Growth and cardiovascular measures in hyperactive individuals as young adults and in matched normal controls.

Height, weight, pulse rate and blood pressure were measured in 65 hyperactive individuals 17 to 24 years of age who had not taken stimulant medication during childhood and in 39 control subjects matched for age, sex, intelligence quotient and socioeconomic class. There were no significant differences in the physiologic measures between the two groups. Both the hyperactive and the control subjects seemed to have reached their growth plateau by the age of 17 to 24 years, though the exact time the plateau was reached was not determined. Hyperactive individuals who had taken phenothiazines during childhood were significantly taller (P less than 0.046) than those who had never taken medication. This finding may reflect stimulation of growth by phenothiazines at a critical period of growth, but more detailed reserach on this finding is necessary. The physiologic measures obtained in the hyperactive individuals who had never taken stimulant medication provide an important baseline against which to assess values in hyperactive individuals who have taken such medication.


Human amniotic membrane: a versatile wound dressing.

Human amniotic membrane proved to be a versatile and useful temporary biologic dressing in studies involving 120 patients. Wounds, both traumatic and nontraumatic in origin, responded to a protocol that allowed coverage of tissues as diverse as exposed bowel, pleura, pericardium, blood vessels, tendon, nerve and bone. Wounds unresponsive to usual therapeutic measures responded to membrane application. Ease of availability, negligible cost and facilitated wound healing make this temporary biologic dressing generally superior to either cadaver skin allograft or pigskin xenograft. Human amniotic membrane dressings are therefore a useful adjunct in the care of the complicated wound.


Deliveries in teenagers at a Newfoundland general hospital.

A study of deliveries in teenagers was undertaken for the year 1975 in a hospital that had recorded 2797 births, 371 (13%) of which were to women under 20 years of age. Conception had occurred out of wedlock in 314 (85%) of the 371 pregnancies; 124 of the 314 women had married during the pregnancy, most often in the 3rd or 4th month of gestation. The peak months for conception out of wedlock were June and December. This was not the first pregnancy for 65 women (18%), 21 of whom had married during a previous pregnancy. Of the "heads of the households" 36% were labourers and 27% were unemployed. Cesarean section was the method of delivery for 51 (14%) of the women, and 63 (17%) were reported as having had toxemia. There were seven perinatal deaths and seven infants had severe congenital abnormalities. The frequency of low birth weight was 6% overall but 13% for the infants of single women. Five women underwent tubal ligation post partum.


Actinobacillus actinomycetemcomitans endocarditis.

Two patients had infective endocarditis due to Actinobacillus actinomycetemcomitans. One, a 52-year-old woman with a prosthetic aortic valve, was successfully treated with carbenicillin and gentamicin. The other, a 47-year old man with calcific aortic valve disease, required emergency valvectomy and prosthetic valve replacement and responded to a combination of penicillin and gentamicin.


Metastasis of cancer of the thyroid gland as a cause of goitre.

In three cases of cancer (arising in the pancreas, the breast and the lung) that had metastasized to the thyroid an unusual primary thyroid lesion was the presenting problem. While reputedly rare, metastases in the thyroid gland are not infrequently encountered at necropsy. These cases illustrate the varied causes of goitre, the value of needle aspiration and cytologic study in thyroid disease and the need for histologic vigilance. Worthwhile palliation by simple means can be obtained in such cases.


Puerperal uterine inversion: report of nine cases.

Acute puerperal inversion of the uterus is considered to be rare. In one institution there were nine cases during an 11-year period, a rate of one for every 2176 vaginal deliveries. Analysis of these cases failed to identify any contributing factors occurring during the first or second stage of labour. Six cases were directly attributable to failure to administer an oxytocic preparation or, particularly, failure to await uterine contraction before attempting to expel the placenta by fundal pressure or cord traction. Although active management of the third stage of labour may reduce the incidence of postpartum hemorrhage, incomplete application of its principles is extremely hazardous. Immediate uterine replacement was efficacious in seven cases, but the inadvisability of removing the placenta prior to replacement was demonstrated.


Chronic renal failure in children.

Seventy-seven children with chronic renal failure were examined at one hospital in the province of Quebec between 1970 and 1975; this represents an incidence of 2.5 per million population per year. The entities responsible for chronic renal failure were urinary tract malformation (in 36%), chronic glomerulonephritis (in 22%), congenital renal parenchymal malformation (in 21%) and hereditary nephropathy (in 13%). The evolution of chronic renal failure in children with either vesicoureteral reflux or a posterior urethral valve seemed to be related more to the initial severity of the disease than to the age at the time of diagnosis. Hence any screening program designed to detect kidney disease in schoolchildren would not prevent chronic renal failure, since at that age renal parenchymal damage seems to be irreversible. The manner in which chronic glomerulonephritis evolved depended on whether the nephrotic syndrome was present and on the type of histologic lesion. Children with congenital renal hypoplasia or dysplasia often presented with seizures due to hypertensive encephalopathy without obvious symptoms or signs of pre-existing renal disease. Among patients with familial nephropathy many of those with cystinosis underwent successful renal transplantation early in life.


Near-drowning in Canadian waters.

Near-drowning is a subject of ever-increasing importance. Two recent cases are presented that illustrate many of the problems encountered. For a current understanding of the etiologic and pathophysiologic aspects and of the prognosis of near-drowning, an updated review of the literature is provided. The importance in treatment of the recognition of hypothermia, the use of positive end-expiratory pressure and the controversy over the role of corticosteroid therapy are discussed.


Hyperactive individuals as young adults: current and longitudinal electroencephalographic evaluation and its relation to outcome.

In a 10-year follow-up study electroencephalograms (EEGs) of 31 hyperactive and 27 matched control subjects of mean ages 19.17 and 18.59 years respectively showed no significant differences in any of the features assessed. Sequential EEGs, available for only the hyperactive subjects, suggested that a much greater proportion were normal at the 10-year follow-up assessment than at the 5-year follow-up assessment and that the normalization tended to take place mainly in the second 5-year period. This supports the hypothesis that EEG abnormalities of hyperactive persons are those of an immature pattern that tends to normalize with age. Correlation between EEG findings at the 10-year follow-up assessment and global outcome measures was not significant. Initial and 5-year EEGs also failed to predict global outcome at the 10-year follow-up assessment.


Polyarthritis and bone lesions complicating traumatic pancreatitis in two children.

The association of bone lesions, polyarthritis and cutaneous nodules with pancreatic disease is being recognized and reported more frequently. In adults all forms of pancreatitis and carcinoma of the pancreas have been involved, but in the few children described these complications have been associated with acute traumatic pancreatitis. This paper describes two cases of acute traumatic pancreatitis in which polyarthritis and limb pains were noted after 2 to 3 weeks. In one child osteolytic lesions and periostitis were seen on roentgenograms 7 weeks after the onset of pancreatitis. In the other child minor roentgenographic changes were not seen until 5 months after the onset; however, bone scans showed clear-cut abnormalities after 1 month. Almost complete resolution could be expected within a year. Serum lipase and amylase concentrations remained elevated during the acute illness. Disseminated fat necrosis is apparently related to the excess amounts of circulating lipase.


Strongyloides stercoralis.

Strongyloides stercoralis, a nematode not well known to many Canadian physicians, infects 35% of some tropical populations. Larvae can be isolated from the stools in 25% of cases and from duodenal aspirates in 95%. Treatment is with thiabendazole given twice daily in a dose of 25 mg/kg up to a maximum of 1.5 g/d. Frenquently an individual with a previously asymptomatic infection presents with hyperinfection and death rapidly ensues, but usually classical symptoms are present. Such a case is described. Immunosuppression is frequently associated with the hyperinfective state.


Malignant hypertension.

Malignant or accelerated hypertension is a life-threatening disease whose complications may be prevented by rapid reduction of the blood pressure. Diazoxide is presently regarded as the preferred therapeutic agent, but drugs such as trimethaphan, sodium nitroprusside, phenoxybenzamine and hydralazine may be useful in particular situations. Treatment is best carried out in an intensive care unit, where appropriate monitoring and study of the patient can be done. Since the introduction of antihypertensive agents the life expectancy of these patients, even those with renal insufficiency, has increased.


Improving physician performance by continuing medical education.

In 1973 the division of continuing medical education of the University of Saskatchewan initiated a 3-year study to determine the effect of hospital-based education on the prescribing accuracy of physicians. This study was undertaken in response to an urgent need to develop more effective methods of continuing medical education and improved techniques of measuring their effectiveness. The educational program focused on common prescribing problems that had previously been defined by experts in the field. Problem frequency was determined by the monitoring of hospital records prior to institution of the educational program and at 3, 6 and 12 months after the program had concluded; this was found to be a satisfactory method of identifying educational needs and is considered to provide a measure of the quality of medical care. Fifteen physicians at three rural hospitals participated in the study. Seventeen physicians at two similar hospitals served as controls. The average problem frequency for topics selected at the study hospitals was reduced by 63% (the percentage of possible improvement), whereas at the control hospitals the frequency of the same problems declined by 32% over the same period. The results of this study provide evidence that an intensive, problem-based program on therapeutics can improve physician performance.


Quantitative assessment of the quality of medical care provided in five family practices before and after attachment of a family practice nurse.

The standards of patient care were maintained in five urban medical practices after the introduction of family practice nurses. Evaluations were achieved before and after their appointment by the indicator condition method. Minimal explicit criteria for the management of patients with 12 indicator conditions and by the use of 14 drugs were approved by an ad hoc peer group of community physicians. These cirteria were applied to the five practices by the use of a single-blind design and the abstraction of unaltered medical records. A standardized score for each practic e permitted comparison of scores for the management of indicator conditions and for the clinical use of drugs before and after attachment of the family practice nurses. For each of the indicator conditions and the drugs assessed in the five practices similar levels of adequacy were observed in the two study periods. These explicit (objective) audit resutls agreed with the implicit (subjective) assessments of the family practice nurses by their physician colleagues.


The consultation process and physician satisfaction: review of referral patterns in three urban family practice units.

To improve communication in the referral process a standard referral form was composed that seeks to involve the patient in the referral process. It has been well received by the consulted physicians, the family practitioners who use it in everyday office parctice and the patients. A review of referral patterns in general practice showed many similarities from practice to practice and from country to country. Ophthalmologists were the most frequently consulted, followed by obstetricians and gynecologists, general surgeons, otolaryngologists and orthopedic surgeons. A follow-up assessment of referral outcome revealed a poor response from the teaching clinics of one tertiary-care hospital to the referring physicians. This resulted in a substantial decrease in the proportion of patients referred from one family practice unit to the hospital over a 3-year period.


