Febrile convulsions--what do parents do?

To find out about the medical and parental management of children having their first febrile convulsion a hospital-based questionnaire study was carried out in which parents were asked what they did at the time. Fifty-four out of 89 parents brought their child directly to hospital while the remainder attempted to contact their general practitioner, usually successfully, and were then referred to hospital. Whichever course of action the parents chose the outcome was satisfactory. Eighty-seven per cent of convulsions lasted for less than 15 minutes and in only two instances did they last longer than 30 minutes. One child who had convulsions for an hour was given intramuscular phenobarbitone at home without success, and the fit was finally terminated with intravenous diazepam. Parental management of the fit was often widly inappropriate. Only a few parents laid the child on his side and waited for the fit to stop. The parents were bewildered and frightened--30% thought their child was dying or dead. Education of patents of young children is needed. Simply written instructions on how to reduce the temperature of a febrile child and manage a convulsion might help.


Consultation-liaison scheme for self-poisoned patients in a general hospital.

In a prospective clinical trial 276 self-poisoned patients consecutively admitted to hospital were randomly allocated to medical teams or to psychiatrists for an initial psychiatric assessment and a decision about "disposal." Junior doctors and nurses received instruction in this work. While awaiting the outcome of the trial the randomisation was continued for 13 months and 729 allocations were made altogether. Physicians requested psychiatric opinions for roughly one in five of their patients. In other respects medical teams performed similarly to psychiatrists. Provided that due attention is given to teaching junior staff and to ensuring that psychiatric treatment and social-work support are available once patients have been assessed, such a consultation-liaison scheme could be adopted in other hospitals. This would help to change unfavourable attitudes towards self-poisoned patients and contribute to the general training of doctors and nurses.


Travel and ischaemic heart disease.

The hypothesis that travel precipitates acute ischaemic heart disease (IHD) was tested in a case-control study of holidaymakers admitted to hospital in Great Yarmouth.  The distance that patients with IHD had travelled to reach Great Yarmouth was on average greater than that travelled by patients with other diseases. I conclude that the greater distances travelled by patients with IHD may have helped to precipitate the attack.


Psychiatric morbidity in men one week after first acute myocardial infarction.

One week after a first myocardial infarction 35 out of 100 consecutive men patients aged under 65 were found by standardised clinical interview to have psychiatric morbidity. In 16 the morbidity had been evident before the infarct, and these patients showed a wider range of psychopathology than those whose symptoms had been precipitated by the infarct. The results suggest that psychiatric morbidity in patients with heart disease is not necessarily a result of the disease process. Thus characterising psychiatric morbidity and identifying the patients' individual needs are important if rehabilitation is to be effective.


Jaundice after repeated exposure to halothane: a further analysis of reports to the Committee on Safety of Medicines.

Aanalysis of data derived from 170 reports of jaundice developing after anaesthesia with halothane received after January 1974 confirmed the relations between multiple exposure to halothane and jaundice and between the number of exposures and the rapidity with which jaundice develops after exposure. When these reports were combined with 130 received earlier complete anaesthetic histories were available for 251 patients, 205 (82%) of whom had been exposed to halothane more than once; of these patients, 154 (75%) had been exposed more than once within 28 days. Altogether 139 (46%) of the 300 patients died.


Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimer's dementia, but the precise role of the system in this disease remains to be elucidated.


Fluid loading to reduce abnormalities of fetal heart rate and maternal hypotension during epidural analgesia in labour.

Fetal heart rate (FHR) was recorded and maternal blood pressure measured in 104 patients in whom lumbar epidural analgesia was induced in labour. Fifty-one patients received an intravenous load of 11 of Hartmann's solution immediately before the epidural injection. This infusion significantly reduced the incidence of abnormalities of FHR from 34% to 12% and of maternal hypotension from 28% to 2%. We did not study mothers with pre-eclampsia and hypertension, but we conclude that there is a strong case for preloading all other mothers in whom lumbar epidural analgesia is induced in labour.


Altered bile in diabetic diarrhoea.

The size and composition of the bile-salt pools in a group of diabetics with neuropathy but no diarrhoea and a group with "diabetic diarrhoea" were compared with those in a group of stable, uncomplicated diabetics. The diabetics with neuropathy had significantly more dihydroxy bile salts, a larger bile-salt pool, and a higher faecal excretion of bile than the controls. The diabetics with diarrhoea had significantly more dihydroxy bile salts, a higher glycine to taurine ratio, a smaller bile-salt pool, and increased excretions of 14C-tracer and total bile salts. We conclude that considerable alterations occur in the bile of diabetics with neuropathy or diarrhoea, and we suggest that in some cases at least these abnormalities may indicate a mechanism for diabetic diarrhoea.


Some observations on the binding patterns of alpha-bungarotoxin in the central nervous system of the rat.

Patterns of alpha-bungarotoxin (alphaBuTX) binding within the brain of the rat have been studied following one of the two procedures: (1) the intraventricular injection of 125I-labeled toxin followed by a survival period of 1--8 days before aldehyde perfusion, or (2) the incubation of fresh cryostat sections of brain tissue in dilute solutions of radioactive toxin. Appropriate controls with nicotine, curare, atropine and native alphaBuTX established that specific nature of the binding. The principal observations were that toxin binding sites are predominantly associated with central areas of the brain in direct receipt of sensory inputs (the main and accessory olfactory bulbs, superior colliculus, ventral lateral geniculate nucleus, cochlear nuclei, the substantia gelatinosa of the spinal cord and spinal trigeminal nucleus, the principal sensory nucleus of the trigeminal, and the dorsal column nuclei) and with limbic areas of the brain (hippocampus, amygdala, olfactory tubercle, medial mammillary nucleus, and the dorsal tegmental nucleus of Gudden). Toxin was not found to bind to cranial motor nuclei with the exception of the dorsal motor nucleus of the vagus and the nucleus ambiguus. The discrete distribution of clusters of silver grains within the granule layer of cerebellar folia I, IX, and X is described as well as the heavy labeling of the inferior and accessory olivary nuclei. In many areas of the brain silver grains were found to overlie cell bodies. It is suggested that this may reflect the presence of both membrane-bound toxin and internalized ligand following initial binding to a membrane receptor site. An attempt was made to correlate the localization of toxin binding sites with the terminal distributions of previously described cholinergic pathways. There appears to be a reasonably good agreement between the distribution of toxin receptors and proposed sites of cholinergic transmission within the hippocampus, interpeduncular nucleus and cerebellum. In most other cases however, lack of data precluded such correlations. The anatomical relationship of alphaBuTX binding activity and neurotransmitters other than acetylcholine is also considered.


Synaptic enhancement in fascia dentata: cooperativity among coactive afferents.

Evidence is presented that long-lasting enhancement of perforant path synapses following high-frequency activity is a cooperative process requiring coactivity of a considerable number of fibers. This was demonstrated in two ways: (1) A threshold stimulus intensity during high-frequency stimulation was required before any enhancement was observed. This threshold was considerably above the stimulus threshold for observing a minimal synaptic response in the fascia dentata. Above the enhancement threshold, the amount of enhancement increased as the intensity of high-frequency stimulation increased. (2) Concurrent high-frequency activation of fibres of the medial and lateral perforant path produced enhancement at intensities where identical but independent stimulation of the two pathways either failed or was less effective. Discharge of the granule cells during the high-frequency stimulation was independently manipulated and found not to be physically coupled to the enhancement generating mechanism.


Total colonic aganglionosis.

This study is based on 17 neonates suffering from total colonic aganglionosis. The male:female ratio was 2:3 and there was a significant familial occurrence. The ages on admission varied between 1 and 90 days. The clinical presentation was extremely variable. Early diagnosis depends on clinical awareness of the condition in neonates who have intestinal obstruction or diarrhea, or both. The most important radiologic indication was retention of barium for 24 hours. Results of manometric studies were misleading. Suction biopsy of the rectum provided the only sure method of  diagnosis, although determination of cholinesterase activity in the biopsy specimen and in the patient's serum was of some value. Two patients died before operation and two died from total colonic and small intestinal aganglionosis. Eight patients survived both the initial ileostomy and subsequent pull through operation. Of the various procedures utilized, the Lester Martin operation has proved to be the most satisfactory.


Staging laparotomy for Hodgkin's disease in children.

Resort to laparotomy for the staging of Hodgkin's disease has been controversial because of its questionable advantage over nonsurgical staging methods. The recent concern over splenectomy and subsequent overwhelming infection has added to this debate. The author reviews experience with Hodgkin's disease in 34 patients whose ages ranged from 6 to 18 years. Seventeen patients underwent staging laparotomy after their disease had been staged by standard nonoperative methods; the duration of follow-up was from 2 to 7 years. In 7 of these 17 patients the stage of their disease was changed as a result of the laparotomy findings. Complications have been late septicemia resulting in death in one patient and subacute bowel obstruction not requiring reoperation in two patients. In the author's opinion staging laparotomy in children with Hodgkin's disease is a valuable means of deciding on their subsequent therapy.


Fine needle aspiration biopsy in the management of palpable breast lesions.

During a 34-month period 2050 fine needle aspiration biopsies of solid or cystic palpable breast lesions were performed. Of the 1182 patients with solid lesions, 384 underwent 405 surgical procedures. Carcinoma was the histologic diagnosis of 118 lesions. Of these, aspiration cytology had identified 92 (78%) as malignant; in 13 (11%) a malignant condition was suspected; 9 (7.6%) had been falsely assessed as benign. Cytology reports were accurate in 237 (83%) of the 287 histologically confirmed benign lesions. There were no false-positive reports. The 243 patients with cystic lesions underwent 572 aspirations for diagnosis and as treatment. Four lesions were excised and found to be benign. Needle aspiration biopsy is a most valuable tool. It is safe, simple, quick, repeatable and easily accepted by patients. Its positive predictive value is excellent (100% in our series). Cytology reports negative for malignant change should be disregarded if cancer is suspected clinically.


Expanded polytetrafluoroethylene prosthetic grafts for blood access in patients on dialysis.

