pancreatic carcinogen in Syrian golden hamsters: N-nitroso-bis(2-acetoxypropyl)amine. Weekly subcutaneous injection of N-nitroso-bis(2-acetoxypropyl)amine (BAP) for 20 weeks to Syrian golden hamsters induced pancreatic neoplasms in 50% of the animals, as early as 15 weeks from the start of treatment. The carcinogenic potency and organotropic spectrum of BAP were similar to those of N-nitroso-bis(2-hydroxypropyl)amine (BHP). Metabolism studies indicated that BAP was readily converted in vivo to BHP and that BHP was also the major urinary metabolite.


Human breast carcinoma: heterotransplantation to newborn rats. Cultured cells from a human breast carcinoma (HBC) were injected subcutaneously in newborn cortisone-treated Sprague-Dawley rats (CNBR). Tumors of predominantly epithelial nature appeared in all within 30 days, and wipespread metastases occured often. Cells cultured from these tumors rapidly produced similar tumors in CNBR. Rat-to-rat passage by implanting fragments of tumor tissue was 100% successful in CNBR. The in vivo model described is simple and inexpensive.


Tumorgenicity of L cell derivatives and hybrid cells derived from them. Hybridization studies on high and low malignant L cell derivatives support our previous conclusions, in showing that crosses between highly tumorigenic and poorly tumorigenic lines to a marked suppression of the malignant phenotype. Malignant behaviour is not, however, suppressed when cells from one highly tumorigenic line are crossed with those of another tumorigenic line. The present results show further that these rules apply even when all the cells crossed are closely related derivatives of one cell line.


Investigations on esophageal carcinogenicity by methyl-phenyl-nitrosamine and ethyl alcohol in rats. Methyl-phenyl-nitrosamine was administered subcutaneously or orally to Sprague-Dawley rats. Carcinomas of the esophagus were found in 46-87% of the animals. The induction period of tumors was 170-290 days. Simultaneous application of 25% ethyl alcohol given instead of drinking water did not alter tumor incidences and induction periods. Hepatotoxic effects of ethyl alcohol were not observed. Mean life expectancies of animals were not reduced.


Vaccinia virus: the possibilities of its oncogenicity in humans. Contrary to the earlier generally accepted view that vaccinia virus replicates in the cytoplasm only of suitable target cells, steadily accumulating data show that the viral genome spends a limited period of time in the nucleus. This, together with the many cases where a close association has been suspected or established between skin cancer and vaccination, suggests that vaccinia virus may, under certain yet undefined physiological conditions, act as an oncogenic virus in humans.


Early membrane alterations in isolated cells treated in vitro with chemical carcinogens. Membrane alterations were detected in isolated epithelial cells treated in vitro with 5 x 10(-4) M dibutylnitrosamine (DBN) or 1.2 x 10(-9) M diethylstilbestrol (DES) for 30 min. Addition of DBN to bladder cells and DES to endometrial cells elicited a striking increment in Con A-mediated hemadsorption, but not Con A binding, to the treated cells as compared to those not treated with carcinogens. Concomitantly, release of the lysosomal proteinase, cathepsin B1, to the extracellular medium was essentially doubled in the preparations exposed to the carcinogens, as compared to corresponding controls. The increased cellular hemagglutination in response to carcinogen treatment was significantly reduced by prior incubation of the epithelial cells with ovomucoid, a proteinase inhibitor that suppresses the activity of cathepsin B1.


Carcinogenic effects of a single dose of diethylnitrosamine in three unrelated strains of mice: genetic dependence of the induced tumor types and incidence. The carcinogenic effects of a single dose of diethylnitrosamine (DEN) were studied in three inbred strains of mice. The most predominant tumors observed were lung adenomas, leukemia, and liver tumors. Mice of strain AKR/J developed both leukemia and lung tumors; SWR/J mice were most susceptible to lung tumor development; and in C57BL/6J mice liver lesions including liver tumors occurred. The influence of the genetic background on the organ susceptibility to DEN-carcinogenesis is discussed.


Modification of photocarcinogenesis by two immunosuppressive agents. The carcinogenic effect of ultraviolet radiation (UVR) on the skin of hairless (hr) mice was modified by two immunosuppressive agents, rabbit anti-mouse lymphocytic serum (ALS), and 6-mercaptopurine (6MP). Daily exposure of mice to UVR resulted in multiple tumor production. Carcinogenesis was measured in terms of affected mice (prevalence) and numbers of tumors produced. By both criteria, photocarcinogenesis was enhanced by ALS but inhibited by 6MP.


DNA damage and repair in intact animals. Single-stranded regions in rat liver DNA following administration of dimethylnitrosamine. Rat liver DNA was radioactively labelled by administration of [3H]thymidine following partial hepatectomy. Two weeks later, the rats were treated with the carcinogen, dimethylnitrosamine. DNA was isolated and fractionated by elution from benzoylated DEAE-cellulose with NaCl and caffeine solution. The caffeine-eluted fraction was increased by administration of dimethylnitrosamine. This increase was proportional to the dose of carcinogen injected and persisted for at least 24 h after administration of the carcinogen. These data, together with the results of hydroxyapatite chromatography, suggest that the DNA contains short single-stranded sections associated with much longer regions of native DNA.


Proliferation of endocrine (APUD-type) cells during early N-diethylnitrosamine-induced lung carcinogenesis in hamsters. Pronounced proliferation of amine precursor uptake and decarboxylase activity (APUD-type) cells was found in the segmental bronchi and bronchioles of Syrian golden hamsters during N-diethylnitrosamine (DEN)-induced lung carcinogenesis. Since similar epithelial alterations did not occur in previous experiments after benzo(a)pyrene (B(a)P) treatment, it is concluded that the initial stages of lung carcinogenesis differ with respect to the carcinogen administered.


On the carcinogenic polycyclic aromatic hydrocarbon benzo(a)pyrene in volcano exhausts. The content of benzo(a)pyrene in the juvenile ashes of the volcano Tyatya (Kunashir Island, Kuriles) and in the soil, vegetation and volcanic mud collected near volcanos in Kamchatka was studied. It was concluded that volcanic activity does not play a large role in forming the background level of this carcinogen in the human environment.


Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine. Groups of male MRC Wistar rats were treated for 2 years either with morpholine (10 g/kg food) together with sodium nitrite (3 g/l drinking water) or with N-nitrosomorpholine (NM, 0.15g/l drinking water). In both cases, a group of rats was given sodium ascorbate (22.7 g/kg food) in addition to these treatments. When ascorbate was present, the liver tumors induced by morpholine and nitrite showed a 1.7-fold longer induction period, a slightly lower incidence, and an absence of metastases in the lungs, indicating that ascorbate had inhibited the in vivo formation of NM. Ascorbate did not affect liver tumor induction by the performed NM. The group treated with morpholine, nitrite, and ascorbate had a 54% incidence of forestomach tumors, including an 18% incidence of squamous cell carcinomas, possibly because ascorbate promoted NM action in this organ.


Decreased transforming ability of a temperature-sensitive mutant of human adenovirus type 12. A mutant of human adenovirus type 12, temperature-sensitive for virus replication an for the enhancement of thymidine incorporation in resting human embryonic kidney cells, is described. The mutant was also temperature-sensitive for transformation of rat cells. The results indicate that a viral gene required for the virus growth cycle is also required for transformation.


Stimulatory effect of staphylococcal leukocidin on granulopoiesis disturbed by cytostatic agents. Functional tests of granulopoiesis (leukocytosis, bone marrow picture, incubation in vitro of bone marrow with [3H]thymidine followed by radioautography and counting of labeled promyelocytes and myelocytes, serum muramidase level, liberation of granulocyte bone marrow reserve, Nitro-BT reduction in blood granulocytes, enzyme cytochemistry, and phagocytosis) were performed in rabbits given bubulphan (10 mg/kg) or 5-fluorouracil (200 mg/kg). Determinations were carried on serially during treatment with cytostatics. Some of the cytostatic-treated animals received intravenous (i.v.) injections of purified staphylococcal leukocidin in daily doses of 0.1 mg/kg. In control animals, theleukocidin resulted in stimulation of granulopoiesis (leukocytosis, increased number of [3H]thymidine-labeled myelocytes, elevated serum muramidase level). Animals receiving cytostatics suffered from marked inhibition of granulopoiesis accompanied by decrease of bone marrow granulocyte reserve. Injection of staphylococcal leukocidin during the period of myelosuppression evoked by cytostatics resulted in partial protection of granylopoiesis and faster regeneration of the leukocyte system.


Random repression, immunological surveillance and hyperthermia. A theoretical model of random repression of genetic information in a cancer cell is related to the efficiency of the immune system in removing cancer cells. It is suggested that at some elevated temperature, binding of a certain repressor molecule to the genome ceases and that the cell loses its random properties. We conclude with the idea that elevated temperature increases the efficiency of the immune system.


Skin tumor initiating ability of benzo(a)pyrene 4,5- 7,5- and 7,8-diol-9,10-epoxides and 7,8-diol. The skin tumor initiating abilities of both K-region and non-K-region epoxides of benzo(a)pyrene(BP) were determined in mice using a two-stage system of tumorigenesis. BP-4,5-epoxide and BP-7,8-dihydrodiol-9,10-epoxide (anti) were found to be weak tumor initiators whereas BP-7,8-epoxide had about a third of the activity as the parent hydrocarbon, BP. However, the 7,8-dihydrodiol of BP was found to be approximately as potent as BP suggesting that it may be a proximate carcinogen.


The effect of withaferin A on human peripheral blood lymphocytes. An electron-microscope study. Cultures of normal human peripheral blood lymphocytes stimulated by phytohaemagglutinin (PHA) were treated with withaferin A and examined by an electron microscope. The compound was found to affect the spindle microtubules of cells in metaphase. There were no intact pole-to-pole microtubules or pole-to-kinetochore microtubules found in the treated cells; the centrioles were located in the center. Furthermore, cells at interphase were also affected, the membrane system of the cells being damaged.


The effect of withaferin A, a natural steroidal lactone, on the fine structure of S-180 tumor cells. Mouse sarcoma 180 (S-180) solid and ascites tumor cells were treated in vivo and in vitro with withaferin A and observed with the electron microscope. The compound was found to effect this spindle microtubules of cells in metaphase. An interesting finding was the double membranes surrounding the chromosomes in the treated cells; probably the nuclei were reconstructed directly from the metaphase stage in the in vivo withaferin A-treated cells. In addition the membranes of the cells in interphase were affected by in vivo or in vitro treatment with the compound.


Effect of chronic administration of dimethylnitrosamine on the excision of O6-methylguanine from rat liver DNA. Rats were exposed chronically to unlabelled N,N-dimethylnitrosamine (25 ppm in the drinking water) then given a single dose of N-[3H]methyl-N-nitrosourea (10 mg/kg body weight). The rates of loss of tritium-labeled 7-methylguanine, O6-methylguanine and 3-methyladenine from the liver DNA in control and dimethylnitrosamine-treated rats were found not to be significantly different. Thus, under the conditions used, inhibition of the O6-methylguanine excision repair system does not seem to be a factor in the induction of liver tumours by chronic DMN application.


Echocardiographic evaluation of adriamycin cardiotoxicity in children. Thirty children with malignant solid tumors receiving adriamycin had serial evaluation of left ventricular (LV) function by echocardiography. The echocardiographic studies showed a progressive decrease in myocardial contractility as evidenced by changes in several parameters of LV function with increasing cumulative doses of the drug. Using the patients as their own controls, serial echocardiography appears to be a reliable method for detecting early alteration of cardiac function in the asymptomatic patient. This technique may prove useful to prevent cardiomyopathy secondary to adriamycin and to prolong therapy beyond the currently established limits.


Induction of renal pelvic tumours in Sprague-Dawley rats by di-isopropanolnitrosamine. Transitional cell papillomas and carcinomas of the renal pelvis were observed in Sprague-Dawley rats after subcutaneous (s.c.) treatment with di-isopropranolnitrosamine (DIPN). These tumours occurred unilaterally and appeared as early as 24 weeks after the commencement of treatment. The tumours frequently filled the entire renal pelvis and compressed the kidney parenchyma. The malignant neoplasms demonstrated infiltrative growth into the adjacent medullary parenchyma.


Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16-213. The lethal and kinetic effects of VP-16-213 were analyzed in a human lymphoid cell line (T1 cells) in vitro. When asynchronous T1 cells were exposed to increasing concentrations of VP-16-213 for 1 hour, an exponential survival curve with a Do (mean lethal dose equal to the concentration required to reduce survival by 63% on the exponential part of the survival curve) of 3 mug/ml was obtained. Increasing exposure time also reduced survival exponentially. Synchronized cells showed age-dependent sensitivity to VP-16-213 with the greatest lethal damage experienced by cells treated in S and G2 phase. The major kinetic response of the T1 cells to VP-16-213 was a delay in G2 phase, the extent and duration of which was a function of drug concentration, exposure time, and cell cycle stage of drug addition; thus, cells in S phase were most effectively blocked in the subsequent G2 phase. Continuous treatment with concentrations of VP-16-213 (greater than 0.5 mug/ml for greater than 3 hours) caused a retardation of S-phase transit with prompt recovery after drug release. Treatment with 10.0 mug/ml for greater than 3 hours resulted in a "frozen state" of the whole life cycle, inducing only minor compartment changes. DNA synthesis was inhibited in the majority of cells with an S-phase DNA content. There was no correlation between the extent of perturbation and lethal effects after treatment with VP-16-213.


Studies of the effects of cyclophosphamide, vincristine, and prednisone on some hepatic oxidations and conjugations. The effects of low and high doses of three anticancer agents, cyclophosphamide, vincristine, and prednisone (given individually or in various combinations), on oxidative and conjugation pathways were studied in Sprague-Dawley male rats. Cyclophosphamide used alone at low doses decreased aniline hydroxylase and ethylmorphine demethylase activities by about 20% and at high doses produced a 30%-50% decrease in the specific activities of several microsomal mixed-function oxygenase activities, in the contents of cytochromes P-450 and b5, and in the magnitudes of type I and II drug-binding spectrum. The levels of microsomal glucouronidase, glucuronyl transferase, and sulfatase per gram of liver were also decreased (30%-50%) by the high dose of cyclophosphamide. The high dose of cyclophosphamide in conjunction with either vincristine or prednisone also produced a noticeable decrease in several activities tested; however, when cyclophosphamide was given at either low or high doses in combination with vincristine and prednisone, the activities tested were comparable to those seen in untreated controls. The mechanism of this protection is presently unknown. Vincristine, at both low and high doses, produced little effect on oxidative pathways; however, at low doses it caused a significant increase (80%) in the specific activity of hepatic microsomal sulfatase. This effect was also discernible when vincristine was given in combination with cyclophosphamide and prednisone. Other than producing a 15% decrease in liver weight and a 40% decrease in the specific activity of microsomal glucuronidase, the high dose of prednisone used had no effect on various activities tested. Results of these studies indicate a potential for drug interaction among anticancer agents and supportive drugs used in combination cancer chemotherapy.


Studies with 2,5-piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride. II. Effects on macromolecular synthesis in cell culture and evidence for alkylating activity. 2,5-Piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride (NSC-135758) inhibited DNA synthesis but not RNA and protein synthesis in Adenocarcinoma 755 cells in culture. The expression of such inhibition was delayed in time; it was necessary to expose tumor cells to NSC-135758 for 10-12 hours before measuring the macromolecular synthesis in order to demonstrate selective inhibition of DNA synthesis. Inhibition of DNA synthesis was demonstrated to be irreversible in human epidermoid carcinoma cells in culture. Exposure of cells in suspension culture to NSC-135758 or to melphalan for 1-4 hours, and then incubation of cells in the absence of an inhibitor for 20 hours, resulted in preferential inhibition of DNA synthesis; inhibition of RNA synthesis was observed under these conditions but was less pronounced. Chemical evidence for alkylating activity of NSC-135758 and of the bis-aziridine derived from it (NSC-201424) was obtained by demonstrating their reaction with 4-(p-nitrobenzyl)pyridine. NSC-135758 was more potent as a cytotoxic agent than was its derivative, a result which suggests that NSC-135758 is the active alkylating agent. Reaction of NSC-135758 with diethylamine was examined; the product obtained upon alkylation of diethylamine by NSC-135758 was identified from its proton magnetic resonance spectrum and by field desorption mass spectral analysis. These results support the view that NSC-135758 acts as an alkylating agent in inhibiting DNA synthesis and cell proliferation of tumor cells in culture.


Studies with 2,5-piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride. III. Biochemical and therapeutic effects in L1210 leukemias sensitive and resistant to alkylating agents: comparison with melphalan, cyclophosphamide, and BCNU. 2,5-Piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride (NSC-135758) selectively inhibits DNA synthesis in L1210/0 leukemia and in cyclophosphamide-resistant L1210 (L1210/CPA). Melphalan (L-PAM) inhibits nucleic-acid synthesis but not protein synthesis in L1210/0 and L1210/CPA. CPA selectively inhibits DNA synthesis in L1210/0 but does not inhibit DNA synthesis in L1210/CPA. NSC-135758 is as active in vivo against L1210/CPA and BCNU-resistant L1210 (L1210/BCNU) as it is against L1210/0. It is inactive against ic implanted L1210/0. These data clearly indicate important differences in the biologic activity of this compound compared to either CPA or BCNU. L-PAM is similar to NSC-135758 in activity against L1210/CPA and L1210/BCNU.


Amino acid-conferred resistance to melphalan. I. Structure-activity relationship in cultured murine L1210 leukemia cells. Melphalan cytotoxicity to murine L1210 leukemia cells in culture was reduced in growth medium containing amino acids. Investigation of the effect of single amino acids revealed that the L-isomers of glutamine and leucine, but not the D-isomers, were the most active in decreasing cytotoxicity. Protection was concentration dependent, with maximum protection occurring at approximately 0.25 mM, a physiologic concentration. The LD90 for melphalan in the presence of 0.1 mM L-glutamine or L-leucine was increased by 7.3- and 10.8-fold respectively, under conditions where the cells had been pre-incubated with the amino acids. These results are interpreted to suggest that melphalan transport by the L1210 leukemia cell is mediated by a system also responsible for the transport of glutamine and leucine and that interaction with such a system may play a significant role in the chemotherapeutic activity of this alkylating agent.