[Spontaneous hypoglycemia and chronic kidney insufficiency].

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.


The role of the psychiatrist in the criminal justice system.

In this article, the author explores the relationship between the lawyer as advocate and the psychiatrist as expert. He argues that the role of the psychiatrist in aiding the Court in the determination of relevant issues is one of increasing importance. Often the diagnostic opinions offered by the psychiatrist border on conclusory legal determination. As such, those opinions must necessarily be subjected to the testing of adversarial processes. The role of the psychiatrist is to proffer a relevant opinion while nevertheless realizing that the inexact nature of the science limits the use such an opinion may have. The lawyer as adversary must subject that opinion to as rigorous an examination as possible. This examination is not an affront to the psychiatrist but rather an attempt to explore and expose the definitiveness of that opinion. It is through this combination of realized opinionating and adversarial examination that relevant legal-medical determinations can best be made within the confines of our existing judicial mode of dispute settlement.


The use of dreams in psychotherapy: practical guidelines.

Although there is a large literature pertaining to the use of the dream in psychoanalysis, there is no systematic approach to working with dreams in psychotherapy. This communication seeks to present some guidelines for the use of the dream in psychotherapy. Reference is made to the significant difference in the "dimensions" of psychoanalysis as compared to psychotherapy. A distinction is drawn between the use of the dream in supportive psychotherapy as contrasted with insight-oriented psychotherapy. In the former, the dream--if used at all--serves supportive functions; in the latter, the goals are to develop better awareness by the patient of himself. Understanding of the dream is reached by inserting it into the context of the patient's psychological life; however, what is actually communicated to the patient will be keyed to the psychologic surface that the patient presents.


Anorexia nervosa in boys.

The literature on primary anorexia nervosa in the male is reviewed and the case histories of 3 new patients are reported. Most surveys comment on the rarity of the syndrome in the male, with the sex ratio in the range of 1 in 10 to 1 in 20. The patients reported here had certain features in common. All the mothers and fathers were overweight, but obesity was marked only in the fathers, who also showed moderate to severe degrees of alcoholism. The mothers were oversensitive, insecure individuals, and the marriages suffered in proportion to the severity of the husband's alcoholism. Preoccupation with food was observed on home visits. There was overt mutual hostility between each father and anorexic son; the boys showed pronounced obsessional traits in their personalities. Dieting in order to ameliorate real or feared obesity was a first step in the development of the syndrome in each boy. In the past 3 years an equal number of boys and girls (new patients) have been referred for treatment in the psychiatric unit. Speculative reasons for this are discussed.


Protracted vomiting following abrupt cessation of psychotropics: a case report.

The case of a 23-year-old patient treated with haloperidol, imipramine, and benztropine mesylate is presented to illustrate an unusually severe reaction to the abrupt cessation of neuroleptic medication. In addition to the description of the withdrawal reaction, a possible explanation of the clinical phenomenon is offered.


Forgiveness, retaliation and paranoid reactions.

It has been suggested that clinical states from grudgingness and habitual bitterness through to delusions of persecution are best resolved by forgiving. The process of forgiving requires that previously unacknowledged impulses, particularly aggressive ones, are accepted in oneself and others. If the therapist is aware of this, he can, in the transference, reinforce the patient's good introjects by providing a non-judgemental, acceptant model for the patient and thereby facilitate the adoption of the forgiving attitude. Sometimes habitual forgiving can occur as a reaction formation, and should be dealt with as such.


Gender identity problems of children and adolescents: the establishment of a special clinic.

Theoretical accounts of the origins of gender identity disturbance are reviewed and then followed by a description of the establishment of a child and adolescent gender identity clinic. Clinical impressions of 16 gender disturbed patients are presented and the position is taken that most patients manifested a confused, as opposed to fixed, core gender identity.


The treatment of chronic lymphocytic leukemia with COP chemotherapy.

Since single drug therapy of chronic lymphocytic leukemia (CLL) has not resulted in prolonged remissions of advanced disease, we initiated a program of combination chemotherapy, COP (cycloposphamide, vincristine sulfate, prednisone) for CLL patients with increasing adenopathy, spenomegaly, and/or signs of marrow failure defined as either anemia or thrombocytopenia. Thirty-six patients received COP either as initial therapy or following progression of disease on single agent therapy. The response rate was 72% with 26 patients responding (16 complete remissions, and 10 good partial remissions). The responses lasted from 8 to 50+ months. Sixteen of the responding patients remain in remission, 2 have active disease and 8 have died. Median survival has not yet been reached but the two-year survival from initiation of COP of the responding patients (complete and good partial response) is 90%. Ten patients had either poor partial or no response with median survival of 18 months. The median survival of the entire group of 36 patients is 35 months. COP is an effective and well tolerated therapy for advanced chronic lymphocytic leukemia.


Decreased hepatic drug demethylation in patients receiving chemo-immunotherapy.

The effect of immunotherapy and chemotherapy on hepatic N-demethylation of aminopyrine was studied by means of the aminopyrine breath test (ABT) in 32 patients with cancer. The aminopyrine breath test (ABT) was decreased in 3 of 11 patients (27.3%) receiving intradermal BCG (+/- DTIC) at a dose of 3 X 10(7) viable organisms. One of 4 (25%) patients receiving intradermal BCG (+/- DTIC) at 3 X 10(8) viable organisms per dose developed an altered ABT. Changes were not seen in patients receiving aerosol BCG (2 patients), and intravenous C. parvum (2 patients), subcutaneous C. parvum (3 patients), and intravenous Cyclophosphamide (2 patients). Six of 7 patients (85.7%) receiving both intravenous C. parvum and Cyclophosphamide had a decreased ABT. These data indicate that chemo-immunotherapy depressed hepatic aminopyrine N-demethylation and suggests that patients treated with chemoimmunotherapy should be carefully observed for possible alterations of hepatic drug metabolism.


The superselective and the selective one shot methods for treating inoperable cancer of the liver.

Forty-five patients with inoperable cancer of the liver were treated by the one shot administration of 15-40 mg of Mitomycin C into the hepatic artery, either by the superselective or by the selective one shot method. Fourteen of the patients had primary cancers of the liver, and 31 had metastases to the liver from primary cancers of the stomach, or from the colorectal or other organs. Subjective symptoms improved in 73%, and objective signs improved in 60%. Nineteen patients who received this treatment more than twice showed a mean survival time of 10 months and a 50% survival time of 7.8 months. Therapeutic effects of the selective one shot method were recognized mostly in patients with tumors which were rich in vessels. However, a fairly good result was obtained using the superselective one shot method, even in patients with tumors having relatively few vessels.


Isoantigens A, B and H in urinary bladder carcinomas following radiotherapy.

ABH tissue isoantigens were measured by the Specific Red Cell Adherence (SRCA) test in 66 surgical specimens of urinary bladder, including 53 transitional cell carcinomas, 2 squamous cell carcinomas and 11 controls. The SRCA test was strongly positive in 10 of 11 controls. ABH isoantigens were absent or equivocally present in 68 percent of noninvasive carcinomas (stage 0) and in 65 percent of invasive carcinomas. Clinical histories revealed that all patients with invasive carcinoma who had strongly positive SRCA test results had received prior radiotherapy to the bladder region. None of the patients with invasive bladder carcinoma with negative or weakly positive SRCA tests had been radiated. Histopathology of tumors in both groups was similar. Results of this retrospective study support the hypothesis that radiation may induce differentiation in tumors, possibly through an enhancement of Golgi apparatus function. The SRCA test should not be used as a predictor of the biological behavior of future recurrences in patients with bladder carcinoma who have received therapeutic radiation since radiation may produce "false positive" SRCA test results.


Remineralization of enamel by a saliva substitute designed for use by irradiated patients.

A saliva substitute, VA-OraLube, was evaluated for ability to reharden dental enamel and to relieve intraoral soft tissue symptoms in patients receiving radiotherapy for malignancies of the head and neck. Treatments of 15, 30 and 60 minutes rehardened enamel by 3.1%, 4.0%, and 5.5%, respectively. In the second experiment, treatment for 60 minutes with the complete solution rehardened enamel by 5.2%. Omitting calcium, phosphorus and/or fluoride from the formulation greatly decreased this rehardening potential. Treatment of enamel with fresh whole saliva induced rehardening at a 7.3% level in comparison to the 5.5% and 5.2% derived by using the saliva substitute. Since the xerostomic patient usually uses the product very frequently, there is a remineralization potential of significant consequence. A total of 125 xerostomic patients used the saliva substitute on an ad lib basis over a period of 4 months. Patient responses indicated a very high level of acceptance and the virtual elimination of troublesome problems previously associated with the dry mouth state.


Monocyte function in patients with solid neoplasms during immunotherapy with Corynebacterium parvum.

The present studies were performed in order to evaluate monocyte function in patients with solid neoplasms before and after administration of C. parvum. The results demonstrate that monocytes from cancer patients display increased numbers of C3 and Fc receptor sites after administration of C. parvum. It is concluded that characterization of monocyte receptor activity may be helpful in monitoring the effects of immunotherapy in the immune system.


Clinical and immunologic studies of disseminated BCG infection.

Eight patients with disseminated BCG infection following injection of BCG into primary melanomas have been studied. These patients developed persistent fevers beginning 9 to 20 days following BCG injection. Severe liver function abnormalities occurred in all patients and peaked approximately 20 days following BCG injection. The persistent fevers, and clinical signs and symptoms of disseminated BCG infection lasted from 7 to 22 days before subsiding. Liver function abnormalities sometimes took six months to return to normal. Evidence of granulomas in liver and bone marrow were present. The natural course of this disease did not appear to be affected by therapy with isoniazid (INH). In vitro immunologic studies revealed a severe depression of lymphocyte reactivity in five of six patients sequentially tested. Wide dissemination of BCG from the site of injection is a severe complication of BCG therapy. The clinical course of this disease and suggestions for management are described in this paper.


Decreased monocyte function in patients with Hodgkin's disease.

