Chronically and acutely suicidal persons one month after contact with a crisis intervention centre.

This paper describes a follow-up study of 31 suicidal people who contacted Klinic (a crisis intervention centre in Winnipeg) during a 28-day period, and who gave their names and addresses. The suicidal persons were classified as either 'chronically suicidal' (those having a history of psychological instability and/or suicide attempts) or 'acutely' suicidal (those having fairly stable lives with no previous psychological instability or suicide attempts). The majority were classified as chronically suicidal, and they reported that they were still experiencing suicidal feelings with little improvement in their life situations. In contrast, none of the acutely suicidal persons were still experiencing suicidal feelings and all felt that their life situation had improved considerably. The majority of suicidal contacts was made by chronically suicidal persons and crisis intervention had a negligible impact on their suicidal feelings and psychological problems. Alternative treatment approaches for this group are recommended.


The role of anonymity in suicidal contacts with a crisis intervention centre.

In follow-up studies of telephone crisis centres the clients who choose to remain anonymous cannot be included in any follow-up group. It is therefore important to try to determine if there are some ways in  which the anonymous group is unrepresentative of the total sample. The results of this study indicate that tha anonymous group tend to be more lonely and more likely to withhold information than the non-anonymous group. However, it would seem that follow-up studies would not be seriously invalidated by the non-availability of the anonymous group. A possible explanation of the role of anonymity in suicidal calls is presented, and the results are further discussed in terms of a counselling approach for anonymous suicidal callers and implications for further  research.


A follow-up of patients found "unfit to stand trial" or "not guilty" because of insanity.

Fifty-six patients who were found unfit to stand trial or not guilty by reason of insanity were followed up after their release from a maximum security psychiatric institution. At the time of follow-up 50 percent lived in the community, 43 percent were in psychiatric facilities and 5 percent were in correctional facilities -- 9 percent of the patients were either returned to the maximum security hospital or had committed new offences. The twenty-seven ex-patients who were interviewed generally exhibited little psychiatric symptomatology and there was evidence that they had adjusted well to the psychiatric facility or community in which they lived. As a group they appeared to have made a better vocational than social adjustment.


A two-year review of court examinations.

This paper reports on a review of 518 Psychiatric Court Examination conducted at the Ottawa Court House in 1972-1973. Characteristics of the sample are described,  and an attempt is made to relate the effects of some of these characteristics to decisions resulting from the psychiatric examination. It was concluded that those examinations help to identify obviously mentally distubed persons, advise the Court about the mental condition of people first appearing in Court, and do not unduly alter the legal process.


Long-term results of reinforcement therapy in children with acute leukemia.

A total of 180 children with acute leukemia was randomized to one of two induction regimens: vincristine plus prednisone, or 6-mercaptopurine plus prednisone. Of 170 patients evaluable for induction therapy, a hematologic remission was achieved in 83% (72/87) on vincristine plus prednisone, and in 93% (77/83) on 6-mercaptopurine plus prednisone. When hematologic remission was achieved, patients were randomized to one of three maintenance schedules: 6-mercaptopurine alone, 6-mercaptopurine plus prednisone for 4 weeks every 3 months, or 6-mercaptopurine plus prednisone plus vincristine for 4 weeks every 3 months. The durations of hematologic remission were compared from the achievement of hematologic remission to bone marrow relapse. The survival data were presented as an overview of the effect of this initial therapy on duration of survival. There was no statistical difference between the two induction regimens. The most important finding in the comparison of the three maintenance schedules was that reinforcement of 6-mercaptopurine maintenance therapy with either prednisone or prednisone plus vincristine resulted in significantly longer durations of remission. Vincristine added to prednisone for reinforcement after induction of remission by vincristine plus prednisone did not increase the duration of hematologic remission or survival over prednisone reinforcement alone.


Adriamycin in the treatment of childhood solid tumors. A Southwest Oncology Group study.