Combination chemotherapy with mitomycin C, 5-fluorouracil, and cytosine arabinoside in gastrointestinal cancer.


Comparison of the biologic activity of VP-16-213 given iv and orally in capsules or drink ampules.


Combination cytotoxic chemotherapy for metastatic cutaneous malignant melanoma with DTIC, BCNU, and vincristine.


Phase II study of ICRF-159 in patients with metastatic colorectal carcinoma previously exposed to systemic chemotherapy.


Combination therapy with mitomycin C,5-fluorouracil, and cytosine arabinoside in P815 ascites and solid mouse neoplasms.


Pigmentation of the tongue after treatment with adriamycin.


Antiestrogens in the treatment of breast cancer.


Radiosensitizers of hypoxic cells in solid tumors.


Enol acetates of nucleoside-5'-aldehydes: potential intermediates for substituent incorporation at C-4'.


Prostaglandins and cancer.

Prostaglandins and cancer.


Utilization of unsaturated amino sugars in the synthesis of nucleosides.


Synthesis of 2-acetamido-2-deoxy-3-O-beta-D-mannopyranosyl-D-glucose. Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-alpha-D-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside (2) gave an alpha-D-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-alpha-D-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2,-O-(l-ethoxyethylidene)-alpha-D-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-alpha-D-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2 O-acetyl-3,4,6-tri-O-benzyl-beta-D-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the beta-D-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-beta-D-mannopyranosyl-D-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the alpha-D-linked analog.


The synthesis of 2-acetamido-2-deoxy-4-O-beta-D-mannopyranosyl-D-glucose. Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-alpha-D-mannopyranosyl bromide with 2-amino-2-N,3-O-carbonyl-5.6-O-isopropylidene-D-glucose diethyl acetal gave, unexpectedly, 2-amino-2-N,3-O-carbonyl-2-deoxy-4-O-(4,6-di-O-acetyl-2,3-O-carbonyl-alpha-D-mannopyranosyl)-5,6-O-isopropylidene-D-glucose diethyl acetal, futher transformed, by de-esterification followed by acetylation, into the previously known 2-amino-2-N,3-O-carbonyl-2-deoxy-5,6-O-isopropylidene-4-O-alpha-D-mannopyranosyl-D-glucose diethyl acetal and its tetra-O-acetyl derivative. Benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside was condensed with 2-O-acetyl-3,4,6-tri-O-benzyl-beta-D-glucopyranosyl bromide to give benzyl 2-acetamido-4-O-(2-O-acetyl-3,4,6-tri-O-benzyl-beta-D-glucopyranosyl)-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside. Removal of the 2-O-acetyl group, followed by oxidation with acetic anhydridedimethyl sulfoxide, gave a beta-D-arabino-hexosid-2-ulose (25). After reduction with sodium borohydride, removal of the benzyl groups gave crystalline 2-acetamido-2-deoxy-4-O-beta-D-mannopyranosyl-D-glucose (27). The anomeric configuration of the glycosidic linkage was ascertained by comparison with the alpha-D-linked disaccharide.


Synthesis of prumycin and related compounds. Prumycin (1) and related compounds have been synthesized from benzyl 2-(benzyloxycarbonyl)amino-2-deoxy-5,6-O-isopropylidene-beta-D-glucofuranoside (4). Benzoylation of 4, followed by deisopropylidenation, gave benzyl 3-O-benzoyl-2-(benzyloxycarbonyl)amino-2-deoxy-beta-D-glucofuranoside (6), which was converted, via oxidative cleavage at C-5-C-6 and subsequent reduction, into the related benzyl beta-D-xylofuranoside derivative (7). Benzylation of 3-O-benzoyl-2-(benzyloxycarbonyl)-amino-2-deoxy-D-xylopyranose (8), derived from 7 by hydrolysis, afforded the corresponding DERIVATIVES (9,11) of beta-and alpha-D-xylopyranoside, and compound 7 as a minor product. Treatment of benzyl 3-O-benzoyl-2(benzyloxycarbonyl)amino-2-deoxy-4-O-mesyl-beta-D-xylopyranoside (10), formed by mesylation of 9, with sodium azide in N,N-dimethylformamide gave benzyl 4-azido-3-O-benzoyl-2-(benzyloxycarbonyl)amino-2,4-dideoxy-alpha-L-arabinopyranoside (13), which was debenzoylated to compound 14. Selective reduction of the azide group in 14, and condensation of the 4-amine with N-[N-benzyloxycarbonyl)-D-alaninoyloxy]succinimide, gave the corresponding derivative (15) of 1. Reductive removal of the protecting groups of 15 afforded 1. Prumycin analogs were also synthesized from compound 14. Evidence in support of the structures assigned to the new derivatives is presented.


The synthesis, binding, and agglutinating activity of 6-aminohexyl beta-D-mannopyranoside.


Synthesis of O-beta-D-galactopyranosyl-(1 linked to 4)-O-(2acetamido-2-deoxy-beta-D-glucopyranosyl)-(1 linked to 2)-D-mannose and its interaction with various lectins. 2-Methyl-[3,6-di-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-alpha D-glucopyrano]-[2,1-d]-2oxazoline (4) was prepared from 2-acetamido-3,6-di-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-alpha-D-glucopyranosyl chloride. Condensation of 3,4:5,6-di-O-isopropylidene-D-mannose dimethyl acetal with 4 in the presence of a catalytic amount of p-toluenesulfonic acid afforded O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1 linked to 4)-O-(2-acetamido-3,6-di-O-acetyl-2-deoxy-beta-D-glucopyranosyl)-(1 linked to 2)-3,4:5,6-di-O-ispropylidene-D-mannose dimethyl acetal (6) in 8.6% yield. Catalytic deacetylation of 6 with sodium methoxide, followed by hydrolysis with dilute sulfuric acid, gave O-beta-D-galactopyranosyl-(1 linked to 4)-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1 linked to 2)-D-mannose (7). The inhibitory activities of 7 and related sugars against the henagglutinating activities of various lectins were assayed, and 7 was found to be a good inhibitor against Phaseolus vulgaris hemagglutinin.