Monocyte function in nine untreated and nine treated patients with Hodgkin's disease in different stages was studied simultaneously with normal controls. Monocyte chemotactic responses were decreased in 6 of the 14 patients with advanced disease regardless of previous therapy. None of our patients with stage II disease had abnormal results. Decreased monocyte chemotactic responses correlated with the presence of cutaneous anergy. In addition, decreased chemotaxis was associated with diminished monocyte bactericidal activity. This suggests that decreased bactericidal activity may be related to abnormal migration and possible diminished ingestion. The data support the hypothesis that depressed monocyte function may contribute to the increased susceptibility to infections of patients with Hodgkin's disease and it may be an additional factor favoring tumor dissemination in the advanced stages of the disease.


Studies on the fine structure of osteoblastoma with notes on the localization of nonspecific acid and alkaline phosphatase.

Electron microscopy of two osteoblastomas revealed the existence of three distinct types of cells in this tumor: osteoblast like, macrophage like, and multinucleated giant cells. In addition to the lysosomes, most Golgi cisternae and vesicles in the osteoblast like cells showed evidence of acid phosphatase activity. Deposits of lead phosphate indicating the site of this enzyme in the macrophage like cells were confined to the large and abundant lysosomes. Wide spread deposition of final product was noted in the cytoplasm of the multinucleated giant cells, both in conventional lysosomes, Golgi regions and special organelles probably corresponding to GERL. With regard to nonspecific alkaline phosphatase, final product indicating the location of enzyme activity was confined to the plasma membranes and associated vesicular and vacuolar structures in the osteoblast like cells. The findings suggest that the giant cells in osteoblastomas participate in lytic bone destructive and resorptive processes while osteoblast like cells appear to be osteoid and bone forming carriers of the neoplastic properties of the tumor.


Ultrastructural identification of a benign perineurial cell tumor.

A solitary tumor which by light microscopy was calssified as a neurofibroma was found by electron microscopic study to be composed of parallel, elongate cells with collagen rich intervening matrix. The cells showed thin, polar cytoplasmic processes which extended long distances, frequent junctional complexes between cell processes, numerous surface vesicles, and either no or fragmented and variable basement membrane. Perineurial cells from small peripheral nerves of skin were demonstrated to have similar morphologic characteristics as the tumor cells. The present study, together with previous ultrastructural findings, indicate that benign peripheral nerve sheath tumors should be placed in at least three categories: Schwannoma, neurofibroma and perineurioma.


Leiomyosarcoma of the scrotum: a case report with electron microscopy.

A case of leiomyosarcoma of the scrotum is presented. The tumor measured 3 X 2.5 X 2 cm and had been present as a slowly enlarging mass in the right scrotum for three months prior to excision. Light microscopy demonstrated the typical interlacing fasicles of neoplastic cells with eccentric cigar-shaped nuclei and electron microscopy confirmed the neoplastic cells to be of smooth muscle origin. A review of the world's literature revealed this to be the fifth reported case of leimyosarcoma confined to the scrotal wall.


Biologic markers in breast carcinoma. IV. Serum fucose-protein ratio. Comparisons with carcinoembryonic antigen and human chorionic gonadotrophin.

Serum fucose-protein ratio was evaluated as a potential biologic marker for patients with metastatic breast cancer. By analysis of the same blood samples, comparisons were made with carcinoembryonic antigen (CEA) and human chorionic gonadotrophin (hCG). For 150 patients with metastatic breast cancer, 85% had a value for serum-fucose protein ratio above the normal range in comparison to 75% for CEA and 40% for hCG. Serum fucose-protein ratio was exclusively increased in 12% of the patients, CEA in 4% and hCG in 2%. Both  serum-fucose protein ratio and CEA were elevated in 39% of the patients, and together, either in combination of alone, were increased in 93% of the patients. Raised values for serum fucose-protein ratio as well as for CEA decreased with change in disease status from pretreatment to response for patients with measurable disease parameters and increased correspondingly with overt disease progression. Preliminary data indicate both serum fuxose-protein ratio and CEA frequently become elevated when patients progress from a disease free interval after surgery to recurrence.


Uveal melanomas: correlation of cytologic features with prognosis.

Forty uveal melanomas were examined, half of which had proved fatal. Twenty cells were selected from each tumor, and six cytologic features were measured on each of these cells. It was found that the cells selected from fatal tumors had longer nuclei, more nucleoli, and greater nuclear pleomorphism than those selected from nonfatal tumors. Also, cells from melanomas classified as mixed cell type by the Callender classification had wider nuclei and longer nucleoli than those from tumors classified as spindle B cell type. Since the former cell type is associated with a worse prognosis, these features would probably assist in assigning prognosis to a large group of randomly selected malanomas. Thus, five nuclear characteristics (long nuclei, wide nuclei, long nucleoli, multiple nucleoli, and nuclear pleomorphism) should prove useful for predicting death from the dissemination of uveal melanoma.


A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas.

Twenty-eight uterine tumors originally diagnosed as leiomyosarcomas were histologically reclassified without prior knowledge of follow-up or clinical data. Thirteen (46%) neoplasms were reinterpreted as cellular or pleomorphic leiomyomas. They had sparse mitotic activity with three or fewer mitotic figures per 10 high power microscopic fields (MF/10 HPF). None recurred or metastasized, and all patients were alive from 6.3 to 23 years after operation (median of 14.2 years). In 15 cases the diagnosis of leiomyosarcoma (LMS) was confirmed. All showed hypercellularity, nuclear atypism and high mitotic activity. Mitosis counts ranged from 6 to more than 50 MF/10 HPF with 93% of LMS having at least 15 MF/10 HPF. These patients all died of LMS after post-operative intervals of 3 months to 7.5 years (median survival of 13 months). No consistent correlation was found between length of survival and the patient's menopausal status or histologic grade of LMS. The degree of mitotic activity is the single most reliable diagnostic criterion of malignant potential, albeit not the only one. Surgery alone is ineffective treatment for LMS and combination therapy with radiation therapy and/or chemotherapy should be considered.


Leukemic reticuloendotheliosis: report of a case with peripheral blood remission on androgen therapy.

Leukemic reticuloendotheliosis (LRE) has been generally considered to be poorly responsive to therapy other than splenectomy. The patient presented below developed a complete peripheral blood remission after prolonged therapy with an androgen (oxymetholone). There is very little published experience with androgen therapy in LRE. The experience with this patient suggests that androgens may produce a clinical remission by inducing significant improvement in the peripheral blood in some patients with this disease.


Norepinephrine-producing tumors of bilateral breasts: a case report.

There was a tumor in the left breast which was suspected to be carcinoid tumor at excisional biopsy. Autopsy revealed the same tumor in the right nipple. In the cells of the bilateral tumors a number of argylophil granules were diffusely demonstrated and the neurosecretory ones were verified electronmicroscopically. In the urine of the patient a moderate amount of norepinephrine was excreted. It was presumed that the norepinephrine might have been produced from the breasts. In the literature reviewed, the case of breast carcinoid has not been reported previously.


Patho-radiologic correlation of invasive pulmonary aspergillosis in the compromised host.

The autopsy findings and antemortem radiographic abnormalities were correlated in 20 patients with invasive pulmonary aspergillosis to define typical radiographic patterns, their progression and anatomic basis. Sixteen (80%) patients had radiographic abnormalities due to aspergillosis. Fifty-nine percent of the specific radiographic abnormalities seen in these patients were caused by anatomic lesions of asperigillosis and 67% of such anatomic lesions were radiographically definable. The most common initial radiographic pattern was a patchy density (single or multifocal) or a well defined nodule. The densities remained stable in half the patients but progressed, over several weeks to either diffuse consolidation or cavitation in the others. Most anatomic lesions were categorized as either nodular ("target") lesions (1-3 cm in diameter) or hemorrhagic infarctions (5-10 cm in diameter), both due to vascular invasion causing thrombosis and ischemic necrosis. Unlike pulmonary candidiasis, which is usually radiographically undetectable, invasive pulmonary asperigillosis frequently caused radiographically visible lesions.


Well differentiated adenocarcinoma of the prostate.

One hundred and one adenocarcinomas of the prostate that over a five-year period had been classified as being "well differentiated" or "grade 1" were reviewed and reclassified. Thirty-eight of the cases met strict criteria for such a classification. Twenty-six patients died of prostatic carcinoma. Seventy-five patients (74%) survived for five years, including 87% of the patients with clearly well differentiated carcinomas and 67% of those with somewhat less differentiated tumors. Forty-six percent of all patients including 22 of the 38 well differentiated review cases (58%) are now alive 7-11 years after prostatectomy without evidence of residual disease. Grading appears to be useful and the prognosis of well differentiated carcinomas is better than average but some cases even if focal and incidentally found will terminate with disseminated disease, usually more than five years after the original diagnosis.


Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma.

A familial cancer aggregation comprising sarcomas, brain tumors, leukemias, and carcinomas of breast, larynx, lung, adrenal, cortex, and other sites has been studied from a pathologic--genetic standpoint. Based upon sibships segregating for cancer, the genetic segregation parameter is estimated to be 45.6 +/- 11%  which is compatible with that expected for a rare deleterious autosomal gene showing complete dominance. Pathologic review of 16 tumors by bright field microscopy revealed variable occurrences of intranuclear cytoplasmic invaginations, intranucleolar bodies, and acidophilic intracytoplasmic inclusions in eight lesions. Two tumors showed both intranuclear cytoplasmic invaginations and intranucleolar inclusions. Morphological findings coupled with the observed pattern and distribution of cancer in the subject kindred suggest that the cancer-prone genotype interacts with one or more exogenous factors in causing this familial tumor association.


The microcirculation in two transplantable melanomas of the hamster. I. In vivo observations in transparent chambers.

Twenty-eight transparent chambers were inserted into the cheek pouches of hamsters and daily serial observations made of the changing vasculature of transplants of 2 varieties (A-Mel-4B32, ZGYP1) of amelanotic melanomas. The tumor A-Mel-4B32 grew at a rate which covered 50% of the viewing area in 3--4 days, while the tumor ZGYP1 covered less than 10% of the viewing area at this time and did not cover 50% of the viewing area until 9.5 days after transplantation. The difference in growth rate was not reflected in any differences in the morphology of the vascular network and distribution of the venous arcades.


The microcirculation in two transplantable melanomas of the hamster. II. Scanning electron microscopy.