Ninety-eight children with solid tumors resistant to conventional chemotherapy received adriamycin 90 mg/m2, either as a single intravenous injection or in 6 divided doses administered every 6 hours. Of the 88 evaluable children, 6 (7%) achieved a complete response and 26 (29%) achieved a partial response. Tumors which demonstrated significant response rates were: neuroblastoma (9/18), Wilms' tumor (7/13), rhabdomyosarcoma (4/11), and lymphoma (4/8). The toxicities observed with this regimen included: alopecia, leukopenia, thrombocytopenia, nausea, vomiting, stomatitis, febrile episodes, and ST-segment changes.


Osteonecrosis of the femoral head in patients with lymphoma treated with intermittent combination chemotherapy (including corticosteroids).

Four adult patients with malignant lymphoma were treated with combination chemotherapy including an alkylating agent, vincristine, procarbazine (in all but one case), and intermittent high-dose prednisone. Twenty to 42 months after initiation of therapy, osteonecrosis of the femoral head developed. This was bilateral in two patients and unilateral in two, and presumably represented a complication of steroid administration, even though three of the patients received only 4 to 6 weeks of therapy. Necrosis of bone may be a low-frequency long-term complication of combination chemotherapy in lymphoma.


Comparison of 5-fluorouracil with 5-fluorouracil, cyclophosphamide, and methotrexate in metastatic colorectal carcinoma.

Thirty-eight patients with metastatic colorecal carcinoma were treated with 5-fluorouracil (5-FU), and 38 patients were treated with the combination of 5-FU, cyclophosphamide, and methotrexate. In terms of percent response, response duration, and survival there was no apparent difference between the two regimens. Combination chemotherapy was found to be effective in 6 of 16 patients refractory to treatment with 5-FU alone, but was associated with more morbidity.


Intensive chemotherapy as primary treatment for rhabdomyosarcoma of the pelvis.

Twenty-six cases of childhood rhabdomyosarcoma involving the pelvis were treated at Childrens Hospital of Los Angeles between 1950 and 1972. The median survival of 17 patients treated up to 1970 was 6 months. Of a group of 9 patients treated with intensive chemotherapy (ICG) prior to surgery and/or x-ray therapy, 5 are surviving from 12 to 60 months and have a relative survival rate of 4.5 times that of the mixed therapy group (MTG) (p = 0.01). Deaths have occurred only in patients with Stage IV disease. The use of preoperative chemotherapy with or without x-ray therapy followed by local surgical excision when necessary can be as effective in prolonging the survival of children with pelvic rhabdomyosarcoma as those obtained with more traditional approaches; this limitation in use of surgery is likely to preserve the quality of life, should the child live to adulthood.


Intra-arterial infusion chemotherapy as preoperative treatment of locally advanced breast cancer.

Intra-arterial infusion chemotherapy was made through the internal mammary artery and subclavian artery in 12 cases of locally advanced breast cancer. Continuous infusion of 5-fluorouracil and intermittent injections of Mitomycin C were jointly made for 1 to 4 weeks in each artery. Marked response in not only the primary tumor but also lymph node metastasis was clinically observed, permitting extended radical mastectomy successfully in all cases. Remarkable regressive changes were histologically observed in cancer foci, especially in small ones, of resected specimens including axillary, parasternal, and supraclavicular lymph nodes. All cases except 1 have been healthy without any recurrence for 22 to 78 months after treatment. Intra-arterial infusion chemotherapy will this method is a useful preliminary procedure for surgical treatment of locally advanced breast cancer.


Frequent low doses of intravenous mechlorethamine for late-stage mycosis fungoides lymphoma.

Ninety-two courses of daily low-dose intravenous nitrogen mustard were administered to 46 patients with advanced cutaneous lymphomas (mycosis fungoides, Sezary syndrome and lymphoma cutis). Seventy-eight % of patients showed objective clinical remission, and 35% reached a clinically disease-free state following 1 or more courses. The response rate was greater in patients with the plaque-tumor type of mycosis fungoides than in those with erythrodermic variants. Therapy was free of significant side effects.


Comparison of serum concentrations of methotrexate after various routes of administration.

Serum concentrations of methotrexate (MTX) were compared in 20 patients after administration of 15 mg/m2 MTX orally, intramuscularly, orally in divided doses, and/or intravenously. Higher and more sustained concentrations usually occurred after intramuscular administration of the drug. Approximately 50% of the patients had measurable serum concentrations 24 hours after a dose, except when the drug was given intravenously. In patients continued on MTX twice a week antimetabolic effects appeared sooner in persons with more sustained serum levels.