Methylation studies of the polysaccharides resulting from sequential Smith-degradations of the galactan from the snail Strophocheilus oblongus. When the galactan from the albumen glands of the snail Strophocheilus oblongus was submitted to three Smith-degradation, the degraded polysaccharide, isolated in 6% yield, was much more linear. Methylation analysis showed that the Smith-degraded polysaccharide gave an increased percentage of 2,4,6-tri, decreased percentages of 2,3,4,6-tetra-and 2,4-di, and a large variation in the amount of 2,3,4-tri-O-methyl-D-galactose. The sugars in the polysaccharide which result in the formation of 2,3,4,6-tetra- and 2,3,4-tri-O-methyl-D-galactose are destoryed in subsequent degradation procedures. The above observations suggest that the degradation by periodate oxidation proceeds via non-reducing end-groups and though some internal residues that are exposed as the degradation proceeds. As a result of the overall process, new non-reducing end-groups are formed and new (1 leads to 6)-linked D-galactose residues are then exposed. The  isolation of glycosides of low molecular weight supports the suggestion that the molecule, in the main, is sequentially degraded from the external layers.


Chemical modification of aminocyclitol antibiotics. The aminocyclitol antibiotic neamine has been chemically modified at the hydroxyl group on C-6 of the 2-deoxystrepatamine moiety. The partially acetylated neamine derivatives, 6,3,4-tri-O-acetyl- (3) and 5,3-57,4-tri-O-acetyl-1,3,2,6-tetra-N-(ethoxycarbonyl)neamine (4), were prepared by random hydrolysis of the 5,6-O-ethoxyethylidene derivative (2), followed by chromatographic purification. Condensation of 4 and 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride led to 6-O-(beta-D-ribonfuranosyl)neamine (7). Analogous condensation of 4 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide or 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide afforded the corresponding 6-O-(D-hexopyranosyl)neamines.


Changes in carbohydrate content of surface membranes of human erythrocytes during ageing. The carbohydrate content (neutral hexoses, fucose, sialic acid, and hexosamine) of human erythrocytes is significantly higher in young than in old erythrocytes. The differences observed in the carbohydrate content of surface glycopeptides, obtained after incubation with either Pronase or trypsin, is still more striking, suggesting important modifications of the carbohydrate moeties of the erythrocyte membrane during in vivo ageing.


Studies of the epimerization of 2-acetamido-2-deoxy-D-glucopyranose:selective deuteration at C-2 of 2-acetamido-2-deoxyaldoses.


The synthesis of N-(benzyloxycarbonyl)-3-O-E13,4,6-tri-O-acetyl-2-deoxy-2-(2,4-dinitroanilino)-beta-D-glucopyranosyl]-L-serine methyl ester, and its condensation with activated esters of amino acids.


Synthesis of O-beta-D-glucopyranosyl-(1 linked to 3)-O-alpha-L-fucopyranosyl-L-threonine.


Isolation of 3-O-methyl-D-ribose from a Rhizobium polysaccharide.


Venous pressure and exercise tolerance.

Venous pressure and exercise tolerance. Compared to the number of contractions obtained when a blood pressure cuff on the upper arm was at zero pressure, inflation of the cuff to pressures ranging between 5 and 40 mm Hg resulted in an augmentation of the number of hand contractions that could be performed prior to the development of ipsilateral severe fatigue or intolerable pain. Cuff pressures of 60 mm Hg reduced the number of contractions below the control level. These results are consistent with the concept that exercise during venous congestion facilitates the washout of the toxic catabolite presumed to be produced during muscular contraction.


Factors affecting the transvalvar pressure difference in a hydraulic model of aortic stenosis. Mechanical factors that can modify the peak transvalvar pressure differences (delta P) in aortic stenosis were evaluated in a model. A latex rubber sac simulated the ventricle. Expansion of the walls of the sac by means of a negative pressure applied to its outer wall introduced a measure volume into the sac and placed the wall materials under tension. The stretched sac was then permitted to contract and to expel its contents through "aortic valvar" orifices of various severities of stenosis, into an aortic standpipe of selected diameters (compliances). Factors that increased the peak delta P included the strength (thickness) of the ventricular wall, the rate at which it mobilized and applied its tensile force to compress the sac contents, the unstressed volume of the sac, the total volume in the sac at onset of contraction, the severity of the valvar stenosis, the compliance of the aorta, the rate of arterial run-off, and the aortic diastolic pressure. Loss of forward stroke volume due to mitral regurgitation lowered the peak delta P. Elevations in diastolic arterial pressure also lowered delta P. All of these mechanical factors should be considered in the analysis of the severity of clinical aortic valvar stenosis and in decisions for medical therapy and surgical correction. The several factors which do not depend directly on the orifice area or on the forward stroke volume vitiate the sole use of the orifice formula in the analysis of the dynamics of aortic stenosis. The application of this approach in related problems is indicated.


Pericarditis associated to acquired toxoplasmosis in a child.


Massive left atrial thrombus: a case report. This case report describes a patient with aortic and mitral valvular disease who had a massive left atrial thrombus. The left atrial thrombus produced a disappearance of signs of mitral stenosis and a reversed pan diastolic mitral valve gradient. This gradient occurred in the absence of any diastolic mitral insufficiency and may have been due to artifactual lowering of the left atrial pressure by an organized left atrial clot.