The difficulties in maintaining vascular access in patients on long-term hemodialysis are well recognized. The author's experience with bovine grafts in such cases had been that late failure from sepsis or thrombosis was common, as reported in the literature by others. In May 1976 the expanded polytetrafluoroethylene (PTFE) prosthesis became the substitute of choice as a vascular graft. In the last 18 months these grafts have been placed as subcutaneous arteriovenous fistulas in 22 patients. Three early failures occurred as a result of graft thrombosis but one graft was salvaged by thrombectomy using a Fogarty catheter. Two late failures occurred, one after 3 and another after 6 months. All other grafts are functioning satisfactorily. Expanded OTFE grafts provide satisfactory vascular access for maintenance hemodialysis in selected patients and their use may prove to be the procedure of choice for hemodialysis in small children.


Radionuclide test for gastric bile reflux.

The authors conducted a study using radioactive endogenous bile to detect gastric bile reflux in healthy volunteers and patients suspected of having bile gastritis. When 7 muCi of pyridoxylideneglutamate of hydroxyiminodiacetic acid labelled with technetium-99m is injected intravenously it is excreted by hepatocytes, and sequential gamma camera images visualize the bile ducts and show subsequent activity in the gut. Following such an injection, the authors determined the presence of isotope-labelled bile in the stomach in fasting subjects by assaying count rates in serial gastric aspirates obtained by means of a nasogastric tube positioned in the antrum. The results were related to the clinical history and gastroscopic findings. In normal persons only extremely low counts were detected, possibly due to free activity; high counts (in excess of 50 000/min) indicated abnormal reflux. It is suggested that this test is a useful adjunct, and is more physiologic than endoscopy, in the assessment of bile reflux.


Effect of wheat bran on serum lipoproteins and biliary lipids.

In this study nine patients with gallstones and nine healthy volunteers were given a high bran diet for 4 weeks. At the outset and at 4 weeks bile specimens were obtained for determination of biliary lipid values, size of the bile-acid pool and bile-acid ratios, and blood specimens were drawn to determine the serum concentration of triglycerides and of lipoprotein-bound cholesterol. Three patients with gallstones remained on the high bran diet for 6 months or more and samples were analysed again. The high bran diet produced a substantial decrease in biliary cholesterol values in patients with gallstones after 4 weeks, and a significant increase in the concentration of high density lipoprotein-cholesterol in the serum of patients who course was followed for 6 months or longer.


Mediastinoscopy for diagnosing diseases of the lung other than primary carcinoma.

Mediastinoscopy is an efficient method of assessing lymphatic spread in carcinoma of the lung. It is also valuable in providing a definitive diagnosis of other lung diseases. At the Montreal Chest Hospital Centre diagnostic mediastinoscopy was performed in 60 patients with diseases of the lung other than primary carcinoma. All had preoperative radiologic evidence of hilar adenopathy. A definitive diagnosis was obtained in 91.7% of cases. Nonspecific adenitis was diagnosed in four patients and in none was there evidence of serious intrathoracic disease subsequently. Morbidity was minimal and there were no deaths. Mediastinoscopy is a safe, accurate and efficient aid in the evaluation of primary or secondary disease of the anterior intrathoracic lymphatic system.


Peripheral arterial insufficiency due to giant cell arteritis.

Progressive peripheral arterial insufficiency developed in a 53-year-old man who was referred for investigation of fever of unknown origin. Angiograms showed a smooth beaded appearance to both deep femoral arteries and biopsy of an occluded popliteal artery disclosed the lesions of giant cell arteritis. An excellent clinical response was obtained with steroid therapy.


Orthopedic outpatient surgery.

Changes in provision of health care by the province of Ontario have included forced reduction in the number of hospital beds. In this situation the needs of patients with orthopedic disabilities have been met by a dramatic increase in outpatient surgery. At the Hotel Dieu Hospital, Kingston, the total number of surgical procedures increased from 5516 in 1970 to 7260 in 1975. During this period the number of outpatient surgical procedures performed under general anesthesia rose from 820 in 1970 to 2927 in 1975, an increase of 264%. Of 1197 orthopedic procedures performed in 1975, 632 (52%) were performed on an outpatient basis. In the author's personal experience of outpatient surgery, which in 1975 included 38 meniscectomies, 10 major shoulder repairs, 28 foot reconstructions, 11 nerve releases, 14 tendon releases and 4 elbow arthroplasties, patient acceptance has been good. Adequate clinic facilities, trained nurses, appropriate anesthesia and patient education are essential if management in this locale is to be successful.


Compression treatment of hypertrophic scars in burned children.

The formation of hypertrophic scars is common following healing of the burn wound, particularly in children. The control of scar formation is an important part of overall treatment in these cases and this paper describes a newer method that applies compression to the burn scar in an attempt to improve the ultimate appearance. The 35 patients treated by this method included some with partial-thickness and others with full-thickness burns. The results of treatment with compression garments were assessed at 6 months and at 12 months, using a grading system based on colour, consistency and thickness of the scar. The design of facial moulages and their use in compression of facial scars are dealt with. Overall there was a 75% to 80% improvement in the state of burn scars. The reasons for this improvement are discussed.


Major amputation following vascular reconstructive procedures (including sympathectomy).

To study the effects of vascular reconstruction or sympathectomy, or both, on the level of amputation, the number of revision procedures performed and the mortality following amputation, the authors reviewed the records of 504 patients from three Toronto teaching hospitals who had one or both limbs removed at or above the below-knee level. It appears that (a) previous vascular surgery or sympathectomy, or both, actually increases the number of patients in whom a below-knee amputation is successful, (b) the number of revision procedures necessary is increased after failed vascular surgery or sympathectomy, or both and (c) revision procedures following amputation do not affect the mortality from lower limb amputation.


Bilateral carcinoma of the breast: frequency and mortality.

Of 3558 women with cancer of the breast, 129 were found to have bilateral primary cancers. In approximately one quarter (33) of these women the two cancers developed synchronously; in the remainder (96) the second cancer developed metachronously, more than 6 months after the appearance of the first primary tumour. In two thirds (64) of the women in the latter group the second cancer made its appearance within 4 years after the first was detected. The 15-year survival curve for the 129 patients shows a 50% mortality at approximately 10 years, slightly better than that for the total group of 3558. At the time of our study (April 1975) 70 were alive and 59 were dead; 53 died as a result of their breast cancer and 6 from other causes. Only 3 of the 48 women in whom the first cancer developed before the age of 70 years died of causes other than breast cancer, giving a mortality due to breast cancer of 90%. The clinical stage, the recorded histopathology, the type of operation and the duration of time at risk after the first diagnosis did not differ significantly between those who lived and those who died. The authors conclude that age, stage or type of growth, operative therapy or time at risk do not determine the time of death or alter the 90% certainty that death will be due to carcinoma of the breast.


Esophagoatrial fistula.

The author describes a case of esophagoatrial fistula--an extremely rare condition. A 79-year-old-man had had epigastric pain for 4 weeks. Physical and roentgenographic examinations disclosed atrial fibrillation with a systolic murmur and an ulcer of the lower esophagus which, on histologic examination, was benign. No specific treatment was recommended. The patient died suddenly 3 months later from massive gastrointestinal hemorrhage which, at autopsy, was found to be due to an esophagoatrial fistula. A review of the literature showed that this case differed from others previously reported in that the duration of symptoms up to the time of death was only 4 months and the patient had no embolism.


24-hour infusion of cis-platinum in head and neck cancers.

Eighteen patients with advanced squamous cell cancer of the head and neck were treated with cis-diamminedichloroplatinum in a 24-hour infusion. The most frequent dose used was 80 mg/m2 repeated every three weeks. Six were treated preoperatively for Stage III or IV disease, and twelve were treated for recurrent disease. The overall response rate was 72% with one complete remission, greater than 50% regression in six patients, and 25--50% regression in six patients. Toxicity was minimal: creatinine greater than 2 in 6% of courses, leukopenia in 9%, anemia in 29%, vomiting in 76%, and documented minimal hearing loss in one patient. Plasma and urine platinum levels during infusion are presented. The dosage of 80 mg/m2 administered over 24 hours gives a response rate in head and neck cancers equivalent to that reported with higher doses given by rapid infusion, and toxicity is minimal.


o,p'-DDD (mitotane) therapy of adrenal cortical carcinoma: observations on drug dosage, toxicity, and steroid replacement.

Four patients with adrenal cortical carcinoma were treated with standard doses of o,p'-DDD. Plasma levels of o,p'-DDD and its metabolites o,p'-DDA and o,p'-DDE were measured. o,p'-DDD was measurable for up to 8 months after stopping therapy, and trace levels of metabolites were detectable at 18 months. Although 2 of 3 patients with measurable disease had objective tumor response and one patient achieved a complete response, severe drug toxicity occurred in all patients and signs of adrenal insufficiency occurred in three. Low dose therapy with o,p'-DDD is suggested, together with full gluco and mineralocorticoid replacement. Measurement of o,p'-DDD and its metabolites in plasma may prove clinically useful in developing effective but less toxic dosage schedules.


An evaluation of protracted low dose rate irradiation from an acute dose survival curve.

A method of transformation from an acute survival curve to a protracted low dose rate survival curve based on the concept of the dose equivalent sublethal damage advanced by Oliver is introduced. The transformation was done by solving a differential equation which was formulated between the slope of both survival curves and which was able to be applied to the situation where the dose rate might change with time, e.g., in using short-life radioisotope or the complexity of the recovery of sub-lethal damage. The effects of the short-life radioisotopes (radon seeds and radiogold grains) in radiotherapy were estimated by using this method and applying it to Lajtha-Oliver's model; our data are compared with the data obtained by Orton.


Responses of patients with neoplastic diseases to influenza virus vaccine.

Little information is available concerning influenza immunization in patients with malignancies receiving chemotherapy. A large number of ambulatory patients are receiving chemotherapy for metastatic disease as well as adjuvant chemotherapy for microscopic disease, and they should be considered at higher risk for complications should they contract influenza. Seventeen oncology patients and 15 control subjects were given bivalent influenza vaccine (A/NJ/76-A/Vic/75) and their serologic responses were monitored. Although their responses were less than controls, nearly 50% of the oncology patients had a greater than fourfold rise in antibody titer, suggesting that a humoral antibody response could be achieved in spite of their underlying disease and immunosuppressive chemotherapy. No adverse reactions or deterioration of patient's clinical status were noted with vaccination. We conclude that significant antibody titer responses can be achieved in this population of patients.


Chromosome studies in preleukemic states. IV. Myeloproliferative versus cytopenic disorders.