Medullary carcinoma of the thyroid. Cellular immune response to tumor antigen in a heritable human cancer.

We have found inhibition of mononuclear leukocyte migration in response to tumor antigen in a group of patients with medullary carcinoma of the thyroid, a cancer inherited as an autosomal dominant. This immune response was not present in a group of family members who do not have cancer.


Successful transurethral intralesional BCG therapy of a bladder melanoma.

An isolated metastasis of malignant melanoma to the urinary bladder of a patient was sucessfully eradicated by transurethral intralesional injection of BCG. Total destruction of the tumor was confirmed by subsequent excision. Lymphocyte blastogenesis studies revealed no significant alteration in immunocompetence secondary to the therapy, except for an increased responsiveness to PPD. There was no evidence of presence of blocking factors following therapy; cytotoxicity against MLA-14 melanoma cells sharply increased after the intralesional injection. Humoral antimelanoma antibody levels, determined by complement fixation, were decreased before the intralesional therapy, but increased markedly immediately following the transurethral BCG injection.


Intestinal-type carcinoma of gallbladder. A histochemical and immunologic study.

Two intestinal carcinomas of the gallbladder are presented. In both carcinomas the structure was papillary in superficial parts; the deeper ones also tended to an adenomatous structure. One of the tumors was bordered by a mucosa, with both intestinal- and antral-type metaplastic islands. The tumor was mainly a typical papilloma with malignant degeneration and infiltrative growth. The intestinal structure was morphologically clear in the papillary area of both carcinomas, but not distinct in the invasive part of the tumor. In both tumors, goblet cells and columnar cells with a distinct brush border were noted. Histochemical and immunologic methods were used in the identification of the glycoproteins of the tumor cells. With both methods the intestinal character of the tumor could be shown. A positive fluorescence was achieved with an intestinal antiserum in well-differentiated tumorous areas containing goblet cells, as well as in the intestinal metaplastic areas. In the same areas the gallbladder-specific antigen was negative. The antiserum isolated from the normal gastric mucosa and corresponding to neutral glycoprotein gave a positive fluorescence only in the nontumorous metaplastic gastric superficial-type epithelium and in the metaplastic antral-type glands.


Biomedical program leading to therapeutic trials on pion radiation at Los Alamos.

Hypoxia and variations in cell cycle phase protect tumor cells being treated with x rays or gamma rays (cobalt). Heavy particles can overcome these protective effects, because of the dense ionization they deposit in tissues. Pions (negative pi mesons) can be directed to and stopped in a specific area, where they are captured by the nuclei of atoms, rendering the nuclei unstable. The nuclei disintegrate, releasing densely ionizing radiation. By confining the dense ionization to the tumor-bearing volume, pions have the potential of increasing the tolerance of the area under treatment to radiation, thus increasing the probability of destroying the tumor. A special channel at the proton factory at the Los Alamos Scientific Laboratory is producing pions for biomedical research. Considerable physical dosimetry has been completed. Cellular studies are underway to provide depth-dose-biological-effect curves. Animal studies will provide information on acute and late effects, which will permit the safe  application of pions to a series of anatomical sites established by protocols for radiotherapy clinical trials.


Delayed cerebrovascular consequences of therapeutic radiation. A clinicopathologic study of a stroke associated with radiation-related carotid arteriopathy.

A young woman, successfully treated for Hodgkin's disease with radiation and MOPP chemotherapy, incurred a devastating stroke months after radiation therapy to the neck and other areas. There was no premonitory clinical history of cerebrovascular attacks. Autopsy showed unilateral thrombotic occlusion of the internal carotid artery unassociated with neoplastic or fibrotic annular constriction of the vessel. There was medial thickening and fibroblastic proliferation within the carotid artery. Areas of focal elastic membrane degeneration involved the cervical portions of the carotid. Thrombus was organized to the damaged vessel wall and was propagated into the intracranial vessels. Aneurysm formation and arterial hemorrhages were absent. These vascular changes occurred in an area of extensive radiation (7200 rads). Pathoanatomical studies in this patient indicate that radiation-induced vascular changes were associated with a "delayed" stroke.