Effect of ischemia and infarction on regional content of adenine nucleotides and derivatives in canine left ventricle. Samples of myocardium from four areas of ischemic and infarcted canine ventricle were examined over a 20-day period for content of the three adenine nucleotides as well as inosine, hypoxanthine, adenosine, and inosine monophosphate. The adenosine triphosphate (ATP) content of central and peripheral areas within the infarct fell to 11% and 8% of control, respectively, 1 day after coronary occlusion. The total adenine nucleotide (TAN) content in these areas fell to 17% of control and showed no significant recovery during the period of study. In the functional myocardium immediately surrounding the infarct the ATP content was depressed to 58% control after 1 day, and the TAN content was also depressed. In the healthy myocardium near the apex, the ATP content was significantly depressed only at the 3-day sample period. Adenine nucleotide derivatives were detected only at 30 min in the central ischemic area. The absence of the nucleoside and nucleobase compounds formed during adenine nucleotide degradation is attributed to their high membrane diffusibility. Loss of these compounds is considered a contributing factor in the prolonged depression of adenine nucleotide content in both ischemic and non-ischemic regions.


Capping of eucaryotic mRNAs.

Capping of eucaryotic mRNAs.


A radiological analysis of the transcription units for heterogeneous nuclear RNA in cultured murine cells. Ultraviolet irradiation of cultured murine cells damages chromosomal DNA, thus causing premature termination of synthesis of hnRNA chains. We have utilized this effect for measuring the sizes of transcription units for the various classes of hnRNA. Target size analyses of the loss of synthesis of hnRNA species suggest that hnRNA, through its entire size range, constitutes mostly primary transcripts-that is, the shorter RNA molecules are not processed from longer precursors. Polyadenylated hnRNA appears to be a primary transcript as well. Our data, however, are also consistent with processing of precursors to poly(A)+ hnRNA from the 5'termini of larger hnRNA molecules. They are not consistent with models which postulate that poly(A)+ hnRNA sequences originate at the 3' termini of precursors which are considerably larger (greater than 30%) than the polyadenylated hnRNA molecules themselves. Finally, we have found that the process of polyadenylation is not measurably affected by ultraviolet irradiation of cells.


The expression of three abundance classes of messenger RNA in mouse tissues. Using the technique of mRNA-cDNA hybridization, we have shown that there are between 11,500 and 12,500 different mRNAs in three different mouse tissues:kidneys, brains, and livers. Several experiments suggest that in each tissue the mRNAs are organized into three abundance classes rather than as a continumm with respect to concentration. Cross-hybridization experminets show that the most abundant class of mRNA in each tissue is characteristic, and that a high proportion of the total sequences are common between tissues. For a more complete analysis, cDNA was fractionated into three classes. Studies using isolated abundant cDNA show that some abundant sequences of liver and kidney are present in other tissues, but among the lower frequency classes. Thus tissue-specific differences in mRNA populations may be related to abundance as well as qualitative differences. Using isolated middle frequency cDNA of the kidney, it was shown that of the 550 or so sequences in this class, approximately 500 are shared with the liver. Similarly, between 9,500 and 10,500 of the low frequency kidney cDNAs are shared with the brain and liver, respectively, suggesting that the majority of mRNAs may be involved with "housekeeping" activities. In an attempt to see whether abundance of mRNA is related to repetition of the sequence in the genome, it was shown that abundant and middle frequency cDNA of the liver and kidney contain a component that anneals with DNA repeated approximately 100 fold. However, the low frequency cDNA of the kidney contains no repeated sequences.


Control of lysozyme induction in the differentiation of myeloid leukemic cells. A system has been developed with clones of mouse myeloid leukemic cells in culture to study the induction of synthesis and secretion of lysozyme in relation to other steps in myeloid cell differentiation. Lysozyme was initially absent in all the clones studied. The different clones can be divided into three types according to their ability to be induced to undergo normal cell differentiation by the protein inducer MGI (macrophage and granulocyte inducer). One type of clone that can be induced by MGI to form Fc and C3 receptors and differentiate to mature macrophages and granulocytes (MGI+D+) was also induced by MGI to synthesize and secrete lysozyme. Lysozyme was induced after Fc and C3 receptors, and labeling with 35S-methionine has shown that the induced lysozyme was newly synthesized. MGI+D+ clones were also induced to synthesize and secrete lysozyme by dexamethasone, prednisolone, cytosine arabinoside, or thymidine and in one of four clones by dimethylsulfoxide but not by sodium butyrate. Inhibition of cell multiplication by itself was not sufficient to induce lysozyme synthesis. A second type of clone which can be induced by MGI to form Fc and C3 receptors but not mature cells (MGI+D-) was more weakly inducible by MGI for lysozyme and was not inducible by any of the other compounds. A third type of clone (MGI-D) MGI for receptors or mature cells. One of four MGI-D- clones was induced to synthesize but not secrete lysozyme by dexamethasone together with sodium butyrate, but there was no lysozyme induction by MGI or any of the other compounds separately. The different clones maintained their different properties for at least 6 months in culture. The results indicate that clones with different hereditary blocks in the ability to be induced to differentiate by specific compounds can be used to dissect the process of myeloid cell differentiation, that the sequence of differentiation is induction of Fc and C3 receptors leads to lysozyme leads to mature cells, and that there are separate controls for these developmental steps.


Identification and characterization of multiple forms of actin. Multiple forms of actin have been found in a variety of mammalian cell lines and tissues by the use of high resolution, two-dimensional gel electrophoresis. One form (alpha actin) was found only in differentiated muscle cells, and its synthesis is induced during myogenesis in culture. Two other forms (beta and gamma actin) are present in all nonmuscle cell types examined, and they continue to be synthesized in cultured muscle cells after fusion. Tryptic peptide comparisons have shown that muscle actin is distinguished from the two "nonmuscle" actins by several peptide differences, and that the two non-muscle actins are nearly identical. All three forms contain equimolar amounts of N-methylhistidine, and extensive controls have shown no evidence of artifactual heterogeneity. In addition to the three major actins, two other proteins were identified as probably forms of actin by affinity for DNAase I-agarose. These proteins are similar in charge and molecular weight to the major actin forms, but are unstable and have lifetimes in the cell of less than 2 hr.


The effect of ecdysterone on nonhistone proteins in salivary gland chromosomes of Sciara coprophila. Synthesis and transport of proteins to the cell nucleus during puff induction was studied in S. coprophila. Changes in grain distribution along chromosomes (L-methionine [35S] incorporation into protein) were correlated with puffs induced by ecdysterone in vitro; A pattern of specific labelling at the sites of incipient puffs was noted within 2 h after the addition of the hormone, i.e. grains on the chromosomes were in clusters, characteristic for this time point and not seen in the controls (where only non-specific labeling was noted 0-4 h). Characteristic chromosomal puffs appeared between 3-4 h after the addition of ecdysterone. It was concluded that during ecdysterone-induced puff formation in salivary gland chromosomes, proteins which had been previously synthesized were selectively transported from the cytoplasm to specific sites on the chromosomes.