The prognostic value of marrow chromosome studies was examined in 112 "preleukemic" patients followed for at least one year or until death. Based on recent definitions, 49 patients were classified as myeloproliferative disorders (MPD) (polycythemia vera, myelofibrosis, undifferentiated myeloproliferative disorder, essential thrombocythemia), and 58 as cytopenic states (refractory anemia, pancytopenia). In each group, approximately one-third had a chromosomally-abnormal clone. For MPD, this had little predictive value, but in the cytopenias, 77% with a cytogenetic abnormality developed leukemia versus 39% without. Twelve cytopenic patients had multiple alterations involving more than 2 chromosomes and 11 died within 6 months, 9 with leukemia. Such patients may warrant consideration for aggressive chemotherapy before the appearance of clinical leukemia. Banding studies did not reveal any specific chromosome abnormalities consistently associated with these various preleukemic disorders, or with progression to leukemia, but nonrandom alterations were noted involving chromosomes 1, 5, 7-9, and 20 in the MPD group, and chromosomes 6 and 16 in the cytopenic patients. Correlation of these data with other reports indicates that certain cytogenetic abnormalities involving specific segments of the human genome confer a selective growth advantage on hemic clones which may present clinically as either preleukemia or leukemia.


Banding studies of chromosomes in a patient with mycosis fungoides.

Chromosomes from a patient with mycosis fungoides were examined in detail with banding techniques. Hyperdiploid cells from a lymph node had common anomalies of certain chromosomes which formed three similar clones. The abnormalities involved chromosomes No. 1, 2, 5, 8, 9, 10, 14, and 18, in addition to an unkwown small metacentric marker (M3). Although there were a number of mitotic cells in peripheral blood cultured both with and without PHA, none of the few cells with abnormal karyotypes was similar to the clonal cells of the lymph node. One of the abnormalities in the lymph node was a 14q rearrangement, which could be the result of a translocation of Nos. 8 and 14 involving a third chromosome, No. 2. An abnormality in the blood resulted from a translocation between the long arms of Nos. 1 and 14. These findings could be useful for studies in which mycosis fungoides is compared with the Sézary syndrome and other lymphoid malignancies.


Heterotransplantation of human cancers into nude mice: a model system for human cancer chemotherapy.

More than 200 human cancers have been successfully transplanted into nude athymic mice in our laboratory. Strict sterile techniques must be applied in caring for these animals and meticulous attention given to the preparation of the surgical specimens. That the tumors remain human in the mice has been documented by isozyme and karyotype analyses. Also, histopathologic comparisons between the original human tumors and their transplanted counterparts in the mice are strikingly similar or identical. Preliminary results of chemotherapy of human cancers in the nude mice are extremely encouraging. At this point, we believe that the greatest potential for the nude mice lies in their use in testing anticancer therapies for human neoplasms without placing the patients at risk.


The regressing thin malignant melanoma: a distinctive lesion with metastatic potential.

To validate the supposition that thin malignant melanomas (less than 0.76 mm thick) of ordinarily low risk but with areas of regression may paradoxically metastasize, we observed 121 thin malignant melanomas over a six year period. Of these, 23 displayed readily apparent areas of regression, of which five (21.7%) metastasized. The incidence of metastases in their 98 counterparts without regression was 2.0% (2/98). The difference between the two is statistically significant (p = less than .01). Of the entire group of the two is statistically significant (p = less than .01). Of the entire group of thin melanomas, those with regression represented 19.0% (23/121) yet accounted for a disproportionate 71.4% (5/7) of all metastases. We conclude that regression is a relatively poor prognostic sign, whose occurrence within an otherwise thin melanoma represents a significant caveat to the current histologic staging system that equates thinness with low risk. We thus submit that patients whose malignant melanomas display regression be followed rigorously for evidence of metastases irrespective of the tumor's actual measured thickness or level of invasion.


Trabecular carcinoma of the skin: an ultrastructural study.

We report the electron microscopic studies of three trabecular carcinomas of the skin. The presence of neurosecretory granules in all three tumors suggests that trabecular carcinoma originates from one of the neurocrest derivatives, most probably, Merkel cells. The ultrastructural findings confirm Toker's original concept that trabecular carcinomas comprise a distinct group of skin tumor. The recognition of these tumors would enable one to make such a diagnosis on frozen section, which, in turn, might provide an opportunity for more specific cytochemical and immunofluorescent characterization.


Immunoblastic lymphadenopathy associated with methyldopa therapy: a case report.

The case of a 71-year-old woman who developed generalized weakness, lymphadenopathy, and a skin rash during methyldopa therapy is described. The prompt disappearance of symptoms following the discontinuation of the drug implicates it in the initial triggering of the abnormal lymphoid proliferation. Shortly thereafter, florid immunoblastic lymphadenopathy developed, and the patient subsequently responded to corticosteroid therapy. The frequent occurrence of immunoblastic lymphadenopathy during or shortly after the administration of various therapeutic medications is emphasized. The nature of the disorder and its differential diagnosis are discussed.


Ectopic production of human chorionic gonadotropin in malignant tumors.

The prevalence of human chorionic gonadotropin (hCG) was estimated by measuring immunoreactive hCG in plasmas and tumor tissues from patients with various neoplasms. To detect small amount of plasma hCG in the presence of luteinizing hormone (LH), plasma hCG level was measured by heterologous radioimmunoassay using anti-hCG-beta antiserum and compared with plasma LH level measured by heterologous radioimmunoassay using anti-LH-beta antiserum. All 56 samples obtained from control subjects were found to be negative for hCG, while 10 of 100 plasma samples from patients with malignancies were positive for hCG. The prevalence of hCG in 64 tumor tissues was 42% (27/64); it was 32% (8/25) in so-called amine precursor uptake and decarboxylation (APUD) tumors and 49% (19/39) in non-APUD tumors. The difference in the prevalence of hCG in APUD vs. non-APUD tumors was not statistically significant. However, the amounts of hCG in APUD tumors were found to be less than 50 ng/g wet tissue, whereas those of non-APUD tumors ranged from several ng to thousands of ng/g wet tissue. These results suggest the APUD tumors produce less amounts of hCG than do non-APUD tumors.


Characterization of an ovarian carcinoma cell line.

A long-term ovarian carcinoma cell line is described in terms of its morphology, original histopathology, electron microscopic features and chromosome features before and after transplantation into an athymic nude mouse. The microscopic features of the tumor nodule grown in the nude mouse are compared with the original pathology. Epithelial characteristics of the cells were maintained in culture and after retrieval from the nude mouse. Three markers were identified in all karyotypes and trisomy was noted in chromosomes 1, 2, 3, 6, 11, 12, 16, and X and monosomy of 17 and 21.


Prolymphocytic leukemia: clinical, histopathological, and cytochemical observations.

The clinical, histopathological, and cytochemical features of eight patients with prolymphocytic leukemia, a rare variant of chronic lymphocytic leukemia, were reviewed. Six of the patients had clinical evidence of "massive" splenomegaly at the time of diagnosis, and in four of these this clinical impression was confirmed by splenic weights in excess of 2000 g. No patient had significant lymph node enlargement. The initial leukocyte count was elevated in seven patients and was greater than 100 X 10(9)/1 in four of them. The absolute prolymphocyte count ranged from 16.3 to 378.1 X 10(9)/1 and was greater than 100 X 10(9)/1 in four patients. Splenectomy in four patients had no lasting effect on the peripheral leukocyte count. In the four patients in whom the disease was shown by surface marker or immunocytochemical studies to be of B-cell origin, the histopathologic features were distinctive and were characterized by a pattern of infiltration which was nodular and diffuse in both the splenic red pulp and the bone marrow, whereas involvement of the lymph nodes was pseudonodular. In one patient in whom the prolymphocytes had cytochemical characteristics suggestive of T-cells, the distribution of the abnormal cellular proliferation in the lymph nodes was paracortical and the infiltrations of the spleen and the bone marrow were diffuse.


Variables predictive of bone marrow metastasis.

Metastasis to bone marrow, though frequently occult, is an important clinical finding. Variables which correlate with carcinoma metastatic to bone marrow were studied retrospectively in 103 patients with malignancy whose bone marrow biopsies demonstrated metastatic disease. Sixty-six patients with metastatic cancer whose bone marrow biopsies were negative, served as controls. Since no single finding was diagnostic of marrow cancer, multiple variables were analyzed by stepwise discriminate analysis program. The four parameters which strongly correlated with marrow involvement were the leukoerythroblastic blood pattern, a serum lactic dehydrogenase over 500 IU/liter, a platelet count under 100,000/microliter and bone pain. Four parameters correlated less well and included a positive bone scan, hematocrit under 30%, uric acid over 10 mg/dl and blood urea nitrogen over 25 mg/dl. These data should help the clinician select those cancer patients with a high probability of marrow involvement.


Ultrastructural studies on neuroblastoma: evaluation of cytodifferentiation and correlation of morphology and biochemical and survival data.

Fifteen cases of neuroblastoma, ganglioneuroblastoma and ganglioneuroma were studied by electron microscopy. Ultrastructural features of cytodifferentiation, including numbers of dense core neurosecretory granules (NSG) and neuritic processes, were used to evaluate variation within the neuroblastoma group to determine whether differences in cytodifferentiation exist where light microscopic variations are not evident. These studies revealed that undifferentiated neuroblastomas do show ultrastructural variations not evident by light microscopy. The ultrastructural findings for each case were compared with initial urinary catecholamine excretory patterns, the latter having recently been shown to have valuable prognostic significance. There was a positive correlation, in the undifferentiated neuroblastomas, between increased numbers of NSG and prognostically favorable biochemical excretory patterns. Conversely, low numbers of NSG were associated with an unfavorable biochemical pattern and fatal clinical course. These correlations between ultrastructural differentiation and the biochemical secretory pattern indicate that ultrastructural evaluation of undifferentiated neuroblastomas would appear to have prognostic value, particularly in cases lacking initial biochemical data or as an adjunct to biochemical studies.


Nonepithelial tumors of the nasal cavity, paranasal sinuses and nasopharynx. A clinicopathologic study. IX. Plasmacytomas.