Normal and tumor vessels observed in vivo on the hamster cheek pouch membrane in transparent chambers were examined by scanning electron microscopy. Large, thin walled veins were found in the reactive zone around the 2 amelanotic melanomas of the hamster. Sinusoidal vessels and channels contained red cells, which did not possess any vascular wall, were seen in the main substance of the tumors. In this system all the vessels within the central mass of the tumor transplant comprise newly formed vessels. The surfaces of the tumor cells and the lining of the tumor vessels were examined by this technique. The biological history i.e., age of the vessel and location from the growing edge of the tumor, were known. The surface of the tumor cells on cut section differed in appearance from the areolar tissue of the pouch membrane. Scanning electron microscopy of the inner aspect of newly formed tumor vessels permits much greater sampling of the tissue than transmission electron microscopy and further work should reveal aspects of the interaction of the blood with tumor stroma.


Metabolism of benzo(a)pyrene in animals with high aryl hydrocarbon hydroxylase levels and high rates of spontaneous cancer.

Ambystoma tigrinum found in a sewage polluted pond had high levels of aryl hydrocarbon hydroxylase (AHH) activity that decreased to the basal level of control animals after being held several months in clean water. The qualitative formation of benzo(a)pyrene (BP) metabolites by salamander hepatic microsomes was similar to those seen for other species. Inhibition of epoxide hydrase activity did not alter the total metabolite production but did change the ratio of metabolites. A correlation appears to exist between high AHH induction, the presence of polycyclic hydrocarbon pollutants, and the high rate of spontaneous cancer in salamanders.


Further improvements in the hepatocyte primary culture DNA repair test for carcinogens: detection of carcinogenic biphenyl derivatives.

DNA repair in hepatocyte primary cultures was induced by simultaneous treatment with the carcinogen and [3H] thymidine for 18 h beginning immediately after attachment of cells. The unscheduled DNA synthesis elicited by carcinogens was determined by counting grains with an automatic grain counter. In 5 biphenyl derivatives, a correlation was found between carcinogenicity and the ability to induce DNA repair. Hence, the method offers promise as a means of screening chemical carcinogens.


The identification of a cell culture inhibitor in a tumour extract.

An extract of Harding-Passey mouse melanoma was found to inhibit the proliferation of the same cell line grown in culture when measured by both thymidine incorporation and by the increase in cell number. The active ingredient was purified by ultrafiltration, column chromatography and preparative electrophoresis. The purified material was identified by mass spectrometry and by gas chromatography as spermidine. The partially purified material reversed the methylglyoxal Bis-guanyl hydrazone (Methyl-GAG) inhibition of cultured cells to the same extent as spermidine. Very low concentrations of Methyl-GAG were found to suppress the spermidine inhibition of thymidine incorporation into cells. The inhibitor extracted from melanoma tumours behaved in the same way as spermidine at all Methyl-GAG concentrations. Thus, it is unlikely that the active ingredient in the biological extract is anything other than spermidine.


Synthesis of the urinary glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl.

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl believed to be the carrier form responsible for transporting the active N-hydroxy compound from its site of formation in the liver to its site of carcinogenic action in the bladder has been prepared synthetically. The synthetic conjugate is identical by infrared and chromatographic analyses with the conjugate isolated from urine, thus unequivocally establishing its structure as an N--C conjugate, sodium (N,4-biphenyl-N-hydroxy-D-glucuronosylamine).


Double stranded RNA in heterogeneous nuclear RNA from normal and chronic lymphocytic leukemic lymphocytes.

Tritium labelled heterogeneous nuclear RNA (HnRNA) from normal and chronic lymphocytic leukemic (CLL) lymphocytes was investigated before and after fractionation into non-poly(A) containing (-HnRNA) and poly(A) containing (+HnRNA) HnRNA with respect to double stranded RNA (dsRNA). Statistically significant higher amounts of rapidly labelled RNA were recovered from CLL lymphocytes when compared to normal cases. Within the CLL cases a significant linear correlation (r = 0.95) was found between white blood cell counts and the amount of dsRNA in total HnRNA. After fractionation into (-) and (+) HnRNAs the ratios of dsRNAs, expressed as the dsRNA in (-) HnRNA divided by the dsRNA in (+) HnRNA, was lower than the corresponding values in normal cases for all the CLL cases except one. The relationship between (+) HnRNA and the total dsRNA level was different when comparing CLL and normal lymphocytes indicating a RNA processing abnormality.


Delayed hypersensitivity response to oxazolone in neonatally estrogenized mice.

Neonatal NMRI mice were treated with diethylstilbestrol (DES) fof the first 5 days after birth. At 6 and 9 months the same animals were tested for delayed hypersensitivity reaction using an ear test with oxazolone. The DES treated animals had a diminished response to oxazolone compared with controls.


Hydroxyurea-sensitive thymidine incorporation in rat liver and kidney following administration of dimethylnitrosamine.

In rats treated with dimethylnitrosamine (DMN), the sensitivity of [3H] thymidine incorporation to inhibition by hydroxyurea was determined in the liver and kidney. A 70% inhibition was produced in control animals with doses of hydroxyurea from 50 to 250 mg/kg body wt. Twelve hours after administration of DMN, hepatic thymidine incorporation was unaffected by 50 mg/kg hydroxyurea, progressive reduction in incorporation occurred as the dose of inhibitor was increased. A similar result was obtained in kidney only by dietary conditioning of rats to ensure a high renal metabolism of the DMN. In contrast, at 72 h after DMN treatment thymidine incorporation in both liver and kidney was rapidly inhibited by administration of 50 mg/kg hydroxyurea. The data, assessed together with various parameters of DMN-induced repair and replicative DNA synthesis, suggest the use of hydroxyurea as a means to study DNA repair in intact animals.


Induction by degraded carrageenan of colorectal tumors in rats.

Degraded carrageenan derived from the red seaweed Eucheuma spinosum was given to Sprague-Dawley rats through the diet, in drinking water or by stomach tube for up to 24 months. Carrageenan-induced squamous cell carcinomas, adenocarcinomas and adenomas in the colorectum were observed. Some rats had metastases to the regional lymph nodes of squamous cell carcinomas. These results show that degraded carrageenan is carcinogenic to the colorectum of the rat.


Urinary excretion of N-nitrosodiethanolamine administered orally to rats.

N-Nitrosodiethanolamine (NDE1A) was administered by gavage to male rats in single doses of 1000, 500 and 100 mg/kg body wt. More than 70% of a given dose was excreted unchanged in the urine, essentially within the first 24 h after exposure. This high excretion rate might explain the relatively low carcinogenic potential of NDE1A, and also offers a possible method of monitoring exposure to this compound under occupational and/or environmental conditions.


Potentiation of chlorambucil activity by phenylbutazone.

Phenylbutazone increased the cytotoxicity of chlorambucil to L1210 and P388 leukemia cells in vitro by displacing alkylating agent bound to serum of the tissue culture medium. Administration of phenylbutazone with chlorambucil to mice bearing the P388 tumor lowers the dose of chlorambucil required to achieve maximum increase in life span, but also lowers the dose required for host toxicity. No therapeutic advantage is obtained by the combination.


Fecal constituents of a high-risk North American and a low-risk Finnish population for the development of large bowel cancer.

Feces collected in Kuopio, Finland, a low-risk population for colon cancer, and in the New York metropolitan area, a high-risk population for colon cancer, were compared. The dietary intake of fat and protein were the same in the two populations, but the sources of fat were different, a greater portion coming from meat in New York, and from dairy products in Kuopio. The daily stool output was higher in Kuopio due to the high intake of cereal products rich in fiber. The concentration of fecal secondary bile acids and the bacterial beta-glucuronidase activity were lower in Kuopio, but the daily output of these constituents was the same in the two groups. The daily fecal excretion of neutral sterols was higher in Kuopio than in New York. Our data suggest that the greater fecal bulk in Kuopio may dilute tumorigenic compounds which come in direct contact with the colon mucosa.


Antibody stimulation of benzo(a)pyrene carcinogenesis.

Benzo(a)pyrene (BP) was conjugated to horse serum albumin (HSA) and then attached to aldehyde fixed human erythrocytes. These cells were used in a passive hemagglutination test to measure BP antibody. BP antibodies were found to be induced in Swiss mice injected with tumorigenic doses of BP. Of the mice treated with BP, those which developed tumors soonest had the highest levels of BP antibody. This observation suggested that the antibody to BP may stimulate tumor development. When rabbit antibody to BP was injected with BP a significantly increased tumor formation occurred. Active immunization using BP conjugated to a foreign protein also significantly increased tumor formation when the mice were treated with BP. Our findings suggest that the immune response to carcinogens is an important component of the carcinogenic process.


Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo(a)pyrene in bovine serum albumin in Syrian hamsters.

The chronic effect of benzo(a)pyrene (B(a)P) administered intratracheally in bovine serum albumin was studied in Syrian golden hamsters. Dose levels of 0.1 mg, 0.33 mg and 1.0 mg of B(a)P induced papillomas and carcinomas of the trachea, stem bronchi and bronchioles. In addition to such tumours, the mucosa of the respiratory tract revealed a variety of atypical epithelial alterations. Although survival time exhibited a dose-dependency, tumour incidence did not. The incidence of respiratory tract tumours was higher in female hamsters than in males. The results of these investigations are statistically evaluated.


Carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in European hamsters.

Laboratory-bred European hamsters received intragastric administrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) once weekly for 20 weeks. The animals showed mainly squamous cell papillomas and carcinomas of the fore-stomach. The tumour incidence was higher in males (80%) than in females (30%). The average tumour latency was comparatively short (25 weeks).


Inability of vitamin A deficiency to alter benzo(a)pyrene metabolism in Syrian hamsters.

Syrian golden hamsters were placed on a control or vitamin A-deficient diet. When their serum vitamin A content was significantly reduced, i.e., to less than 10% of controls, the hamsters were killed and lung aryl hydrocarbon hydroxylase activity and metabolism of benzo(a)pyrene were determined. The benzo(a)pyrene metabolite profile was similar with control and A-deficient systems, and only few quantitative differences were noted. Addition of beta-retinyl acetate to the in vitro incubations did not substantially affect benzo(a)pyrene metabolism.


Effects of radiation type and dose and the role of glucocorticoids, gonadectomy, and thyroidectomy in mammary tumor induction in mammotropin-secreting pituitary tumor-grafted rats.