Changes in type of collagen synthesized by chick fibroblasts in vitro in the presence of 5-bromodeoxyuridine. Chick embryo fibroblasts cease to synthesize their normal collagen product when grown in the presence of the thymidine analogue, 5-bromodeoxyuridine (BrdU). The drug causes an alteration of synthesis from the normal Type I collagen (alpha1 (I)2alpha2) to a mixture of Type I and Type I trimer (alpha1(I)3). While the significance of the synthesis of Type I trimer is unclear, it has been noted that chondrocytes synthesize this collagen type following in vitro senescence and in the presence of BrdU. Since BrdU may cause a switching in the temporal pattern of collagen biosynthesis in chondrocytes and in fibroblasts it is proposed that BrdU may alter the normal regulatory controls acquired by the cells during the course of their differentiation. The synthesis of type I trimer might provide a marker for such a break-down in a wide variety of cell types.


Selection of temperature-sensitive CHL asparagyl-tRNA synthetase mutants using the toxic lysine analog, S-2-aminoethyl-L-cysteine. We developed a procedure, using the toxic lysine analog S-2-aminoethyl-L-cysteine (thialysine) as the selective agent, to obtain mutant Chinese hamster lung (CHL) fibroblasts with temperature-sensitive defects affecting protein synthesis. The procedure is efficient, rapid, and simple. Using this selective system, we isolated six temperature-sensitive mutants that fail to grow (plating efficiencies less than 10-5) and synthesize protein at 39 degrees C. The temperature-sensitive phenotype of five of the six mutants is suppressed in vivo by exogenous asparagine. In the mutant studied in the greatest detail, asparagyl-tRNA synthetase activity is extremely thermolabile in vitro. Asparagine-suppressible, temperature-sensitive mutants are induced at a high frequency by the mutagen ethylmethane sulfonate (EMS), and they can be efficiently recovered using the proper selective conditions. Our results suggest that CHL cells have only one functional copy of the gene encoding for asparagyl-tRNA synthetase.


Evidence of hormonal control of the nucleolar activity in Sciara ocellaris. The nucleolus organizing region in the salivary gland of Sciara ocellaris becomes gradually less active as the larvae approach pupation. The cytological visible condensation of the nucleolar puff is paralleled by a decrease in the incorporation of [3H]-uridine into the ribosomal RNA. Alterations in the nucleolar behavior were brought about by extirpation of the neuroendocrine glands at six stages of development. There is a 'critical stage' during the 7th day of the 4th instar when the hormonal stimulus for pupation occurs. If the ligature is performed before this stage the NOR remains expanded and the larval-pupal ecdysis is inhibited; if done later on the NOR condenses at a normal rate and the ligated larvae mount to head-less pupae. These results suggest that inhibition of rRNA synthesis and consequent condensation of the NOR is under the control of the moulting hormone.


Recombination of embryonic haemoglobin chains during the development of the chick. Embryonic differentiation is at present interpreted as the expression of variable gene activity. It is commonly thought that derepression of operator gene groups is the main cause of progress during development. However it is equally possible that gene repression plays a role in the appearance of new phenotypic characteristics. This paper illustrates such a possibility. It is known that in chickens embryonic haemoglobins exist which are replaced by other haemoglobins at about the sixth day of incubation. Analyses of globin chain composition of these haemoglobins by chromatography and urea/starch gel electrophoresis as well as TLC-fingerprinting and amino acid analyses of the individual globin chains showed that the haemoglobin switch was not associated with appearance of new globin chains but rather with disappearance of a number of embryonic chains. Moreover the relative proportion of the various chains changed at that time. From these findings we conclude that new haemoglobins arise from a recombination ('hybridization in vivo') of those globin chains which remain after the repression of a gene coding for embryonic chains.


Isolation of an acute hypotensive substance from bovine brain lipid fraction.


Azabicycloalkanes as analgetics. IV. 4-Phenyl-2-azabicyclo[2,2,1]heptanes.


The structures of toxic metabolites of Aspergillus candidus. II. The compound B (xanthoascin), a hepato- and cardio-toxic xanthocillin analog.


A comparison of 19-iodocholesterol-131I with 6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol-131I as an adrenal-scanning agent.


Autoradiographic studies on the distribution of quaternary ammonium compounds. IV. Adsorption of bisonium ions to rat tissues as revealed by in vitro whole-body adsorption autoradiography.


Further investigations of the effect of riboflavine photolysates on the intestinal absorption of certain drugs in rats and their mechanisms of action.


Fluorometric determination of cephalexin in urine.


Constituents from seeds of Alpinia galanga Wild, and their anti-ulcer activities.


Mechanism of the inhibitory effect of polysorbate 80 on intramuscular absorption of drugs.


Purification and characterization of hypocalcemic protein from porcine parotid gland.


Effect of ginseng saponins on nuclear ribonucleic acid (RNA) metabolism. I. RNA synthesis in rats treated with ginsenosides.


Antitumor effect of bisbenzylisoquinoline alkaloids.


Biosynthesis of streptothricin antibiotics. II. Catabolite inhibition of glucose on racemomycin-A production.


Synthesis of 4-d1-testosterone and 4-d1-androstenedione.


Studies on the syntheses of heterocyclic compounds. DCLXXI. An alternative total synthesis of yohimbine.


Intestinal absorption of drugs from solubilized systems of long-chain fatty acids in the rat.


Quantitative analysis of the isomers of hydroxyphenylalanine by ion-exchange chromatography.


Studies on prostaglandins. II. Synthesis of 4-alkoxymethyl-2-norbornen-5-one and its oxidation reaction with m-chloroperbenzoic acid.


Studies on prostaglandins. I. The resolution of dl-(2-beta-benzyloxymethyl-3alpha-hydroxy-4-cyclopenten-1alpha-yl)acetic acid using L-arginine).