Plasmacytomas occasionally may arise in extraosseous sites, of which the upper respiratory tract is the most common. In our series of 256 nonepithelial tumors involving the nasal cavity, paranasal sinuses and nasopharynx, 10 (4%) were apparently primary extramedullary plasmacytomas. Of our patients with adequate follow-up information, four died of disseminated disease 2, 4, 5 and 6 years after the initial diagnosis. One was alive 6 years after diagnosis with locally persistent tumor. Another was living without recurrence 12 years later. Based on our findings and on the cases reported in the literature, extramedullary plasmacytomas arising in the head and neck area may evolve into one of several different patterns. 1) Some patients have localized disease which is apparently controlled (by surgery, radiotherapy or both) and which never recurs locally or becomes disseminated. 2) In some cases, the tumor recurs locally and is controlled by further therapy. 3) Other patients have a locally persistent and aggressive lesion which cannot be eradicated and which eventually leads to the patient's death by uncontrolled local growth. 4) Still other patients eventually develop evidence of plasma cell neoplasms elsewhere in the body and/or multiple myeloma.


Metastasizing pleomorphic adenoma of the salivary gland.

A case of metastasizing pleomorphic adenoma in which both the primary tumor and metastasis were composed of benign pleomorphic structures is reported and previously reported cases reviewed. The metastasis commonly developed many years after the excision of the primary tumor and was usually preceded by local recurrences. The most common sites of metastasis were the bone and lung. Mitotic activity and infiltrative growth pattern are the histologic features in the primary tumor important in predicting the metastasizing potential. The treatment of choice for the metastatic tumor appears to be surgical excision. Radiotherapy seems to have a limited role other than providing temporary palliation.


Hemangiopericytoma: a clinicopathologic, angiographic and microangiographic study.

A clinicopathologic study of 11 hemangiopericytomas is reported, and the results of clinical angiography in 4 patients and a correlated microangiographic-histologic study of 1 tumor are presented. Six of the tumors were collected and accepted as hemangiopericytomas in a review of 42 tumors registered as hemangiopericytoma in the Swedish Cancer Registry during the period 1958--1968. The other 5 tumors occurred in patients treated by us. The histologic examination and the follow-up information showed that it can be difficult to predict the prognosis on morphologic grounds, that borderline tumors exist and that a recurrence as well as a metastasis may dedifferentiate. The tumors studied by clinical angiography all proved to be highly vascular. Irregular vessels of varying caliber were filled with contrast medium and, in addition, a prominent diffuse opacification took place. Early filling of veins was not noted despite the high vascularity. The correlated microangiographic-histologic study suggests that the irregular vessels seen on clinical angiograms corresponded to wide, angulated, thin-walled vessels without muscle coat or elastic tissue, while the diffuse opacification was caused by a dense network of delicate, branching, slit-like capillary spaces.


Carcinoembryonic antigen in carcinoma of the uterine cervix. 1. The prognostic value of serial plasma determinations.

Plasma carcinoembryonic antigen (CEA) determinations were obtained prior to therapy in 300 patients with invasive carcinoma of the uterine cervix followed at the University of Kentucky Medical Center from 1971 to 1976. Carcinoembryonic antigen levels were elevated (greater than 2.5 ng/ml) in 48% of cervical cancer patients, and varied directly with stage of disease and histologic differentiation of the tumor. Plasma CEA levels were more commonly elevated in patients with endocervical adenocarcinoma than in those with squamous cell carcinoma, but were not related to vascular invasion in the specimen or regional lymph nodal morphology. Two hundred and four patients had 2 to 15 (mean = 5) follow-up plasma CEA determinations after treatment. Thirty patients had progressively increasing plasma CEA levels following therapy, of which 29 developed recurrent cervical cancer. A progressive rise of plasma CEA preceded the clinical diagnosis of recurrence by 1 to 23 months (mean = 6 months) in 13 of these patients, and occurred at the same time or after the clinical diagnosis of recurrence in 16 cases. Patients with progressively rising plasma CEA levels following therapy for cervical cancer should be extensively evaluated to rule out the presence of occult recurrence.


Clear cell carcinoma of the uterine endocervix with an in situ component.

In the past all clear cell carcinomas of the female genital tract were thought to arise from mesonephric remnants. Recently increasing evidence has related their origin to müllerian rather than mesonephric epithelium. One of the main reasons that has been advanced to support their mesonephric origin has been their occurrence in the uterine cervix and vagina, sites of mesonephric remnants. However, no clear evidence for mesonephric origin of clear cell carcinoma of the cervix and vagina has been ever provided. In contrast, there is substantial evidence that diethylstilbestrol-related clear cell carcinomas of the cervix and vagina are müllerian in origin. We report here a case of an exophytic clear cell carcinoma with an in situ component, involving the endocervical epithelium. The in situ lesion clearly indicates müllerian origin of the tumor, which occurred in the absence of prenatal exposure to diethylstilbestrol. This supports the general agreement that clear cell carcinomas of the cervix are müllerian in origin, whether diethylstilbestrol-related or not.


The changing trends of uterine cancer and cytology: a study of morbidity and mortality trends over a twenty year period.

Data on squamous carcinoma of the cervix from a 20 year study period (1955 to 1974) in metropolitan Toledo revealed a 66% reduction of the average annual age-adjusted incidence rate and a 61% reduction in death rate of cervical squamous carcinoma when the first time period (1955 to 1958) was compared with the last time period (1971 to 1974). The decrease for both morbidity and mortality rates was more pronounced in women age 50 years and younger. The age-adjusted death rate during this study period revealed 15.5/100,000 for black women and 8.7/100,000 for white women. The reduction in death rate of 83% in black women is more prominent than 54.5% in white women. The decrease in both morbidity and mortality for cervical squamous carcinoma has a close relation to cytologic screening activity. The factors of age and race, probably related to socioeconomic status, are two known determinants of risk for cervical squamous carcinoma. Data for endometrial carcinoma during this study period revealed 15.5/100,000 women in the average age-adjusted incidence and an increase of 13.8% in average yearly rates when the first time period (1955 to 1958) were compared with the last time period (1971 to 1974). The peak age was 60 to 64 years old in the first time period and shifted to 70 to 74 years old in the last time period. The trend in metropolitan Toledo is comparable to that of Louisville, Kentucky. The mass cytologic screening program which contributed to a remarkable reduction in morbidity and mortality for the cervical squamous carcinoma, did not have any beneficial effect on endometrial carcinoma.


Malignant histiocytosis: report of five Chinese patients.

Five Chinese patients with malignant histiocytosis are described, the diagnosis being based on microscopic evidence of infiltration of at least three different tissues by noncohesive atypical phagocytic histiocytes, without total obliteration of normal architecture of those tissues. The mean age of the patients was 28 years; all presented with pyrexia (of 2 weeks to 2 1/2 years duration) and all had circulating neoplastic cells. Two patients showed remission with quadruple chemotherapy and one is alive and without symptoms 6 years after onset of his illness.


Solitary meningocerebral metastasis from squamous cell carcinoma of the esophagus: a case report.

A case of a solitary meningocerebral metastasis from an esophageal carcinoma is described and the rarity of such an occurrence, as compared with cerebral metastases from other organs, is stressed. A possible metastatic pathway from the esophagus to the brain through the vertebral veins is postulated.


Gallbladder disease and gallbladder cancer among American Indians in tricultural New Mexico.

Previous studies have reported high rates of gallbladder disease and gallbladder cancer among all American Indians. Data from the New Mexico Tumor Registry confirm these findings, specifically showing high rates for New Mexico's American Indians, as well as for the state's Spanish population. This review explores several risk factors, including parity, obesity, age, cholesterol level, and genetic factors. From the available evidence, genetic factors appear to be the most important, with parity a contributing factor.


A retrospective study of 131 cases of carcinoma of the posterior pharyngeal wall.

Between 1958 and 1973, 131 patients with carcinoma of the posterior pharyngeal wall were treated at the Institute Gustave-Roussy (127 men, 4 women, mean age 61 years). Nine had a tumor of the oropharynx, 37 of the hypopharynx and 85 of the oro-hypopharynx. Nine had T1 tumors, 19 T2 and 103 T3 (TNM-UICC 1975). 122 patients were treated by irradiation: 83% were T3 lesions, 81% were more than 4 cm in diameter, 80% were ulcerated and 42% were staged N3. The survival rate of these patients was very poor (3% at five years). The nine patients who had been treated by surgical excision had a better survival rate and three are alive at 5 years, but the initial prognostic factors were better in this group. It seems that the indications for surgery should be widened to increase the survival rate in these poor prognosis cancers.


Effect of dietary undegraded carrageenan on colon carcinogenesis in F344 rats treated with azoxymethane or methylnitrosourea.

The effect of dietary undegraded carrageenan (Viscarin 402) on colon carcinogenesis was studied in female inbred F344 rats. Weanling rats were fed semipurified diets containing 0 or 15% undegraded carrageenan. At 7 weeks of age, all animals except controls were given azoxymethane (AOM) s.c. at a dose rate of 8 mg/kg body weight per week for 10 weeks or methylnitrosourea (MNU) intrarectally at a dose level of 2 mg/rat twice a week for 3 weeks. The AOM groups were autopsied 40 weeks and the MNU groups 30 weeks after the first injection. No tumors were induced in the colon or in other organs of untreated rats fed the control diet. One untreated rat fed the carrageenan diet showed a colon adenoma. The animals fed the carrageenan diet and treated with AOM or MNU had a higher incidence of colorectal tumors (number of rats with colorectal tumors and number of tumors per tumor-bearing rat) than did those fed the control diet and treated similarly. The undegraded carrageenan (Viscarin 402) in the diet had an enhancing effect in colorectal carcinogenesis in rats evoked by AOM or MNU.


Isolation and partial characterization of a 67Ga-binding glycoprotein from Morris 5123C rat hepatoma.

A Glycoprotein, particularly high in tumors, has been extracted from Morris 5123C rat hepatomas and purified. The compound constitutes a major binding component for 67Ga in this hepatoma. It has a molecular weight of approximately 45,000. Its molecular weight was determined by sodium dodecyl sulfate:polyacrylamide gel electrophoresis and by Sephadex G-200 superfine gel filtration. The steps involved in its extraction and purification include ultrafiltration, gel filtration through Sephadex G-200 superfine, ion-exchange chromatography on diethylaminoethyl Sephadex A-50, and hydroxylapatite chromatography. The homogeneity of the compound was established by gel electrophoresis. The NH2-terminal residue, the percentage of nitrogen, the nonamino carbohydrate content, and the amino acid composition are reported.