Three experiments on the induction of mammary neoplasms by total-body 11- to 100-rad neutron or 50- to 500-rad gamma-radiation of female Fischer or W/Fu rats are reported. Grafts of mammotropin-secreting pituitary tumor were used to elevate mammotropic hormone levels. The results (a) confirm and extend previous reports that neutrons are more efficient in carcinoma induction than are gamma-rays (the neutron relative biological effectiveness for first carcinomas was 3.68) and (b) demonstrate that the potentiation of carcinoma induction by adrenalectomy is reversed by glucocorticoid replacement. Statistical analysis of the data by procedures that take into account time at risk as well as tumor frequency indicates that multiple mammary tumors do not occur independently (i.e., a first mammary neoplasm significantly increases the probability of development of another neoplasm). The statistical procedure used in this analysis is presented.


Growth fraction as the major determinant of multicellular tumor spheroid growth rates.

Multicellular tumor spheroids (MTS) from seven murine solid tumors have been compared in terms of their growth rate and the fraction of the cells that are in cycle. Growth rates ranged from a low of 19 micron/day through a maximum of 106 micron/day, demonstrating a far wider range of growth rates than is observed when the same tumors are grown as monolayers. Through the use of an [125I]iodouridine deoxyribose incorporation assay, it has been possible to demonstrate that cells within the MTS that are in cycle double at a slower rate than they do in monolayers and that the depth of the dividing shell ranges from less than 20 to more than 100 micron. The depth of the dividing shell or the growth fraction is highly correlated with the MTS growth rate (r = 0.97). We conclude that the major factor that determines the wide range of MTS growth rates, in spite of relatively uniform doubling times in monolayer, is the fraction of the cells that are in cycle.


Cell population kinetics of fast- and slow-growing transplantable tumors derived from spontaneous mammary tumors of the DBA/2 Ha-DD mouse.

The proliferation kinetics of a fast-growing spontaneous mouse mammary tumor subline (SMT-F) and a slow-growing spontaneous mouse mammary tumor subline (SMT-S) tumor have been determined autoradiographically at 2 different stages of tumor growth. The length of the cell cycle and the growth fraction for SMT-F were 11.2 hr and 0.85, respectively, on Day 14 and 12.1 hr and 0.78 on Day 28. For SMT-S these same parameters were 15.6 hr and 0.50 on Day 14 and 16. 1 hr and 0.45 on Day 28. On Days 14 and 28 the mitotic indices were 1.3 and 1.0%, respectively, for SMT-S, compared to 2.2 and 1.9% for SMT-F. The cell loss rate, cell loss factor, and cell loss were significantly higher for SMT-F than for SMT-S. The difference in the growth rates for these 2 tumor lines was attributable to a slight prolongation of the length of the cell cycle and a reduction in the growth fraction of SMT-S.


Aryl hydrocarbon hydroxylase activity and microsomal cytochrome content of human fetal tissues.

Aryl hydrocarbon hydroxylase (AHH) and microsomal cytochromes were measured in tissues of human features aborted by prostaglandins. Cytochrome P-450 concentrations and AHH activity were about 4 times higher in adrenal glands than in liver. AHH was present in testes, ovaries, and vagina and uterus at levels equal to or greater than those in the liver. In lung, kidney, and intestines it was present at levels lower than those in the liver. Mean hepatic AHH and hepatic and adrenal cytochromes P-450 and b5 were not significantly different in prostaglandin and hysterotomy abortuses; mean adrenal AHH was significantly lower in prostaglandin abortuses, but the ranges in both groups were overlapping. Neither fetal sex nor maternal cigarette smoking affected hepatic or adrenal AHH activity or microsomal cytochrome concentrations or difference spectra. Hepatic and adrenal AHH activities were concentrated in microsomes and were correlated with microsomal P-450 content. These findings are constant with P-450 mediation of AHH in human fetal tissues. The data demonstrate the utility of prostaglandin abortuses for studies of fetal tissue mixed-function oxidase activity and point to the endocrine glands and target tissues in addition to the liver as potential sites for activating chemical carcinogens and cytotoxins in the human fetus.


Concanavalin A-mediated hemadsorption by normal and malignant human mammary epithelial cells.

The concanavalin A (Con A) reactivity of malignant and normal human mammary epithelial cells in culture was determined with a hemadsorption assay. Human erythrocytes were treated with various concentrations of Con A, and these indicator Red Blood Cells were incubated with the test cells in situ in culture dishes. The Con A concentration at which approximately 50% of the test cells adsorbed erythrocytes ([Con a] 1/2 max) was determined. Five malignant epithelial cell lines and the primary cultures derived from 3 pleural effusions and 20 solid tumors were tested. Primary cultures of normal epithelial cells were established from human milk samples obtained from 3 separate donors. The average [Con A] 1/2 max value for the 5 cell lines and the pleural effusion cultures was 6 and 5 microgram/ml, respectively. The average [Con A] 1/2 max value for the 20 solid breast tumors was 20 microgram/ml. In contrast to the malignant cells, normal mammary epithelial cells did not adsorb erythrocytes coated with as much as 100 microgram Con A per ml. These results show that Con A reactivity distinguishes normal from malignant human mammary epithelial cells.


Induction of spleen cell growth and DNA polymerase activity by Corynebacterium parvum.

Corynebacterium parvum induces rapid proliferation of spleen cells with concomitant rapid increases in DNA synthesis as measured by [3H]thymidine uptake and increase in DNA polymerase activity. Cell number increased exponentially over 10 days. DNA polymerase activity increased 8-fold after C. parvum stimulation. The rapidity of response indicated a population response to the stimulus, and the data are consistent with a direct stimulation of spleen cell proliferation by C. parvum.


Generation of anti-MOPC-315 cytotoxicity in uneducated or in vitro educated spleen cells from normal or MOPC-315 tumor-bearing mice pretreated in vivo with Bacillus Calmette-Guérin.

Cultured spleen cells from normal or MOPC-315 tumor-bearing BALB/c mice that were pretreated in vivo with Bacillus Calmette-Guérin (BCG) exhibited in vitro cytotoxicity against MOPC-315 plasmacytoma. In vitro education of BALB/c spleen cells from normal or tumor-bearing mice by cocultivation with mitomycin C-treated MOPC-315 stimulator cells also resulted in antitumor cytotoxicity. The combination of BCG pretreatment of donor mice with the in vitro education of their spleen cells resulted in a level of anti-MOPC-315 cytotoxicity that was greater than the sum of the levels of cytotoxicity exhibited by spleen cells subjected to either process alone. The levels of cytotoxicity exhibited by educated or uneducated spleen cells from BCG-pretreated mice were dependent on the dose of BCG used and on the time interval between in vivo pretreatment and the initiation of in vitro culture. Thus, our findings suggest that educated spleen cells from tumor-bearing hosts that were pretreated with BCG might be useful in immunotherapeutic regimens requiring histocompatible cells with augmented antitumor cytotoxicity.


Tumor induction in the trachea of hamsters with N-nitroso-N-methylurea.

Experiments were conducted to study the tumor response of hamster tracheas to N-nitroso-N-methylurea. Tracheas were exposed repeatedly with the use of a tracheal catheter. Ten to 30 exposures were given over a period of 5 to 20 weeks. The carcinoma incidence (including carcinoma in situ) was 0,42, 67, 88, and 94% for 10, 15, 20, 25, and 30 twice-weekly exposures, respectively. With 10 exposures 2 of 12 hamsters developed benign tracheal tumors. Mean tumor induction time decreased when frequency of exposure was increased from 50 weeks with 10 to 15 exposures to 28 weeks with 25 to 30 exposures. The major histological types of invasive carcinomas observed were epidermoid carcinomas (54%), anaplastic large-cell and small-cell carcinomas (26%), adenocarcinomas (13%), and combined epidermoid-adenocarcinomas (7%). Sacrifice studies revealed that with 10 to 20 twice-weekly exposures only metaplastic lesions with varying degrees of cellular atypia are present at the time of the last exposure. Neoplastic lesions develop during the subsequent exposure-free interval. The data suggest that this tracheal tumor induction system may be well suited for studying problems related to development and progression of neoplastic disease.


Carcinogenicity and mutagenicity of benz(a)anthracene diols and diol-epoxides.

Benz(a)anthracene (BA) and its five possible trans-dihydrodiols were evaluated for determination of their skin tumor-initiating activity and their mutagenic activity in Chinese hamster V79 cells. In addition, the skin tumor-initiating abilities of five diol-epoxides of BA were tested. Results showed (+/-)-trans-3,4-dihydroxy-3,4-dihydrobenz(a)anthracene (BA 3,4-dihydrodiol) to be approximately 10 times more mutagenic than was BA and about 20 times more mutagenic than were the other possible dihydrodiols in the V79 cells cocultivated with irradiated hamster embryo cells. As a skin tumor initiator, BA 3,4-dihydrodiol was approximately 5 times more active than BA, whereas the other BA dihydrodiols were all less active tumor initiators. (+/-)-trans-3alpha,4beta-Dihydroxy-1alpha,2alpha-epoxy-1,2,3,4-tetrahydrobenz(a)anthracene was found to be approximately 20% more active as a tumor initiator than was BA 3,4-dihydrodiol, whereas the other diol-epoxides of BA were less active than BA itself. The results suggest that the bay-region diol-epoxide of BA may be the ultimate carcinogen and mutagenic form of BA.


Regional differences in the incidence and growth of mouse tumors following intradermal or subcutaneous inoculation.

Tumor cells inoculated intradermally or s.c. into more cranial regions of the lateral trunk show strikingly greater tumor growth and development than do similar cells injected more caudally. At low tumor cell doses the incidence anteriorly may be double that found posteriorly and tumors become detectable more rapidly anteriorly; at higher cell doses the anterior:posterior ratio of tumor weight may be 4:1. The effect appears to be independent of the type of tumor used (mastocytoma, sarcoma, teratoma, lymphoma, or adenocarcinoma) and of the strain of mouse host; it does not appear to be influenced by the sex of the host animal, the immunogenicity of the tumor, or the immunological competence of the tumor recipient. The results are discussed both in terms of practical considerations for developing adequate tumor transplantation and treatment protocols and in terms of the biological significance in relation to spontaneous or induced oncogenesis.


Biological activity and metabolism of the retinoid axerophthene (vitamin A hydrocarbon).