Mucinous tumors of the ovary. Ultrastructural studies of mucinous cystadenomas with histogenetic considerations.

On the basis of light microscopic and scanning and transmission ultrastructural observations, we have classified benign mucinous ovarian neoplasms into two types: a pure endocervical type and a mixed intestinal endocervical type. We have also reviewed the literature pertinent to the histogenetic origin of the ovarian mucinous cystoma and found convincing support for a mesodermal, coelomic epithelial, rather than a teratomatous, derivation.


Lung cancer at autopsy in A-bomd survivors and controls, Hiroshima and Nagasaki, 1961-1970. II. Smoking, occupation, and A-bomb exposure.

The apparent effect of ionizing radiation on lung cancer in A-bomb survivors has not been large enough to still doubts as to its validity. It has seemed essential to determine whether the apparent radiation effect could have resulted from a confounding of heavy smoking and high radiation dose, or if the occupational exposure of high-dose subjects with lung cancer was suggestive of the influence of environmental hazards other than radiation. The available series consists of 204 subjects with lung cancer verified by autopsy, 61 of whom were low-dose (less than 1 rad) and 13 high-dose (200 + rads) subjects. No evidence could be found that the influence of either smoking or occupational exposure upon lung cancer was exerted so as to suggest that the apparent radiation effect is other than real. The study also provides additional evidence of the relationship between lung cancer and smoking in Japanese.


Chromosomes and causation of human cancer and leukemia. X. Banding patterns in cancerous effusions.

Cells from five cancer effusions (two ovarian carcinomas, two lung cancers, and one carcinoma of the breast) were analyzed by G-, C-, and Q-banding techniques. The following observations were made: 1) The origin of some marker chromosomes could be traced accurately by these banding techniques. 2) Several chromosomes, which appeared normal with conventional staining techniques, were found to be re-arranged ones and, hence, abnormal. 3) Chromosomes No. 1, No. 3 and No. 11 were the most frequently involved in aberrations, whereas No. 12, No. 13, No. 17-20, and No. 22 Were least frequently involved. Only in one case each was the X chromosome or the Y chromosome involved in aberrations. The Y chromosome was found to be missing in all cancer cells of one lung cancer. 4) Each effusion had characteristic markers, invariably present in each cell, whether the cells were near diploid, or polyploid. 5) No common markers were observed in the two ovarian carcinomas studied, whereas the two lung cancers had a few common markers.


Abnormalities of chromosome 1 in myeloproliferative disorders.

Three patients with myeloproliferative disorders showed a similar chromosome abnormality, accompanied by other abnormalities that were different in each case. Marrow cells from all three patients were trisomic either for the entire chromosome 1 or for its long arm. Patient 1 had a brief period of anemia and thrombocytopenia which preceded a terminal acute leukemia; Patient 2 had polycythemia vera (P.V.) that terminated in acute leukemia; and Patient 3 has P.V. The detection of an abnormal karyotype in Patients 1 and 2 was an important factor in establishing the diagnosis of acute leukemia. Preliminary evidence supports the suggestion that some chromosomal changes are nonrandom in myeloproliferative diseases. Nonrandom abnormalities involving the same chromosome have been observed in several human neoplastic disorders.


On the ultrastructure of hibernoma.

An electron-microscopic study of hibernoma and a review of the histogenesis, development, and post-natal structural composition of brown and white adipose tissue are presented. The ultrastructural features of hibernoma include multivacuolated and univacuolated cells containing variable numbers of lipid vacuoles, abundant moderately pleomorphic mitochondria with transverse cristae, lysosomes, lipofuscin granules, pinocytotic vesicles, well-formed basal lamina, and prominent subplasmalemmal condensations. The latter have not been previously reported in hibernoma, brown adipose tissue or white adipose tissue, although gap junctions have been observed in brown adipose tissue of newborn mice. It is concluded that the ultrastructural observations support the concept proposed decades ago that hibernoma represents the neoplastic counterpart of brown adipose tissue.