Fecal profiles of anaerobic microflora of large bowel cancer patients and patients with nonhereditary large bowel polyps.

It has been postulated that the intestinal anaerobes play a role in the etiology of large bowel cancer. This study was designed to characterize and compare the fecal anaerobes of patients with large bowel cancer, patients with nonhereditary large bowel polyps, and healthy control subjects. Although some distributional variations of the anaerobic genera were observed among the study groups, significant differences in fecal anaerobic microflora and total aerobic counts were not noted. This suggests that taxonomic grouping of fecal bacteria is an inadequate measure of relative risk of developing large bowel cancer. However, the fecal microbial 7alpha-dehydroxylase and cholesterol dehydrogenase activities of large bowel cancer patients and patients with nonhereditary large bowel polyps were significantly higher than those of healthy control subjects. On the other hand, no significant difference in fecal microbial beta-glucuronidase activity was noted among the study groups. It may be that assessment of the total metabolic activities of the intestinal microflora will provide a better understanding of their potential role in the genesis of large bowel cancer.


Inhibitory effect of 13-cis-retinoic acid on urinary bladder carcinogenesis induced in C57BL/6 mice by N-butyl-N-(4-hydroxybutyl)-nitrosamine.

The effect of 13-cis-retinoic acid on the induction of urinary bladder carcinoma by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) was studied in male C57BL/6 mice. Animals received a total dose of either 90 or 140 mg of OH-BBN via gastric intubations of 7.5 or 10.0 mg of OH-BBN 2 times each week for 6 or 7 weeks, respectively. Seven days after the last OH-BBN intubation, animals were fed laboratory chow diet supplemented with either 200 mg of 13-cis-retinoic acid per kg or its placebo. Animals were killed at 6 months after the first carcinogen intubation. Highly invasive squamous and transitional cell carcinomas of the urothelium were found at autopsy. In the majority of these carcinomas, invasion of the bladder muscle wall by tumor cells had occurred. At the two dose levels of OH-BBN, feeding of 13-cis-retinoic acid reduced the incidence of both carcinomas and noninvasive papillomas, as well as the extent of neoplastic development in the urinary bladder. In mice receiving the lower dose of OH-BBN, the feeding of 13-cis-retinoic acid prevented the appearance of both squamous and transitional cell carcinomas with a reduction in incidence from 33 to 0% (p less than 0.01). The results of this study indicate that 13-cis-retinoic acid reduced not only the severity of highly invasive urinary bladder carcinomas but also the incidence of such cancers.


Partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in primary hepatocellular carcinomas.

The activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, the rate-controlling enzyme of cholesterol synthesis, was studied in normal livers and in 64 primary hepatocellular carcinomas from rats fed a basal diet or a diet containing either 2% cholestyramine or 5% cholesterol. The average enzyme activity in hepatocellular carcinomas from rats fed the basal diet was more than twice that in normal liver. Dietary cholesterol caused a reduction in activity to one-ninth of the normal hepatic enzyme activity, whereas cholestyramine feeding resulted in a 7-fold increase above the basal level. The data tended to confirm the previously documented observation that "diet-induced feedback inhibition" of cholesterol synthesis is not expressed in hepatomas, since the enzyme activity was reduced only slightly in cancers from rats fed cholesterol. However, the activities from cancers of cholestyramine-fed rats were 2.7 times greater than those from cholesterol-fed rats. Thus, a degree of control was clearly demonstrable, although it represented only 4% of that seen in normal liver. To our knowledge this is the first report of at least partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in hepatocellular carcinomas grown in vivo.


Enhancement of liver microsome epoxide hydratase activity in rodents by treatment with 2(3)-tert-butyl-4-hydroxyanisole.

Administration of the antioxidant 2(3)-tert-butyl-4-hydroxyanisole (BHA) in the diet caused a marked increase in the specific activity of epoxide hydratase (EC 4.2.1.63) in hepatic microsomes of CD-1 mice. The increases in epoxide hydratase activities produced by BHA were far greater (11-fold) than were those produced by the administration of well-known enzyme inducers such as 3-methylcholanthrene, phenobarbital, and Aroclor 1254 (2- to 3-fold). The near-maximal increase in epoxide hydratase activity was observed after feeding of the BHA diet for 3 days. When BHA was administered by gastric intubation, the level of increase was only 75% of that attained by feeding BHA in the diet. The increase in epoxide hydratase activity produced by BHA treatment of Sprague-Dawley rats was not as pronounced (less than 3-fold) as that observed in CD-1 mice.


Elimination of hypoxic protection by 5-thio-D-glucose in multicell spheroids.

The effect of 5-thio-D-glucose on oxic and hypoxic V79-171 Chinese hamster cells was studied in vitro with single cells and multicell spheroids. At concentrations that were not toxic to oxic cells, this compound killed hypoxic cells with a D0 of 1 hr with a 5 mM concentration and more rapidly at 10 mM beginning 2 hr after incubation at 37 degrees. 5-Thio-D-glucose also sensitized hypoxic cells to radiation and protected oxic cells from radiation damage. Multicell spheroids irradiated after incubation with the compound demonstrated increased radiosensitivity, although the relative contribution of cytotoxicity and hypoxic cell sensitization could not be evaluated. Spheroid reoxygenation by decreased cell respiration was determined not to be a contributing factor, suggesting that the spheroid-sensitizing effect was due to drug effects on hypoxic cells. The dramatic increase in multicell spheroid radiosensitivity that resulted from treatment with 5-thio-D-glucose suggests that this compound may be used to increase the effectiveness of radiotherapy by eliminating hypoxic protection.


Destruction of regional lymph node metastases of rat mammary adenocarcinoma 13762A by treatment with Corynebacterium parvum.

Intratumoral administration of Corynebacterium parvum to 13762A tumor-bearing rats on Day 7 of tumor growth, followed by primary tumor excision on Day 20, regularly cured about 40% of the animals and significantly prolonged survival in the remainder. Rats treated by surgery alone on either Day 7 or Day 20 died with metastases to axillary lymph nodes and lungs. Tumor was established in axillary lymph nodes by Day 7. Therefore, intratumoral injection of C. parvum on Day 7 destroyed metastases already established at this site. Growth of tumor in axillary nodes of rats treated but not cured by C. parvum was significantly slower than growth in untreated rats.


Effects of harman and norharman on spontaneous and ultraviolet light-induced mutagenesis in cultured Chinese hamster cells.

Nontoxic concentrations of harman and norharman were tested in cultured Chinese hamster cells for their effects on DNA repair and mutagenesis. The following effects of harman were observed: (a) the survival of ultraviolet light- or X-ray-damaged cells was reduced; (b) the ultraviolet light-induced unscheduled DNA synthesis was slightly inhibited; and (c) the frequency of spontaneous or ultraviolet light-induced ouabain-resistant (ouar) or 6-thioguanine-resistant (6-TGr) mutations was reduced. Furthermore, the effect of harman on survival and mutagenesis was greater than that of norharman and was detected primarily in treatments in which cells were exposed to harman immediately following ultraviolet light irradiation. Our data clearly indicate that harman decreases the capacity to repair DNA damage and fix mutations in Chinese hamster cells, possibly because of the intercalation properties of this compound.


Different effects of concanavalin A and E-phytohemagglutinin upon lymphocyte glycosyltransferase activities.

We have studied glycosyltransferase activities in human lymphocytes stimulated with the plant mitogens E-phytohemagglutinin or concanavalin A (Con A) and have compared the results with activities found in resting lymphocytes. Compared to resting lymphocytes, Con A-stimulated lymphocytes possess an enhanced capacity to transfer the sugars, sialic acid, galactose, and N-acetyl-glucosamine from their respective nucleotide donors to both endogenous cellular acceptors and added exogenous glycoprotein acceptors. The enhanced glycosyltransferase activity induced by Con A is not inhibited by puromycin despite effective inhibition of de novo protein synthesis, indicating that synthesis of new glycosyltransferase enzymes is not necessary for the observed increases in glycosylation activity. By contrast to the findings in Con A-stimulated cells, the corresponding glycosyltransferase activities of E-phytohemagglutinin-stimulated lymphocytes do not differ from those of unstimulated lymphocytes. These data indicate that individual plant lectins have different effects on the biosynthesis of complex saccharides by cultured human lymphocytes.


Effects of cell density and transformation on the formation of a fibronectin extracellular filamentous matrix on human fibroblasts.

We have studied normal and transformed cultured human fibroblasts by ultrastructural immunocytochemistry with antibodies to fibronectin (the large external transformation-sensitive glycoprotein). Human fibroblasts at low density have very little extracellular material organized into a filamentous form. A diffuse membrane component of low-density fibroblasts reacts with fibronectin antibodies. As normal fibroblasts grow to confluence, an extensive extracellular filamentous matrix forms. The filaments are 15 to 20 nm in diameter, lack periodicity, and frequently occur in a meshwork. Antibody to fibronectin reacts with these filaments as well as with a diffusely distributed membrane component. Cultures of SV40-transformed human fibroblasts lack the extracellular filamentous matrix reacting with fibronectin antibodies; however, fibronectin is detected on plasma membranes. These studies indicate that a major difference between normal and transformed human fibroblasts is the failure of transformed fibroblasts to form a fibronectin-containing extracellular filamentous matrix.


Host genetic factors influencing the occurrence of leukemoid reaction in BALB/cMk mice bearing transplanted tumors.

Host genetic factors influencing the occurrence of leukemoid reaction in BALB/cMk strain mice bearing transplanted tumors were studied. A Mendelian hybridization experiment was performed with BALB/cMk and C57BL/6 strains, and their strain hybrids; the first filial (F1) generation hybrids; the second filial (F2) generation hybrids; and the backcrosses to the two parental strains. The results of these studies suggested a genetic regulation of leukemoid reaction occurrence in BALB/cMk mice bearing transplanted tumors. Genes permissive to the occurrence of the reaction seemed to be dominant to their nonpermissive alleles.


Dependence on cloning method of survival of human melanoma cells after ultraviolet and ionizing radiation.