Biological properties of axerophthene, the hydrocarbon analog of retinol, have been studied both in vitro and in vivo. In tracheal organ culture axerophthene reversed keratinization caused by deficiency of retinoid in the culture medium; its potency was of the same order of magnitude as that of retinyl acetate. Axerophthene supported growth in hamsters fed vitamin A-deficient diets although less effectively than did retinyl acetate. Axerophthene was considerably less toxic than was retinyl acetate when administered repeatedly in high doses to rats. Administration of an equivalent p.o. dose of axerophthene caused much less deposition of retinyl palmitate in the liver than did the same dose of retinyl acetate, while a greater level of total retinoid was found in the mammary gland after administration of axerophthene.


Inhibiting effect of caffeine on spontaneous and urethan-induced lung tumors in strain A mice.

The i.p. injection of caffeine (8, 20, and 40 mg/kg) 3 times weekly for 8 weeks suppressed the development of spontaneous pulmonary adenomas in strain A mice. The same caffeine injection scheme suppressed urethan (0.25 and 1.0 mg/g)-induced lung tumor development when caffeine treatment started 1 week before urethan administration, but this suppression was not significant when caffeine treatment was initiated 1 week after urethan injection. The most pronounced suppression of lung tumor formation occurred when caffeine was given as only two injections 3 hr before and 3 hr after urethan administration. The incorporation of [3H]thymidine into lung tissue DNA of caffeine-treated mice was impaired at the time of urethan administration. Also, caffeine partially antagonized the effects of urethan on lung tissue, as measured by [3H]thymidine incorporation studies. One interpretation of these results is that caffeine-induced suppression of DNA synthesis interferes with pulmonary adenoma induction by decreasing the affinity of lung tissue DNA for urethan. The finding that chronic caffeine treatment produced continued suppression of [3H]thymidine incorporation into lung tissue DNA suggests that caffeine-induced inhibition of spontaneous pulmonary adenoma formation is due to a general suppression of lung DNA-synthetic activity.


Cytocidal and cytostatic ability of Corynebacterium liquefaciens in mouse squamous cell carcinoma in vivo.

The cytostatic and cytocidal action of Corynebacterium liquefaciens was studied in a mouse squamous cell carcinoma in vivo. Kinetic analysis of tumor cells 4 and 8 days after a single i.p. dose of 2.0 mg C. liquefaciens showed a marked prolongation of the mean cell generation time (TG). This prolongation affected most the G1 and, to a lesser extent, the S phases of the cell cycle. The tumor growth factor was decreased, and the mean value of the cell loss factor was increased. Assays to determine the number of tumor cells needed to produce the tumor in one-half of the transplant recipients showed that peritoneal exudate cells collected from mice given injections of C. liquefaciens exerted tumor cell killing that depended on the peritoneal exudate cell tumor:cell ratio. This cell killing was not found with peritoneal exudate cells from normal or proteose peptone-treated mice.


Nuclear translocation of the estrogen receptor in autonomous C3H mouse mammary tumors.

The reason for estrogen independence of C3H mouse mammary tumors has been sought in the initial steps of estradiol action. The characteristics of the estrogen receptors were similar to those observed in estrogen-responsive tissues: high affinity and binding specificity, DNA binding and 8S sedimentation constant as shown by sucrose gradient centrifugation. Their concentration averaged 18.5 +/- 3.5 (S.E.) fmol/mg cytosol protein in the cytosol and 3.5 +/- 1.0 fmol/mg cytosol protein in the KCl nuclear extract. The nuclear translocation of the cytosol receptor was investigated with the use of biopsy and in vivo injections of radioactive estradiol. No nuclear translocation of estrogen receptor could be ascertained with the dextran-coated charcoal assay since the free and nonspecifically bound estrogen conjugate(s) were also assayed by this technique. However, when the estrogen-receptor complexes were estimated by more specific methods such as protamine sulfate or hydroxylapatite precipitations, the estrogen receptor translocation into the nucleus was clearly shown. We therefore conclude that the estrogen independence of C3H mammary tumors cannot be explained by a defect in the two initial steps of the mechanism of action of estradiol, namely, cytosol binding and nuclear translocation of receptors.


Evidence for bay region activation of chrysene 1,2-dihydrodiol to an ultimate carcinogen.

The tumor-initiating activities of chrysene and the three metabolically possible trans-dihydrodiols at the 1,2-, 3,4-, and 5,6-positions of chyrsene were determined on the skin of female CD-1 mice. A single topical application of 0.4, 1.25, or 4.0 mumol of each compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. The most potent tumor initiator was chrysene 1,2-dihydrodiol, which had approximately twice the tumorigenic activity of the parent hydrocarbon chrysene at all doses tested. Chrysene 3,4-dihydrodiol and chrysene 5,6-dihydrodiol had no significant tumorigenic activity. 1,2-Dihydroxy-1,2,3,4-tetrahydrochrysene, a compound related to chrysene 1,2-dihydrodiol but with the conjugated nonaromatic double bond removed from the 3,4-position of the molecule, had less than 25% of the tumorigenic activity of chrysene 1,2-dihydrodiol. These results indicate that chrysene 1,2-dihydrodiol is a proximate carcinogenic metabolite of chrysene and that a chrysene 1,2-diol-3,4-epoxide, in which the epoxide group forms part of the bay region in the molecule, is a likely candidate as an ultimate carcinogenic metabolite of chrysene.


Tamoxifen retinopathy.

Tamoxifen has been used as a chemotherapeutic agent with no serious side effects noted. Four patients receiving high-dose tamoxifen for greater than 1 year have demonstrated similar retinal changes. Three of the four patients had a significant decrease in visual acuity as the result of a retinopathy, primarily affecting the region about the macula accompanied by macular edema. In addition, three of the four patients had unusual corneal changes. These findings suggest that the corneal and retinal changes are the result of a toxic effect of tamoxifen when used in the doses and duration described.


Combination chemotherapy: arriving at optimal treatment levels by incorporating side effect constraints.

This paper represents a method for determining optimal dose levels in a drug combination by analyzing the dose-response surfaces estimated from experimental data. In addition to using the presence or absence of a favorable response (in this instance, survival for at least twice the median untreated lifespan of B6D2F1 female mice bearing advanced sc implanted L1210 leukemia), the presence or absence of associated side effects is also employed (in this instance, Day-12 weight loss). The technique is potentially superior to existing methods of responding to the occurrence of treatment side effects due to its ability to take into account interactions between drugs. Since this method offers a way to determine optimal dose by including nonlethal toxicity information; it should find application in clinical situations.


Synthesis and antitumor activity of 4-demethoxyadriamycin and 4-demethoxy-4' -epiadriamycin.

Two new analogs of adriamycin have been obtained by chemical synthesis, 4-demethoxyadriamycin and 4-demethoxy-4' -epiadriamycin. Both compounds were highly effective against experimental mouse tumors at doses about ten times lower than those effective for adriamycin. At the optimal dose, 4-demethoxyadriamycin displayed antitumor activity similar to that of adriamycin in solid Sarcoma 180 (S180), L1210, P388, and Gross leukemias, and mammary carcinoma, while it did not markedly inhibit the growth of Moloney sarcoma virus-induced sarcoma in mice treated before the virus infection. At the optimal dose, 4-demethoxy-4' -epiadriamycin was as active as adriamycin against L1210, P388,and Gross leukemias, and less active against solid S180. The results show that anthracycline derivatives characterized by the absence of the methoxyl group at the C-4 position are markedly more potent than the parent compound, and may exhibit a differential antitumor effect on a number of mouse tumors.


High-presssure liquid chromatographic determination of methotrexate and its major metabolite, 7-hydroxymethotrexate, in human plasma.

A rapid high-pressure liquid chromatographic assay is described for the analysis of methotrexate (MTX) and its major metabolite, 7-hydroxymethotrexate (7-OH-MTX), in plasma samples from patients following high-dose therapy. The method involves an ion-pair extraction of MTX from plasma with chromatography on a microparticulate anion-exchange column using ultraviolet detection at either 254 or 315 nm. Maximum sensitivity achieved was 1 X 10(-7) M. In addition to being specific for parent MTX, this procedure was used to detect and quantitate significant concentrations of 7-OH-MTX in several patients. Comparison to a protein-binding method indicated a greater degree of specificity for the chromatographic procedure. The procedure can be used to allow therapeutic monitoring of plasma MTX and metabolite for patients receiving high-dose MTX therapy as well as to determine the purity of formulations of MTX used clinically. In addition, the procedure is applicable to the support of pharmacokinetic studies of MTX in animals and man.


Studies on the distribution of dianhydrogalactitol into the central nervous system of the rat.

The distribution of dianhydrogalactitol-C14 (DAG-C14) which had been administered to rats as an iv bolus injection was studied in plasma and brain tissue. Analysis of samples was carried out by a high-pressure liquid chromatography method which specifically responds to the parent drug. Samples were monitored by both ultraviolet and liquid scintillation spectrometry. Plasma level measurements indicate that intact DAG has a relatively short half-life in plasma (t1/2= 43.7 minutes) and brain (t1/2 = 50.3 minutes). These findings differ significantly from those studies which have measured total radioactivity when monitoring DAG levels; and should be considered in the design of DAG dose regiments. Data from both brain and plasma were consistent with a classic two-compartment open model.


Enhancement by hyperthermia of the effect of BCNU against the EMT6 mouse tumor.

The combination of moderate hyperthermia (43 degrees C water bath for 1 hour) and BCNU against the EMT6 mouse tumor has been studied. The effect was found to be much greater than could have been predicted from the effects of the single modalities and this is true whether the endpoint is tumor cure, growth delay, or in vitro assay of clonogenic fraction. The results indicate that inhibition of "recovery from potentially lethal drug damage" is not the mechanism by which heating potentiates the action of BCNU.


Rat-colonic, mucus glycoprotein.

A glycoprotein was isolated from rat-colonic mucosa. Analytical ultracentrifugation studies showed the glycoprotein to be homogeneous, having an apparent molecular weight of 9.0 X 10(5); no subunits could be detected in the presence of sodium dodecyl sulfate. It contained 14% of protein and 86% of carbohydrate. The principal sugars in the glycoprotein were galactose, fucose, sialic acid, 2-acetamido-2-deoxygalactose, and 2-acetamido-2-deoxyglucose. A small proportion of mannose was also present. The glycoprotein, apart from the usual carbohydrate constituents present in mucus glycoproteins, contained sulfate, but no uronic acid. High amounts of serine and threonine, and low contents of aromatic and traces of sulfur-containing amino acids, reflect a similarity of this glycoprotein to other mammalian mucus glycoproteins; it differs, however, by its high proportions of Asx + Glx (26 mol.%). Cleavage studies with alkaline borohydride indicated O-glycosidic linkages between N-acetylhexosamine and serine, and threonine, of the peptide core in the glycoprotein. Only about one third of the serine and threonine was linked to the carbohydrate side-chains, which averaged about 22 units in length and were apparently branched.