Epithelio-reticular cell thymoma with lymphocytic "emperipolesis." An ultrastructural study.

The ultrastructure of an epithelio-reticular cell thymoma associated with myasthenia gravis is described. The neoplastic cells of an epithelio-reticular nature were dominant in the neoplasm, being closely associated with lymphocytes and scattered non-neoplastic macrophages. The thymic epithelio-reticular cell showed abundant glycogen and some lipid droplets inside the cytoplasm, which was vacuolated and had many elongated processes attached to desmosomes and a very prominent nucleolus. The appearance was similar to that of the immature embryonic epithelial cell of the thymus seen in mammals. Very close contacts existed between the thymic lymphocytes and the epithelio-reticular cells, the appearance being suggestive of the phenomenon of "emperipolesis." Cell death occurred secondarily through nuclear pyknosis and chromatolysis. Lymphocytic debris appeared inside the epithelio-reticular cells and, to some extent, in the cytoplasm of the mesenchymal marcrophages not directly involved in the phenomenon of "emperipolesis."


Ectopic liver tissue mass in the thoracic cavity.

A case is reported in which a liver tissue mass, not connected to the liver, was discovered growing in the right thoracic cavity. This mass appeared following trauma sustained to the liver several years earlier, and was noted to increase slightly in size after its initial detection. After removal of the mass, which proved to be benign hyperplastic liver tissue, the patient did well and remained free of symptoms. It is suggested that during the episode of trauma or during the ensuing surgical repair, a fragment of liver tissue was introduced into the thoracic cavity, and that this fragment eventually developed into a hyperplastic nodular liver mass.


Pseudomyxoma peritonei-nonoperative management and biochemical findings. A case report.

The treatment of choice for pseudomyxoma peritoneai is surgical resection and removal of free mucus. Massive intra-abdominal reaccumulation of viscous mucus has usually been managed by repeat celiotomies. We characterized the  mucus of one patient and showed large amounts of immunoglobulins and carcinoembryonic antigens. Intraperitoneal instillation of 5% dextrose and water made the mucus less viscous and easy to remove by paracentesis. The need for repeat celiotomies was obviated.


Ataxia-telangiectasia with ovarian gonadoblastoma and contralateral dysgerminoma.

Although neoplasms are unusually frequent in patients with ataxia-telangiectasia, the occurrence of primary tumors of the ovary in such patients is exceedingly rare. This report describes a 17-year-old phenotypic female with ataxia-telangiectasia, who was found to harbor an ovarian gonadoblastoma and a contralateral dysgerminoma. The latter tumor has occurred in only one other patient with ataxia-telangiectasia, while an association with gonadoblastoma has never been documented previously. Additional unusual features rarely encountered in patients with gonadoblastoma included origin of the tumor within a histologically proven ovary, and a 46,XX karyotype. The possibility that the dysgerminoma also arose from a gonadoblastoma is discussed.


Increased incidence of cerebral metastases in sarcoma patients with prolonged survival from chemotherapy. Report of cases of leiomysarcoma and chondrosarcoma.

Soft tissue and bony sarcomas rarely metastasize to the central nervous system, particularly to the cerebral hemispheres. In 456 patients with metastatic sarcoma, only 6 (1.3%) had cerebral metastases documented by brain scan at the time of referral for chemotherapy. Adriamycin-containing combination chemotherapeutic regimens have led to a significant increase in the median survival of patients from the start of chemotherapy (18 + months for responders compared, to 7 months in nonresponders). Of 14 patients relapsing after a response or stabilization of disease of 6 months or greater, the cause of relapse was the development of cerebral metastases in 5 (36%). Two of these cases, one a patient with leiomyosarcoma and one with chondrosarcoma, were documented by autopsy and are reported in detail because of their rarity in the medical literature. Although the numbers are small, the increased incidence of cerebral metastases in the group relapsing after a lengthy response suggests that improved chemotherapy for sarcomas resulting in improved survival may be chaning the pattern of metastatic disease, and may require new the;apeutic approaches.


Spindle cell lipoma.