The resistance of a human melanoma cell line (MM96) to both ultraviolet and ionizing irradiation was compared by two different methods of cloning, on plates and in agar. A high level of resistance to both ultraviolet (D0 = 320 ergs/sq mm) and ionizing irradiation (D0 = 4300 rads) was observed when viability of cells was determined by cloning in agar. In contrast, melanoma cells were found to be as sensitive as were other cells when viability after irradiation was determined by cloning on plastic plates. The difference in sensitivity to radiation between the two methods of cloning can be explained in a model involving damage to membranes as well as to DNA. At least for ionizing radiation, this effect is not restricted to melanoma cells since a HeLa subline, HeLa-QB1, showed a similar response. In contrast, a human lymphoblastoid line (JHP) cloned in agar was sensitive under these conditions (D0 = 120 rads).


Intercellular glycosaminoglycans in normal and neoplastic tissues.

Intercellular glycosaminoglycans have been isolated from normal and neoplastic mammalian tissues. They have been characterized by cellulose acetate electrophoresis and by chemical and enzymatic degradation. The electrophoretic pattern of the intercellular glycosaminoglycans is tissue specific. Furthermore, the electrophoretic patterns of all spontaneous neoplasias analyzed differ significantly from patterns obtained from the tissues of origin.


Coronary vascular resistance and myocardial oxygen consumption dynamics in response to catecholamine infusion.

These experiments were performed in order to ascertain whether activation of coronary vascular adrenergic receptors could change the time course of the coronary vasodilatation accompanying increases in myocardial metabolic activity. The left common coronary arteries of dog hearts were perfused in situ with blood at constant flow. Coronary perfusion pressure and coronary sinus blood 02 content were continuously monitored. Norepinephrine was infused into the coronary artery at 0.5 to 5 microgram.min-1. and isoprenaline at 0.5 to 2 microgram.min-1. The amplitude of the vascular resistance change was less with norepinephrine than with isoprenaline infusion for a similar change in oxygen consumption. The time course of coronary vascular resistance, after correction for the effects of vascular transit, lagged significantly behind the time course of coronary sinus 02 content in the case of norepinephrine infusion. On the average, no lag was observed with isoprenaline infusion. It is concluded that stimulation of coronary vascular adrenergic receptors can alter the time course and the magnitude of the coronary vascular response to increases in myocardial metabolic activity resulting from myocardial beta-receptor stimulation.


Evaluation of the elasticity and characteristic impedance of the ascending aorta in man.

In 30 patients, simultaneous measurements of ascending aortic pressure and diameter were performed, allowing one to evaluate: (1) the influence of age, the aortic diastolic pressure, and the radius on the aortic elasticity; (2) the correlations between characteristics impedance of the aorta (Zo), systemic arterial resistance, age and diastolic aortic pressure; and (3) the importance of Zo when comparing two indices of left ventricle performance; one during isovolumic phase ([dP/dt]/Pt)max and the other during the outflow phase (maximum acceleration of aortic blood flow).


Determinants of coronary sinus noradrenaline in patients with ischaemic heart disease: coronary sinus catecholamine concentration in relation to arterial catecholamine concentration, pulmonary artery oxygen saturation and left ventricular end-diastolic pressure.

Arterial and coronary sinus noradrenaline (NA) and adrenaline (A) concentrations, cardiac output, pulmonary artery oxygen saturation (PAO2), coronary sinus oxygen saturation, left ventricular end-diastolic pressure (LVEDP), and arterial pressure were examined in 21 patients with ischaemic heart disease at rest and during exercise before and after intravenous propranolol. The heart had a net uptake of A and a net release of NA. It can be estimated that at least 50% of NA in the coronary sinus derived from the heart. NA in the coronary sinus and in the arterial blood originated therefore, at least partially, in different tissues. The NA concentration showed close correlation with PAO2, but not with cardiac index or arterial blood pressure. Multiple regression analysis also revealed a relationship between LVEDP and arterial and coronary sinus NA independent of PAO2. A very close correlation between arterial and coronary sinus NA (r = 0.93, P less than 0.001) indicates that they are largely controlled by the same factors.


The effect of glucose-insulin-potassium on experimental myocardial infarction in the dog.

The effect of glucose-insulin-potassium (GIK) infusions was studied in 45 dogs after left anterior descending coronary artery ligation. GIK caused a modest increase in lactate concentration in small veins draining the infarct but did not affect glucose uptake. No effect on creatine kinase activity in the infarct was seen from GIK, although there was a slight increase in blood flow to the centre of the infarct. We concluded that GIK did not reduce infarct size in this experimental model.


Electrophysiological study of Syrian hamster hereditary cardiomyopathy.

This study was performed to determine if the intracellular electrical activity of adult cardiac papillary muscle from a strain of Syrian hamster (B10 14.6) with a genetically determined cardiomyopathy was different from that of a control strain (B10 RB). Muscles driven at rates from 1 Hz through the physiological range. Resting potentials of muscle from the two strains were not significantly different, except in increased [C2+]0, where the control was slightly hyperpolarised. Action potential overshoot was significantly greater in the myopathic at all frequencies, while the upstroke velocity was not significantly different, except at 8 Hz where the myopathic value was depressed. Action potential durations at 20, 50 and 95% repolarisation were significantly greater in the myopathic, at all rates and with increased [C2+]0. Response of the muscles to verapamil and D600 were complex, with a decrease seen in duration at 20% repolarisation and an increase in 50% duration at 1 Hz rate. No strain-related difference in sensitivity to the drugs was seen. The results supporty the hypothesis that a sarcolemmal defect is intimately related to the genesis of the cardiomyopathy.


Regional myocardial energetics during brief periods of coronary occlusion and reperfusion: Comparison with S-T segment changes.

In open-chest dogs transient occlusion of the left anterior descending coronary artery induced an immediate decline in the creatine phosphate content of the ischaemic area, a lesser decline of the ATP and total adenine nucleotide contents and a rise in S-T segments. Reperfusion after 15 min restored creatine phosphate level and intramyocardial electrograms to normal whereas ATP and total adenine nucleotide levels stayed down. None of these parameters were modified in the nonischaemic area during the experiments. This study shows that there is no close relationship between electrical and biochemical events during either ischaemia or reflow.


Current thresholds and liminal size in excitation of heart muscle.

End-diastolic current thresholds have been measured in 12 open-chested dogs with epicardial disc electrodes ranging in radius from 0.01 to 9.0 mm. The current threshold for cathodal 1 ms impulses proved to be independent of electrode size for radii smaller than 0.2 mm and proportional to the radius to the power 1.5 for radii greater than 0.4 mm. This relationship can be explained on the assumption that excitation occurs if the current passing through a 'liminal area' with dimensions of about 0.3 mm exceeds a critical value. This result is in agreement with the liminal length concept used to describe excitation of cardiac Purkinje fibres. The existance of a liminal area or liminal lenght for excitation implies that there will be a limit to increasing stimulation efficiency by applying smaller stimulation electrodes.


Exacerbation of coronary occlusion induced ventricular arrhythmias by the vagolytic effect of procainamide.

The influence of the vagolytic effect of procainamide on the early ventricular arrhythmias induced by left anterior descending coronary (LAD) occlusion was studied in chloraloseanaesthetised cats. All control animals developed a ventricular arrhythmia (1119 +/- 166 PVCs per hour), with a consistent onset time, duration, and overall mortality due to ventricular fibrillation (ie 20%). In 18 animals pretreated with procainamide (0.5 mg.kg-1.min-1 for 50 min), there was no effect on the ventricular arrhythmia in terms of ectopic frequency (1020 +/- 180 PVCs per hour), time to onset of arrhythmia, duration of arrhythmia, and mortality incidence (ie 16.7%). However, subdividing the data according to whether or not  vagal blockade had been produced by procainamide revealed that animals exhibiting complete vagal blockade demonstrated significantly more ectopic beats (1606 +/- 310 PVCs per hour) and 33% developed ventricular fibrillation. Treated animals without complete vagal blockade exhibited an ectopic frequency rate of 620 +/- 98 PVCs per hour and none of the animals developed ventricular fibrillation. The haemodynamic parameters were similar between both procainamide treated subgroups. These results suggest that an important factor in response of the ischaemic heart to the cardiac rhythm effects of procainamide is the degree of vagal blockade induced by this agent.


Acebutolol-induced changes in refractoriness and monophastic action potential of the right ventricle of the dog heart in situ.

The effect of acebutolol, a beta-adrenergic receptor blocking agent, on the electrophysiology of the right ventricle was studied in the dog heart in situ. Pentobarbital anaesthesia which is known to increase the sympathetic tone was used. Monophasic action potential recordings were obtained by the suction electode technique and refractoriness was measured by means of programmed electrical stimulation. A stepwise increase in the frequency of stimulation from 170 to 200, 230, and 260 per min caused a progressive decrease in the refractoriness as well as the duration of the monophasic action potential. Intravenous injection of acebutolol 2.0 mg.kg-1 increased the times for 50 and 90% repolarisation of the monophasic action potential. This increase is probably due to beta-adrenergic receptor blockade in the presence of alpha-adrenergic receptor stimulation. The effective and functional refractory periods, however, were increased to an even greater extent than the monophasic action potential duration. It is suggested that this is the result of a blockade of a catecholamine-induced increase in the velocity of the depolarisation.


Cell kinetics and the control of growth in long bones.

The cell kinetics of the cartilage growth plate are outlined and discussed in terms of the probable levels of control on the system. Possible mechanisms of growth control at the cellular level are examined for (i) the rate of cell division in the proliferation zone, (ii) the command to differentiate that limits the size of the proliferation zone and (iii) the ageing process in the cartilage plate. The evidence of cell kinetics does not point unequivocally to any particular mechanism.


Effect of hyperthyroidism on haemopoietic stem cell kinetics in mice.

Changes in the pool of haemopoietic colony-forming units (CFUs) of bone marrow and spleen were studied in experiments with mice fed dried thyroid gland (TH) for 21 days, and during the 13 days that followed feeding. After HU treatment, the number of CFUs in DNA synthesis was estimated. As early as the second day of TH treatment, the pool of CFUs is gradually increased, leading to an increase in the total number of splenic and bone marrow CFUs persisting after TH treatment for the period examined. Simultaneously, the numbers of nucleated cells in the bone marrow and spleen are increased. During TH feeding and following its termination, the total number of erythrocytes and the haematocrit values did not change significantly, whereas an increased number of leucocytes was observed in the peripheral blood after TH treatment. Elevation of the proliferative activity of CFUs occurred early in the period of TH treatment, with the maximum attained by end of the first week of TH feeding. This suggests a rapid response of the haemopoietic stem cell compartment to the administration of TH hormones. The participation of humoral factors controlling CFUs compartments in the mechanism of the stimulatory effect of TH hormones on haemopoietic stem cells is discussed.