Lectin binding to mosquito Aedes aegyptii and human KB cells: structural comparisons of membrane oligosaccharides.

High capacity adsorbents for lectins, including Lotus tetragonolobus L-fucose-binding protein, were readily prepared by conjugation of monosaccharides with commercially available, epoxy-activated Sepharose. Purified, radioiodinated lectins were bound to cells of the mosquito Aedes aegyptii and of human KB tumour. Relative to human KB cells, mosquito cells bound less of lectins specific for the sugars (L-fucose and D-galactose) that are terminal residues in many mammalian glycoproteins, whereas the number of binding sites of lectins specific for core-region sugars (D-mannose and 2-acetamido-2-deoxy-D-glucose) were similar. Neuraminidase, which greatly enhanced binding of peanut agglutinin or soybean agglutinin to human KB cells, had negligible effects on binding of these lectins to mosquito cells. The comparative structures of surface oligosaccharides of mosquito and KB cells are discussed in relation to the lectin-binding studies.


The mechanism of acceptor reactions of Leuconostoc mesenteroides B-512F dextransucrase.

Reactions of dextransucrase and sucrose in the presence of sugars (acceptors) of low molecular weight have been observed to give a dextran of low molecular weight and a series of oligosaccharides. The acceptor reaction of dextransucrase was examined in the absence and presence of sucrose by using D-[14C]glucose, D-[14C]fructose, and 14C-reducing-end labeled maltose as acceptors. A purified dextransucrase was preincubated with sucrose, and the resulting D-fructose and unreacted sucrose were removed from the enzyme by chromatography of columns of Bio-Gel P-6. The enzyme, which migrated at the void volume was collected and referred to as "charged enzyme". The charged enzyme was incubated with 14C-acceptor in the absence of sucrose. Each of the three acceptors gave two fractions of labeled products, a high molecular weight product, identified as dextran, and a product of low molecular weight that was an oligosaccharide. It was found that all three of the acceptors were incorporated into the products at the reducing end. Similar results were obtained when the reactions were performed in the presence of sucrose, but higher yields of labeled products were obtained and a series of homologous oligosaccharides was produced when D-glucose or maltose was the acceptor. We propose that the acceptor reaction proceeds by nucleophilic displacement of glucosyl and dextranosyl groups from a covalent enzyme-complex by a specific, acceptor hydroxyl group, and that this reaction effects a glycosidic linkage between the D-glucosyl and dextranosyl groups and the acceptor. We conclude that the acceptor reactions serve to terminate polymerization of dextran by displacing the growing dextran chain from the active site of the enzyme; the acceptors, thus, do not initiate dextran polymerization by acting as primers.


Purification, characterization, and action-pattern studies on the endo-(1 linked to 3)-beta-D-glucanase from Rhizopus arrhizus QM 1032.

The extracellular (1 linked to 3)-beta-D-glucanase [(1 linked to 3)-beta-D-glucan glucanohydrolase, EC 3.2.1.6] produced by Rhizopus arrhizus QU 1032 was purified 305-fold in 70% overall yield. This preparation was found to be homogeneous by ultracentrifugation (sedimentation velocity and equilibrium studies), electrophoresis on acrylamide gel with normal, sodium dodecyl sulfate, and urea-acetic acid gels, and upon isoelectric focusing. The amino acid composition of the enzyme has been determined and it possesses a carbohydrate moiety compose of mannose and galactose (in the ratio approximately 5:1) that is linked to the protein through a 2-acetamido-2-deoxyglucose residue. The molecular weight, as determined by equilibrium sedimentation, is 28,800 and this number was confirmed by electrophoresis on gels of sodium dodecyl sulfate. The enzyme does not possess subunit structure. It hydrolyzes its substrates with retention of configuration and possesses transglycosylating ability. The rates of hydrolysis of a wide variety of substrates were determined, and its action pattern on a series of oligosaccharides containing mixed (1 linked to 3)-, (1 linked to 4)-, and (1 linked to 6)-beta-D-glucopyranosyl residues was investigated. The enzyme favors stretches of beta-D-(1 linked to 3) linkages, but it can hydrolyze beta-D-(1 linked to 4) linkages that are flanked on the non-reducing side with stretches of beta-D-(1 linked to 3) links. The enzyme will not act on (1 linked to 6)-beta-D-glucosyl linkages located in stretches of beta-D-(1 linked to 3) and will not act on (1 linked to 3) beta-D-glycosidic linkages involving sugars other than D-glucose.


Substrate- and product-affinity resins for adenosine deaminase obtained by immobilisation of adenosine and inosine via 2',3'-cyclic acetal derivatives.

Immobilised inosine (6a) and adenosine (6c) and their 5'-phosphates have been synthesized. Reaction of the nucleosides with ethyl levulinate, followed by saponification or phosphorylation and then saponification, gave the 2',3'-O-[1-(2-carboxyethyl)ethylidene] derivatives 3 and 4 and the corresponding 5'-phosphates 2b and 2d. 6-Aminohexylagarose (5) was severally coupled to 2b, 2d, 3, and 4 through the carboxyl groups to give the polymers 6a-d. Adenosine deaminase converts 3 into 4, and 6c into 6a. The polymers can be used as affinity resins for adenosine deaminase, which is bound more strongly to 6c than to 6a. The operational capacity of 6a for adenosine deaminase is constant at 15--25 degrees, but decreases by approximately 16% from 25 degrees to 35 degrees. The resin 6a has been used to separate adenosine deaminase from mixtures containing other enzymes, for example, guanase or alcohol dehydrogenase.


Myocardial depressant effects of sodium acetate.

Sodium acetate produced a direct, dose-related decrease in myocardial contractile force in the dog and isolated rabbit papillary muscle. In the dog, there was also a decrease in blood pressure which was attributed primarily to the fall in contractile force. However, sodium acetate was found to have weak vasodilator properties as shown by the decreases in hind-limb perfusion pressure.


Effects of oral equiblocking doses of a cardioselective and noncardioselective beta-adrenergic blocking agent on left ventricular function in the normal conscious dog.

The effects of propranolol, a noncardioselective beta-adrenergic blocking agent, and practolol, a cardioselective agent, on left ventricular function were compared in an awake dog model at an equiblocking dose range. Both agents produced modest depression of inotropic state at rest, and during volume and phenylephrine loading. No significant differences between the two agents were detected.


Protective effect of methylprednisolone sodium succinate on the ultrastructure and resting tension of hypoxic heart muscle.

Experiments were undertaken to further investigate the protective effect of methylprednisolone sodium succinate on hypoxic heart muscle. Hypoxia was induced in isolated Langendorff perfused rat and rabbit hearts by gassing the perfusate with 95% N2 + 5% CO2. The hypoxia-induced damage was quantitated in terms of an altered ultrastructure and increased resting tension. When added at the start of the hypoxic episode 6 X 10(-5) mol.litre-1 methylprednisolone sodium succinate protected the fine ultrastructure of the heart, and delayed the increase in resting tension. This protective effect could not be accounted for in terms of the sodium succinate moiety.


Plasma lysosomal enzyme activity in acute myocardial infarction.

N-acetyl-beta-glucosaminidase (EC 3.2.1.30, recommended name beta-N-Acetylglucosaminidase) was found to be a constituent of human cardiac lysosomes. beta-glucuronidase was also found in this tissue, while lysozyme, an enzyme present in leucocyte lysosomes, was not detectable in the heart. The activities of both N-acetyl-beta-glucosaminidase and beta-glucuronidase were elevated in plasma during the first 24 h after the onset of chest pain in patients with acute myocardial infarction and the peak levels of N-acetyl-beta-glucosaminidase correlated well with those of creatine kinase. N-acetyl-beta-glucosaminidase showed a further rise in plasma activity which gave a peak at 72 h after the onset of chest pain and this was accompanied by a rise in lysozyme activity. It is suggested that lysosome disruption caused by myocardial cell necrosis was responsible for the initial rise in plasma lysosomal enzyme activity and that the subsequent inflammatory reaction gave rise to the second peak.


Coronary blood flow in physically trained rats.

Coronary blood flow was measured using labelled microspheres (15 micrometer diameter) in sedentary and endurance trained rats during hypoxaemic conditions designed to develop coronary dilatation (Pa,O2 6.0 to 6.7 kPa [45 to 60 mmHg]). Rats that were trained for 12 to 18 weeks (26.8 m per minute, 15% gradient, 1 hour per day) had a significantly greater coronary blood flow conductance (15.3 +/- 1.0 mm3.min-1.kPa-1 aortic diastolic pressure, n = 20) than sedentary animals (10.8 +/- 0.9, n = 19). Even though cardiac hypertrophy (17%) was found in the trained animals, this increase in perfused mass accounted for only one-third of the increase in total coronary blood flow. Thus, there was a greater coronary blood flow per unit mass of the myocardium in the trained rats.


Changes in plasma noradrenaline concentration following sympathetic stimulation by gradual tilting.

Plasma noradrenaline concentration was determined by a radioenzymatic method in 10 normal individuals who were subjected to a stepwise tilt through 45 degrees. A gradual increase in noradrenaline was observed with maximal values occurring in most subjects following the full 45 degrees of tilt. Maximal levels were sustained for up to 30 min. In two subjects who fainted, the syncopal episode followed an initial sympathetic postural response as shown by a rise in plasma noradrenaline. For the remaining subjects a significant correlation was found between changes in plasma noradrenaline and mean arterial pressure.


Pharmacological protection of mitochondrial function in hypoxic heart muscle: Effect of verapamil, propranolol, and methylprednisolone.