Spindle cell lipoma is a specific type of lipoma that is easily mistaken for a liposarcoma. An analysis of 114 cases of this tumor from the files of the Armed Forces Institute of Pathology reveals that is occurs chiefly in male patients between 45 and 70 years of age and affects the regions of the shoulder and posterior neck almost exclusively. Microscopically, it consists of an intricate mixture of lipocytes and uniform spindle cells within a matrix of mucinous material traversed by a varying number of birefringent collagen fibers. Ultrastructural studies in one case support the fibroblastic nature of the spindle cells. Followup information obtained in 63 patients with this lesion revealed a uniformly favorable clinical course, indicating that local excision is the treatment of choice, and that there is no need or reason for radical surgical procedures.


Cutaneous basal cell carcinoma of vulva.

Eleven cases of basal cell carcinoma of the vulvar skin are reported. There was fairly close correlation between the histologic type and the gross appearance of the lesion. The average age of the patients was 59 years, and the presenting complaint was usually that of a nodule with associated irritation or pruritus. All patients were treated surgically and none have had recurrent or metastatic disease; six patients have been followed for 12 to 25 years. The treatment of choice is wide local excision. One tumor was of particular interest in that it represented a carcinomatous change in a pre-existing premalignant fibroepithelial tumor. Basal cell carcinoma of the skin must be distinguished from adenoid cystic (basal cell) carcinoma of vestibular glands, which is a more aggressive neoplasm and which metastasizes by the lymphatic and blood vascular systems.


Surgical approach for treatment of epidermoid anal carcinoma.

The incidence of malignancy of the anus is rare when compared to colorectal cancer. At The New York Hospital-Cornell Medical Center 43 patients with anal cancer were seen since 1932. Five-year survival for patients treated by local excision, abdominal-perineal resecion, and abdominal perineal resection with associated inguinofemoral groin node dissection was 43%, 66%, and 33%, respectively. Therapy should be guided by location, size, and depth of the local lesion, as well as clinical node status. In general, local excision should be reserved for the most minute lesion. Groin dissection should be carried out when nodes are clinically diseased.


Abnormalities of taste sensation in cancer patients.

In fifty patients with cancer, subjective and objective correlates of anorexia of malignancy were studied. Decreased taste was reported by 25 patients, and an aversion for meat was reported by 16 patients. The decreased taste symptom correlated with an elevated taste threshold for sweet (sucrose), and the symptom of meat aversion correlated with a lowered taste threshold for bitter (urea). The likelihood of having a taste abnormality increased with increasing extent of disease, but not with histologic type of neoplasm. Patients with an abnormality of taste had an increased incidence of weight loss compared with patients with normal taste, even though many in the latter group had other causes of  weight loss. These observations suggest that an abnormality of taste may be one determinant of the anorexia of malignancy. Better understanding of the anorexia in the cancer patient may contribute to the care of the patient.


Dermatofibrosarcoma protuberans metastatic to a regional lymph node. Report of a case and review.

A case of dermatofibrosarcoma protuberans of the lower extremity with metastasis to an inguinal lymph node appearing 5 years after wide excision and skin grafting of the primary lesion is presented. The world literature is reviewed. This case is the 24th instance of metastasis and the 7th case of lymphatic metastasis. The other 17 cases were hematogenous metastases. The clinical and pathologic features of dermatofibrosarcoma protuberans are reviewed, and treatment is discussed, with the aim of emphasizing the need for long-term followup examination of the regional lymph nodes following wide and deep local excision.


The association of economic status with the occurrence of lung cancer.

Lung cancer in men was shown to be inversely associated with economic class by analysis of 1959-61 mortality rates from Buffalo, New York. Using five economis strata, white men below and above age 55 in the poorest group had rates 2.6 and 3.8 times higher than those in the richest. For women, the trend was not significant. The question that was investigated was whether, for males, an economic-class trend for smoking existed which paralleled that for lung cancer. Individuals from a Buffalo sample survey were classified according to cigarette smoking habits. Age was found highly associated with both smoking and economic class. In data from white males stratified for age, no significant association was observed between smoking and econimic class. In women, the upper economic groups smoked more, particularly those above age 55. Thus, a strong inverse economic class gradient for lung cancer in men, observed by other investigators among women, cannot be explained by class-related cigarette smoking patterns alone. The possible interaction of cigarette-smoking with other potential etiologic factors that may be associated with economic class is discussed.