An iron requirement for the synchronous progression of colonic cells following fasting and refeeding.

Evidence is presented to show dietary iron to be a major co-factor in the colonic hyperplasia observed following fasting and refeeding. The iron component serves to remove a fasting induced colonic G1 cycle block and produce the resultant synchronous progression of cells through the cycle. Deleting iron from the refed diet results in no colonic hyperplasia and/or synchronous progression of cells. The results are discussed from the viewpoint of colonic steady state cell renewal and as a possible tool for the study of in vivo steady state cell renewal.


Enhanced post-irradiation recovery of the haemopoietic system in animals pretreated with a variety of cytotoxic agents.

It is known that pretreatment of mice with bacterial endotoxin and certain stathmokinetic agents between 1 and 3 days prior to exposure to ioninzing radiation reduce radiation lethality. In this communication it is shown that pretreatment with cytosine arabinoside, methotrexate, nortestosterone and chlorambucil reduces radiation (1000 rad) induced lethality. This reduction can be ascribed to enhanced regeneration of the haemopoietic system in pretreated animals and not to increased survival of colony-forming cells (CFU) in these animals. Regeneration of CFUs was underway within 24 hr after 900 rad in the pretreated mice but did not start until day 3 in mice treated with gamma radiation only. Two agents, namely radiation itself (either 75 or 150 rad) and busulphan (10 mg/kg) did not reduce the lethal effects of subsequent gamma irradiation nor enhance the regeneration of CFUs, even though radiation, like the protective cytosine arabinoside, induces early CFUs proliferation. The administration of nucleoside precursors of DNA enhanced regrowth of haemopoietic stem cells to an extent comparable with that of the most effective pretreatment, cytosine arabinoside. It is postulated that drugs like cytosine arabinoside operate by causing cell death, providing a source of DNA that con enhance the regrowth of surviving stem cells in the bone marrow.


Pluripotent (CFU-S) and granulocyte-committed (CFU-C) stem cells in intact and 89Sr marrow-ablated S1/S1d mice.

Peripheral blood values, femur cell counts, spleen weights, pluripotent (CFU-S) and granulocyte progenitor cell (CFU-C) concentrations and total content of spleens and femurs have been evaluated in intact (non-marrow-ablated) and 89Sr marrow-ablated S1/S1d and +/+ mice. 89Sr-irradiated mice were studied 6 and 11 days after the administration of 89Sr. In intact S1/S1d mice the femur CFU-S concentration, total femur CFU-S, femur CFU-C concentration and total femur CFU-C were 84, 54, 105 and 68% that of +/+ mice femurs respectively; the respective values for the spleens of S1/S1d mice were 40, 46, 61 and 69%. These are the first simultaneous determinations of CFU-S and CFU-C concentrations, and content of spleens and marrows, of S1/S1d and +/+ mice. In 98Sr marrow-ablated mice, 11 days after injection of the radionuclide: (a) the total content of marrow CFU-C and CFU-S was about 1% of that found in the marrows of intact mice for both +/+ and S1/S1d groups; (b) the spleens of +/+ mice increased in weight to 162% of the control, but the spleens of S1/S1d mice did not increase in weight; and (c) the spleens of +/+ mice had a total content of CFU-C and CFU-S of 800% and 260% of the control, respectively, whereas the respective values for the S1/S1d mice were 120% and 76% of the control. Thus the S1/S1d spleen fails to compensate for marrow ablation by housing additional CFU-S and has an impaired ability to compensate by housing additional CFU-C.


Erythrokinetics in mice bearing tumours in either preirradiated or unirradiated tissue.

Experiments were designed to clarify the causes of anaemia in hosts bearing tumours in either unirradiated or preirradiated tissue. Isotopic methods are described which enable the estimation of erythrocyte destruction and production rates, and the potential red cell life spans in tumour-bearing animals. In this experimental system, anaemia (a) is in large part due to accelerated random erythrocyte loss, (b) is exacerbated as tumours grow by a progressive reduction in the potential erythrocyte life span due to intrinsic erythrocyte defects, (c) is accompanied by an increase in erythrocyte production of six- to ten-fold and (d) is postponed in onset and decreased in magnitude by preirradiation of the tumour transplant site.


Changes in cell population kinetics during epidermal carcinogenesis.

The changes in cell population kinetics in response to a mechanical stimulation by wounding were studied in a hyperplastic epidermis, papilloma and a squamous cell carcinoma of the mouse dorsal skin induced by repeated treatments with 20-methylcholanthrene. The G0 cell population, which consists of about 66% of the basal cells in the dorsal epidermis of the normal mouse, disappeared in hyperplastic epidermis, papilloma and carcinoma. The zone of proliferating cells enlarged in the papilloma, including several supra-basal layers, in contrast to its strict localization in the basal layer in hyperplastic epidermis. Proliferating cells were distributed in almost all areas in the carcinoma without localization. The normal responses to wounding were preserved in the hyperplastic epidermis, except for the absence of G0 cells, while the papilloma and carcinoma showed no increase in proliferating cells or shortening of the cell cycle time. From the view-point of cell population kinetics, papilloma and carcinoma are regarded as the tissues in which the flexible control mechanisms of irreversible cell differentiation to mature cells and of the length of cell cycle time are lacking.


Cell cycle and the concept of physiological age with special reference to pyruvate kinase activity in WI-38 cells.

WI-38 cells were synchronized by mitotic collection and periodically assayed for pyruvate kinase activity. The kinetics of the synchronous cohort were determined by continuous labelling index and by mitotic index. The experimental data were analysed by computer using a state vector model to yield the probability density functions for phase transit times and for cell physiological ages. Pyruvate kinase activity for these cells as a function of physiological age was then examined using the computer model. Considering DNA synthesis, pyruvate kinase activity and mitosis to be markers of physiological age, it was found that a model which assumes that a cohort of synchronized cells desynchronizes irreversibly and uniformly from one age marker to the next is incompatible with the experimental data. For example, the times over which cells entered the S phase were too widely distributed to be consistent with the mitotic index data. Also, for pyruvate kinase activity to be a function of physiological age alone, the cell ages were probably too dispersed to be compatible with the experimental enzyme data. Alternative models for cell physiological ageing are presented, which are compatible with the experimental data.


Removal of the horny layer does not stimulate cell proliferation in neonatal mouse epidermis.

Mechanical treatment of newborn mouse back skin by removal of the horny layer does not stimulate DNA synthesis and mitotic activity. These results are discussed in connection with recent experiments with newborn and adult mouse epidermis, and reveal further evidences for the ontogenetic development of an endogenous growth control (chalones).


Commercial PHA preparations contain different mitogenic components.

Three commercially available purified phytohaemagglutinin (PHA) preparations have been examined both chemically and biologically. Marked differences were observed in both composition and mitogenic effect on lymphocytes; the existence of at least two distinct mitogenic fractions in PHA was confirmed.


Effect of double partial hepatectomies at various intervals on [3H]thymidine incorporation into rat liver DNA.

At various intervals after a 34% hepatectomy, another 34% (50% of the remnant) hepatectomy was performed on rats, and the [3H]thymidine incorporation into the DNA of remaining liver cells was measured 24 hr after the first operation. The values of [3H]thymidine incorporation into liver DNA of rats hepatectomized doubly (34% and 34%) at 6, 8 and 10 hr intervals were greater than the sum of the value of rats which received a single 34% hepatectomy at the start and those of rats which received a single 68% hepatectomy at 6, 8 and 10 hr, respectively.


Immunoelectronmicroscopic localization of vasopressin in the rat suprachiasmatic nucleus.

The classical areas for arginine-vasopressin (AVP) synthesis are the magnocellular supraoptic (SON) and paraventricular nuclei. More recently AVP was also demonstrated in neurons of the parvocellular suprachiasmatic nucleus (SCN) of the rat. This result was substantiated in the present study by means of immunoelectron microscopy, by subjecting sections to antivasopressin plasma. Conventional electron microscopy revealed dense-core vesicles in the SCN cell bodies and fibres (mean diameter 94.7 +/- 0.9 nm and 84.0 +/- 1.1 nm respectively). These vesicles were infrequent within the cell bodies and could not be accumulated by ethanol administration. Immunoelectron microscopy showed a positive reaction in the cell bodies and fibres within vesicles of 96.7 +/- 1.1 nm and 98.5 +/- 1.1 nm and 98.5 +/- 1.2 nm respectively. By comparison, the cell bodies and fibres of the SON showed immunoreactive granules of 143.0 +/- 1.8 and 147.3 +/- 1.8 nm respectively. The presence in the SCN of AVP in vesicles of different size than those in the SON suggests that synthesis of this substance is indeed occurring within the SCN cells.


Fine structure of the axial complex of Sphaerechinus granularis (Lam.) (Echinodermata: Echinoidea).

Three regions of the axial complex in Sphaerechinus granularis can be distinguished: 1) The axial organ which protrudes from one side of the axial sinus; the sinus septum which separates the sinus from the body cavity and encloses the stone canal; the pulsating vessel which runs along the inside of the axial organ. 2) The blindly-ending terminal sinus in which the pulsating vessel broadens out to the contractile terminal process. 3) The ampulla of the stone canal which connects the axocoel and water vascular system and which opens out through the madreporite. A single-layered, monociliated coelomic epithelium surrounds all regions of the axial complex. This epithelium contains smooth muscle cells at the contractile areas. Canaliculi, surrounded by basal lamina, are formed through infolding of epithelia; they end blindly in the fluid- and connective tissue-matrix of the inner structures. The lacunae of the dorso-ventral mesentery connect the periesophageal and the perianal haemal ring with the axial organ. The axial organ contains many coelomocytes rich in pigment and granules. These coelomocytes are separated into compartments by elastic fibres. Phagocytosis of whole cells and transformational stages of coelomocytes suggest storage and degradation functions. An excretory function via the water vascular system is also suggested.


Development of the calyx and lateral oviduct during oogenesis in Aedes aegypti.