Experiments were undertaken to determine if drugs (verapamil, propranolol, and methylprednisolone sodium saccinate) that protect the fine ultrastructure of heart muscle against damage caused by hypoxia, protect mitochondrial function. Mitochondrial function was assessed in terms of oxidative phosphorylating and Ca2 +-accumulating activities. Isolated rabbit hearts were used, and hypoxic conditions induced by reducing the perfusate PO2 from 80.8 to 0.80 kPa (600 to 6 mmHg). The drugs were either added at the start of the hypoxic perfusion or (verapamil and propranolol) the rabbits were pretreated with them. Verapamil, propranolol and, to a lesser extent, methylprednisolone sodium succinate, provided protection evidenced by the maintainance of near normal mitochondrial oxidative phosphorylating and Ca2 +-accumulating activities after 60 min hypoxic perfusion. When added directly to mitochondria isolated from hypoxic-perfused muscle, the drugs had no effect.


Effects on labile metabolites of temporal delay in freezing biopsy samples of dog myocardium in liquid nitrogen.

Sudden hypothermia utilising liquid nitrogen has been used for immediate inhibition of metabolic reactions and preservation of labile compounds in heart muscle. It has been suggested that this rapid transfer of tissue into liquid nitrogen, within 1 to 2 s, is essential for accurate assessment of internal milieu conditions. We tested this hypothesis in normal dogs by measuring phosphocreatin, ATP, glycogen, and lactate concentrations in transmural layers of a core biopsy taken from the posterolateral wall of the left ventricle frozen immediately in liquid nitrogen or held at room temperature for varying times up to 300 s before freezing the tissue. The earliest significant change occurred in phosphocreatine levels after 60 s; only phosphocreatine demonstrated any changes within the first 120 s. These studies indicate that a delay of up to 30 s may be tolerated before freezing tissue without any change occurring in these labile metabolites.


Protective effect of the vagotonic action of morphine sulphate on ventricular vulnerability.

Administration of morphine sulphate to 16 anaesthetised dogs resulted in significant reduction in ventricular vulnerability to fibrillation. The repetitive extrasystole threshold was used as an index of vulnerability to ventricular fibrillation. In 14 dogs, atropine or vagotomy abolished this response. This suggests that central vagal activation by morphine sulphate may be protective against ventricular fibrillation.


The posterior pituitary of the garden dormouse (Eliomys quercinus l.). Evidence of two types of neurosecretory axons on the basis of ultrastructural characteristics.

Ultrastructural examination of the posterior pituitary of the garden dormouse (Eliomys quercinus L) was carried out at different times in the annual cycle of this hibernating rodent. Obvious differences between experimental groups have not been observed, and the results presented here must be considered as general features of the garden dormouse posterior pituitary. Neurosecretory axons and endings can be divided into two types, according to different aspects of neurosecretory granules (NSG) and microvesicles (MV). One type contains spherical NSG with homogeneous cores and round MV. In the other type, NSG have various, often elongated, shapes. Their content shows two types of crystalline structures and most of the MV have flattened aspects. As it is very unlikely that this duality in NSG is a result of an artefact of fixation, three hypotheses are presented as explanation. The duality of NSG might be related either to their hormonal content (oxytocin or vasopressin) or to their degree of maturation. Moreover, both explanations may be valid. In the species studied, pituicytes often contain concentric lamellar structures of the endoplasmic reticulum (whorls), the significance of which remains obscure.


Leptomeric fibrils and T-tubule desmosomes in the Z-band region of the mouse heart papillary muscle.

The papillary muscle of the heart of adult white mice is investigated. Intrafibrillary located leptomeric fibrils, frequently encountered in the Z-band region of the myofibrils. The leptomeric fibrils are always running in a transverse direction and often in close proximity to the transverse tubules (which are also located at this level). There seems to be a close connection between the dense striae of the leptofibrils and the Z-bands of ordinary myofibrils. The leptomeric fibrils are spindle-shaped and have a length varying between 0.6 and 1.2 microgrometer. The banding periodicity of the fibrils is approximately 0.16 micrometer. Occasionally desmosomes are observed in the T-tubule system.


Immunohistochemical identification and localization of pancreatic polypeptide cells in the pancreas and gastrointestinal tract of the human fetus and adult man.

Pancreatic polypeptide (PP)-containing cells were detected by using anti-bovine PP (BPP) serum in the pancreas and gastrointestinal tract of human fetuses, premature infants and in the pancreas, antrum and jejunum of adult man obtained by biopsy from patients with normal gastroduodenal endoscopy. The localization was established by studying the distribution of PP cells in comparison to the distribution of glucagon-, somatostatin- and insulin cells. The first PP cells are seen in the pancreas at 10 weeks of gestation. They are located preferentially in the lower part of the head of the pancreas. The specificity of immunocytological reaction was ascertained by the inhibition of the reaction by bovine pancreatic polypeptide, glucagon and insulin did not modify the immunocytological reaction.


Primary cultures of dispersed cells of rat pineal gland. I. Fine structure and indole metabolism.

In vitro indole metabolism and ultrastructural morphology of the pineal gland of male rats were examined. A comparison of the effect of norepinephrine stimulation on indole synthesis in whole cultured glands and preparations of dispersed pineal cells is discussed. Our studies on the performance of dispersed cells during the first 24 h after preparation indicate a strong dependence of pineal cells upon physical attachment to the culture dish and probably also on cell-to-cell contact.


Sympathetic innervation of the pulmonary artery, ascending aorta, and coronar glomera of the rabbit. A fluorescence microscopic study.

Adrenergic nerve fibres were demonstrated in the connective tissue of the rabbit coronar glomera by means of the formaldehyde-induced fluorescence technique for catecholamines. This type of innervation is similar to the adrenergic nerve supply to the rabbit and cat carotid body. Adrenergic fibres terminate subendothelially and only a few can be traced to type I cells in the glomera coronaria. The sympathetic innervation of the ascending aorta is exceedingly sparse in contrast to the pulmonary trunk, while vasa vasorum of the ascending aorta exhibit a dense sympathetic innervation.


The juxtaglomerular apparatus of rats with hereditary hypothalamic diabetes insipidus.

The juxtaglomerular apparatus (JGA) of rats with hereditary hypothalamic diabetes insipidus (DI) was studied. Plasma concentration of renin and angiotensin II, as well as serum sodium concentration and serum osmolality of DI rats are elevated. The morphological examination reveals no characteristic alteration of the epitheloid cells. The results show that the epitheloid cells are sufficiently adapted for the higher release of renin.


A determination of the volumes of the layers of the rat hippocampal region.

The absolute volumes of the hippocampal and subicular cortical layers in the rat were determined. The boundaries of the various layers were defined on series of sections made through the entire hippocampal region of five rats and stained according to the Timm sulfide silver technique. Coordinates representing the boundaries of the layers on selected sections were fed into a mini-computer programmed to calculate the volume of the layers from the areas of the profiles and the distances between the sections. The distribution of the layers indicates that they constitute the same proportion of the volume of the dorsal and ventral divisions of the hippocampal region, with the exception of the structures lying in regio inferior and regio superior. Although the combined regio superior and regio inferior components of the layers of Ammon's horn occupy the same percentage of the volume of the dorsal and ventral hippocampal regions, the regio superior components occupy a larger percentage of Ammon's horn in the dorsal region than they do in the ventral region. The inter-animal variations in the volumes of the various layers indicate that it is possible to describe quantitatively the subdivisions of the hippocampal region with a precision that is compatible with comparative studies.


Peroxidase activity in monocytes and tissue macrophages of mice.

A description is given of the distribution of peroxidatic (PO) activity in murine monocytes of blood and peritoneal cavity, and in murine macrophages residing in the unstimulated peritoneal cavity as well as in liver, spleen, bone marrow, and small intestine. In the monocytes, PO activity is restricted to some of the cytoplasmic granules; in the tissue (or resident) macrophages present in peritoneal cavity, liver, spleen, and small intestine, the PO activity is located in the nuclear envelope and the rough endoplasmic reticulum. Macrophages in the bone marrow are PO-negative. In the spleen and bone marrow, reticulum cells show PO activity in the nuclear envelope and the RER. Transitional forms between monocytes and tissue macrophages were not observed.


The structures of dorsal and ventral regions of a dragonfly retina.

The apposition eyes of the corduliid dragonfly Hemicordulia tau are each divided by pigment colour, facet size and facet arrangement into three regions: dorsal, ventral, and a posterior larval strip. Each ommatidium has two primary pigment cells, twenty-five secondary pigment cells, and eight receptor cells, all surrounded by tracheae which probably prevent light passing between ommatidia, and reduce the weight of the eye. Electron microscopy reveals that the receptor cells are of two types: small vestigial cells making virtually no contribution to the rhabdom, and full-size typical cells. The ventral ommatidia have a distal typical cell (oriented either horizontally or vertically), four medial typical cells, two proximal typical cells and one full-length vestigial cell. The dorsal ommatidia have only four full-length typical cells, and one distal and three vestigial full-length cells. The cross-section of dorsal rhabdoms is small and circular distally, but expands to a large three-pointed star medially and proximally. The tiered receptor arrangement in the ventral ommatidia is typical of other Odonata but the dorsal structure has not been fully described in other species. Specialised dorsal eye regions are typical of insects that detect others against the sky.


Differentiation of ovarian and testicular interstitial cells during embryonic and post-embryonic development in mice. Ultrastructural observations.

Different steps in mouse ovarian and testicular development have been studied in order to compare the time sequences during the in vivo differentiation of steroidogenic cell populations growing in contact with male and female gonocytes. These time sequences indicated a basic common developmental pattern: early signs of steroid synthesis in the male gonad, but late entering into meiotic prophase of XY germ cells; early meiosis but late steroidogenic activity in the ovary. In both male and female interstitial tissues, signs of involution were found following a period of exponential development.


Histological and cytological studies on the fat body of the cockroach Nauphoeta cinerea during the first reproductive cycle.

The central fat body of the ovoviviparous cockroach Nauphoeta cinerea was studied during the first reproductive cycle of the female by means of light microscopy, autoradiography and electron microscopy. Comparative studies in larval stages were also undertaken. The fat body of Nauphoeta contains a large amount of lipid droplets and the remaining cytoplasm is very scarce. The cytological cyclicity of the fat body is consistent with the known biochemical rhythms of vitellogenin production. The proteosynthetic apparatus appears about 3 days after imaginal ecdysis, along with vitellogenin. The ribosomal endoplasmic reticulum (RER) shows a tremendous increase by the 7th day of the first cycle. The most active period of vitellogenin production lasts from day 7 to 12. The proteosynthetic apparatus then returns to an inactive stage and disappears. This inactive condition lasts to the end of the gestation period. The autoradiographic results are consistent with the cytological features.