Studies on the syntheses of analgesics. XLI Optical resolution of (+/-)-N-cyclopropylmethyl-3-hydroxy-9-azamorphinan (studies on the syntheses of heterocyclic compounds. Part DCLXIX).


Mass fragmentographic determination of d- and l-chloropheniramine with aid of the stable isotope technique.


Antitumor polysaccharide fraction from the culture filtrate of Fomes fomentarius.


Dissolution of slightly soluble drugs. II. Effect of particle size on dissolution behavior in sodium lauryl sulfate solutions.


The particle size evaluation of parenteral suspensions of chloramphenicol and correlation of particle size to plasma levels.


Studies on microcapsules. XIX. Effect of phospholipid treatment on cation uptake by carboxylated polyphthalamide microcapsules.


Synthesis of aristeromycin analogs.

Synthesis of aristeromycin analogs.


Synthesis of 7 alpha-methoxy-7-[2-(substituted thio)acetamido]cephalosporin derivatives and their antibacterial activities.


Determination of aldolase activity in serum.


Studies on benzoheterocyclic derivatives. XVI. Synthesis and analgesic action of benzofuran derivatives.


Effects of 1,2-benzisoxazole-3-acetamidoxime on central monoamine neurons in the rat.


Phosphorus in organic synthesis. XII. Amino acids and peptides. XXII. Reaction of penicillin sulfoxides with diethyl phosphorocyanidate (DEPC).


Physical properties of pyrimidine and purine antimetabolites. II. Permeation of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil through cellophane, collagen, and silicone membranes.


Analysis of the correlation between collagen and desoxyribonucleic acid syntheses under the influence of hydroxyurea in the inflammatory connective tissue.


Studies on drug metabolism by use of isotopes. XVII. Mass spectrometric quantification of urinary metabolites of deuterated l-ephedrine in man.


Molecular weight determination and the secondary structure of the hypocalcemic protein purified from bovine parotid gland.


Molecular orbital index-activity relationship between atrial antiarrhythmic activity and disopyramide derivatives.


Transmucosal fluid movement and intestinal drug absorption in alloxan diabetic rats.


Stimulation of serum protein synthesis in ginsenoside treated rat.


Metabolism of budralazine, a new antihypertensive agent. I. Identification of the metabolites of budralazine in rats.


Anticoccidials. I. Syntheses and anticoccidial activity of 2-amino-5-aryl-1,3,4-oxadiazoles, 5-alkoxy-3-aryl-1H-1,2,4-triazoles, and 3-aryl-delta2-1,2,4-triazolin-5-ones.


Multiple forms of rat kidney mutarotase.


Vespakinin-M, a novel bradykinin analogue containing hydroxyproline, in the venom of Vespa mandarinia Smith.


Fluorophotometric assay of proteins using hypochlorite-thiamine reagent.


Pharmacokinetics and effects of propranolol in terminal uraemic patients and in patients undergoing regular dialysis treatment. Propranolol blood and plasma levels were measured after a single oral dose of 40 mg in patients with chronic renal failure, in patients undergoing regular dialysis treatment, and in healthy volunteers. Peak levels were observed in all cases within 1.5 to 3 hours. However, peak blood and plasma concentrations of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 +/- 41 ng/ml) than those observed in the dialysis patients (47 +/- 9 ng/ml) and in the healthy volunteers (26 +/- 1 ng/ml). The apparent plasma clearance was also significantly reduced in the patients with chronic renal failure. The data suggest a reduced hepatic extraction in chronic renal failure patients. A significant increase in the fraction of the dose available to the systemic circulation was also found, together with a modification of apparent plasma half-life and volume of distribution in regular dialysis patients during the dialysis day as compared with the after-dialysis day. No extraction of propranolol by the dialyzer was noticed. Marked fluctuations in propranolol blood concentrations were also observed in patients on regular dialysis following continuous propranolol treatment. The suppressive effect of propranolol on plasma renin activity did not fully correlate with the hypotensive effect of the drug. On the basis of the reported data, propranolol should be used with great caution and at low doses in chronic renal failure.


Clinical pharmacokinetics in infants and children. Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs.


Photoepicutaneous testing with the chamber method. The chamber test, so far successfully applied to epicutaneous testing, proved to be suitable for photoepicutaneous testing as well. A simple and reliable method was developed by dividing the test areas (after removing the tests from the skin) into two equal parts, one for ultraviolet irradiation and the other for dark control. Variations in the amounts of the test substances had a slight influence on the size but not on the strength of the reactions.


Scindapsus dermatitis.

Scindapsus dermatitis.


Allergic contact dermatitis from propellants in deodorant sprays in combination with allergy to ethyl chloride. Allergic contact eczema from the use of deodorant sprays is sometimes caused by sensitization to the propellants. Positive reactions were seen in three patients when patch testing to Freon 11 (trichloromonofluoromethane). One patient also reacted to Freon 12 (dichlorofluoromethane). Another patient had an eczematous eruption after ethyl chloride was sprayed on the skin prior to taking biopsy. The two other patients showed strongly positive patch tests with this compound. Further investigations of the sensitizing capacity propellants with chemical resemblance have to be carried out to solve the problem of cross-sensitization.


Rejection of metal to metal prosthesis and skin sensitivity to cobalt. Metal to metal prostheses give satisfactory results in 90% of patients. About half of the failure rate may be due to allergic reaction to the metals involved, particularly cobalt. A total of 35 patients in this unsatisfactory group have been patch-tested; 16 were positive to metals, 13 to cobalt, 4 to nickel, and 2 to chromate. Only two patients showed any skin lesions - one a localized dermatitis round the knee joint from nickel sensitivity, and one to cobalt who had a widespread scattered circular erythematous lesion suggestive of a generalized allergic vasculitis. Patients requiring a metal/metal prosthesis should have a careful history taken for metal sensitivity and be patch-tested with the metals. All the patients in this investigation had metal/metal prostheses and no reaction was seen after metal/high density polyethylene implants. Titanium 318 may be a satisfactory substitute for cobalt chrome alloy if reactions are encountered.