The lateral oviduct and calyx of nulliparous Aedes aegypti on a sucrose diet are both flattened sacs, lacking a well defined lumen. Both are formed of an inner epithelial and an outer muscular layer, each one cell thick. The lateral oviduct is surrounded by a circular muscle sheath which is continuous with the ovarian sheath. Each ovariolar sheath is continuous with the outer layer of the calyx. The structure of both the lateral oviduct and the calyx is greatly modified after the initial blood meal. A distinct lumen develops; there is an extensive development of the outer muscular layers, and the inner epithelial layers become invaginated forming deep crypts lined with extensive microvilli. The follicular stem, which joins the primary follicle to the calyx in each ovariole, is not hollow and does not mark the opening into the calyx through which the mature egg can pass. The eggs gain access to the oviductal system after the calyx extends around the follicular epithelium of the primary follicle, when breaks appear in the calyx wall opposed to the follicular epithelium, until the mature eggs, eventually lie in a highly distended thin-walled sac of calyx from which they have direct and easy access to the lateral oviduct. After oviposition, this sac contrasts to occupy once more a compact axial position in the ovary. Remnants of the follicular epithelium, containing many lysosomes are attached to the calyx at this time.


Ultrastructure of the dogfish adenohypophysis.

Granular hormone-producing cells and agranular cells (stellate cells, including giant and pericavitary cells) were electron microscopically studied in the hypophysis of the small spotted dogfish (Scyllium canicula) up to several months after hatching. Comparisons of results obtained in embryos, newly-hatched fish and adults show an increase of the mean granule diameter in the four major endocrine cell types. Small granule cells which are present in all lobes are especially numerous in the ventral lobe. The structures observed in certain cavity boundary cells suggest a role in resorption and transport.


Estrogen-induced alterations in the myoepithelial cells of the rat mammary gland.

Estradiol benzoate was injected into virgin rats, at a concentration of 50 microgram/day, for 7 days. The animals were fixed by perfusion and the mammary glands prepared for electron microscopy. Many myoepithelial cells in the mammary glands were altered as a result of the estradiol treatment. The affected cells had a markedly reduced number of myofilaments that were restricted to a specific region of the cytoplasm. Large foot-like projections with many vesicles extended from the myoepithelial cells into the surrounding connective tissue. The altered cells also had more organelles, suggesting that their metabolic activity was increased. Nuclei in the altered cells had deep infoldings that may reflect an increase in nuclear/cytoplasmic exchanges. The results of this study indicate that estradiol causes specific morphological alterations in myoepithelial cells of the mammary gland.


Apical protuberances of supporting cells in the regio olfactoria of the mole, Talpa europaea, Linnaeus, 1758 (Insectivora, Talpidae).

The regio olfactoria of the mole, Talpa europaea, was studied by scanning and transmission electron microscopy. Peculiar structural differentiations, i.e. ovoid-shaped, balloon-like protuberances were found on the surface of the supporting cells. The apical portion of these protuberances contained finely dispersed granular material, whereas in their central part vesicular extensions of the smooth endoplasmic reticulum were observed.


Production of specific-protein secretion granules by fat body cells of the blowfly, Calliphora erythrocephala. Substitution of an ovarian key factor by beta-ecdysone.

During the first four days of the imaginal stage the fat cells of ovariectomized females of Calliphora develop a protein synthetic apparatus, and produce dense bodies (lysosomes) as do the fat cells of normal females, but apparently they cannot synthesize the protein secretion granules that characterize the productive phase of the fat cells of normal females and that we believe to represent vitellogenin. Injection of ovariectomized females with beta-ecdysone restored the ability of the fat cells to produce the secretion granules. It is suggested that the ovary gives off a factor which induces the production of the protein secretion granules by the fat cells, and that the factor from the ovary can be substituted by beta-ecdysone. This, we believe, is the first ultrastructural evidence for an effect of the ovary and of beta-ecdysone on the synthesis of specific protein.


The epidermis and sensory organs of Dugesia tigrina (Turbellaria: Tricladida). A scanning electron microscope study.

The epidermis of D. tigrina was examined using the scanning electron microscope. Both dorsal and ventral surfaces are extremely irregular in contour, as well as being permeated by large numbers of pores. Cilia are restricted to the ventral surface, the auricles and that part of the dorsum adjacent to the auricles. Club-shaped receptors, as well as cilia, were seen in the auricles. The epidermis anteriad to the eyespots is indistinguishable from that covering the remainder of the dorsal surface. Light rays could not enter the eyespot through this rough epidermal surface without becoming diffracted in an irregular fashion. It was therefore concluded that visual image perception is not a function of the planarian eyespot.


Mixed (chemical and electrical) synapses on frog spinal motoneurons.

Freeze-fracture replicas and ultrathin sections were used to characterize the gap junctions on the somata and large dendrites of frog motoneurons found earlier by Sonnhof et al. (1977). In freeze-fracture replicas one of the specific features of these relatively frequent gap junctions is the presence of circular regions of non-junctional membrane ("fenestrae") within areas of typical gap junction appearance displaying P-face particles or E-face pits. Such "fenestrated" gap junctions are mostly associated with membrane specializations indicative of the active zone of a chemical synapse (including vesicle attachment sites in non anaesthetized animals) to constitute mixed synapses. These findings could be verified in ultrathin sections, which revealed that the vesicles of the chemical component of the mixed synapses were spherical and agranular. Our results suggest that the mixed synapses are predominantly axo-somatic and axo-dendritic. The existence of dendro-dendritic gap junctions in the ventral horn region as described by Sotelo and Taxi (1970) was verified in ultrathin sections; they were rare, solely electrotonic in character, and probably represent the morphological basis for the VR-EPSP (Katz and Miledi, 1963; Kubota and Brookhart, 1963), i.e. electrotonic coupling between motoneurons of different spinal segments (Washizu, 1960). Electrotonic coupling can also be demonstrated between motoneurons and afferent fibers of the dorsal root and the lateral column. Electrotonic potentials recorded within motoneurons during electrical stimulation of dorsal root or lateral column precede the chemical postsynaptic potentials; after Mn2+-blockade of chemical synaptic transmission, the electrotonic component persists. Some fibers of these afferent pathways are therefore assumed to act monosynaptic on the motoneuron via mixed axo-somatic and axo-dendritic synapses.


The oligodendrocytic junctional complex.

The junctional complex of oligodendrocytes was studied by means of different electron microscopical techniques. This complex is composed of the following junctional membrane formations: 1) tight junctional domains in the oligodendrocytic membrane near the some of the cells, 2) fasciae occludentes or focal tight junctions on the outer oligodendrocytic loop of myelin and on the outermost myelin membrane, 3) gap junctions of considerable size variations, either on membranes near the soma or on peripheral oligodendrocytic processes, and 4) non-paranodal transverse bands. The different types of oligodendrocytic junctions are discussed in terms of their functional implications.


Ultrastructural radioautography of the incorporation of tritiated leucine by the rat adrenal medulla in vivo.

Sections of tissues from the adrenal medullae of young rats were subjected to radioautography after a single intravenous injection of L-leucine 4, 5(3)H to identify the sites of synthesis and follow the migration of newly-formed proteins in both adrenaline-storing (A) and noradrenaline-storing (N) cells. As early as 2 min after injection of leucine 3H, the label was highest in the rough endoplasmic reticulum (RER) of A and N cells, suggesting that cisternal ribosomes are sites of protein synthesis. By 5 and 10 min, much of the label had migrated from the RER into the Golgi complex of both cell types. Some label was already present over the secretory granule matrix (chromogranins) by 2 min but the peak was reached at 1 h in both A and N cells. By 4 h, the label over the secretory granules had diminished, indicating a release of newly-synthetized chromogranins outside the cells. The label over the hyaloplasm was relatively high at 2 min but it decreased rapidly to low levels. In contrast, the label over the cell surface continually increased to reach the highest levels among all organelles at 4 h in both cell types. The pattern of increment of the label over the cell surface suggests that the newly-formed proteins of these sites are also synthetized in the RER, pass through the Golgi complex and are transported in the hyaloplasm, before reaching the surface of A and N cells.


Quantitative analysis of epithelial changes during wound healing in palatal mucosa of guinea pigs.

The epithelium of wounded guinea pig palate was subjected to stereologic analysis. A total of 18 biopsies (animals) were used. Biopsies were taken at 18, 48, 96 and 120 h after wounding. Point counting procedures were employed to analyse electron micrographs sampled from one (18 h) or two epithelial strata (48, 96 and 120 h). The essential modulations in epithelial structure as wound healing proceeds were as follows: During the early phases characterized by formation and advancement of epithelial lips (18 and 48 h), migrating cells converged towards a cell type which structurally was less differentiated than normal basal cells. This alteration was expressed by a decrease in volume density of cytoplasmic organelles, mainly mitochondria, free ribosomes and tonofilament bundles, coupled with an increase in volume density of lysosomal bodies. Concomitantly, the volume density of cytoplasmic ground substance rose markedly. Subequent to fusion of contralateral migratory lips (96 and 120 h) reversion to normal epithelial structure was indicated by the increment in magnitude of basal cell parameters. Further structural density gradients from basal towards upper cell layers appeared. This pattern was mainly displayed by mitochondria, free ribosomes, and tonofilament bundles. The magnitude and gradation of most tissue and cell parameters were not yet re-established at 120 h. The density of tonofilament bundles and the density level of cytoplasmic ground substance in particular deviated.


Cell proliferation in skeletal muscle following denervation or tenotomy. A series of autoradiographic studies.

Autoradiographic experiments using 3H-thymidine were designed to analyse cell proliferation which occurs in skeletal muscle after denervation and after tenotomy. In mouse tibialis anterior and tongue muscles during the first 24 h after denervation or tenotomy labelling levels were low and did not differ significantly from sham operated control muscles. By 48 h after denervation and tenotomy of tibialis anterior muscles, increased levels of labelling occurred in both muscle and connective tissue nuclei. Daily pulse labelling for 7 days after denervation produced a labelling level which was 8 times that of sham operated controls, 25--30% of the total nuclear population being labelled. Denervated muscles had twice the level of labelling compared to tenotomised muscles. These results provide conclusive evidence that both denervation and tenotomy stimulate cell proliferation in skeletal muscle and it is suggested that the increased numbers of labelled muscle nuclei are likely to be the result of mitotic activity in muscle satellite cells.