Hematologic and immunologic status in Hodgkin's disease 5 years after radical radiotherapy.

The hematologic and immunologic status was evaluated after 5 years of continuously disease-free survival for 71 consecutive patients treated for Hodgkin's disease by radiotherapy. There was no evidence of residual hematologic depression, even in those patients treated initially with total nodal irradiation. Similarly, quantitative immunoglobulin levels were within the normal range, and the response to delayed hypersensitivity skin testing was intact in nearly all patients. These immunologic studies were consistent with the observed absence of an unusual incidence of infectious complications in these long-term survivors.


Child's play is therapy.

Play can be a simple, effective way of helping the preschool child to deal with the strange and sometimes painful hospital world and to master situations that might otherwise be overwhelming. This type of play can be incorporated easily into the nursing care plan and can become an essential aspect of the care of the hospitalized preschool child. The results are rewarding in terms of happier, less anxious children, parents, and nursing staff.


Is the postpartum period a time of crisis for some mothers?

This was a small descriptive study designed to discover the problems encountered by 3 primiparas and 3 multiparas during the 6 weeks following the birth of their babies. The size and type of sample allows no generalizations to larger groups. Since many problems surfaced for these few families, nurses should continue to explore this maturational period in the family's growth cycle to develop a greater understanding of their potential nursing intervention role.


Cancer epidemiology in populations of the United States--with emphasis on Hawaii and California--and Japan.

The population of California and the San Francisco Bay Area has a number of ethnic components that differ in the frequency with which certain cancers occur. Mortality rates of California Janpanese and incidence data from the cancer reporting system of the Bay Area are analyzed for the cancer sites considered related to nutrition. The American Japanese of California are particularly amenable to epidemiological study because of the cancer data available from Japan for comparison with that of the California Japanese. The cancer rates occurring among the successive generations of the Japanese in California are compared to the rates in Japan and the white rates for the Bay Area. Gastric cancer rates undergo a stepwise reduction from the high rates in Japan to the intermediate rates of immigrant Japanese and the lower rates for the American born. Colon cancer rates are increased about equally in both generations of Japanese and are approaching the white rates. Cancers of the breast, uterine corpus, and ovary in women and the prostate for men are rapidly approaching the rates for the white population. Etiologies are continually being identified or indicated for a number of these cancers by epidemiological studies, and more specific identification of carcinogenic mechanisms should be possible by other disciplines.


Dietary patterns among men of Japanese ancestry in Hawaii.

The dietary patters of 6663 men of Japanese ancestry, living in Hawaii and participating in the Honolulu Heart and Japan-Hawaii Cancer Studies, were analyzed according to country of birth and boyhood education. Approximately 80% of the men were born and educated in Hawaii (Nisei); the others were either born in Japan (Issei) or traveled to Japan for 5 or more years of boyhood education (Kibei). Twenty-four-hr diet recalls, obtained at the first cycle of examinations (1965 to 1968), revealed that the Nisei consumed significantly greater intakes of total and animal protein, total and saturated fat, and cholesterol than the Issei and Kibei. Values for weight, height, skinfold thickness, and serum cholesterol were in the same direction, and the differences were statistically significant. Food frequency questionnaires at the 1st and 3rd examinations covered a 6-year interval. At both time periods, the Issei and Kibei ate Japanese foods more frequently and in greater quantities than the Nisei. In general, the Nisei consumed more Western foods. Both food frequency questionnaires included 6 identical items; coffee, milk, green tea, rice, tofu (soybean curd), and tsukudani (preserved seaweed paste). The frequent and infrequent consumers were similarly characterized over the 6-year period. The findings suggest that the country of birth and education has lasting effects on adult eating patterns. The observed heterogeneity for specific food items and nutrients between the Nisei and Issei-Kibei men augers well for attempts to relate such items to chronic diseases such as cancer.


Some aspects of the epidemiology of esophageal cancer.

The worldwide occurence of esophageal cancer is reviewed, together with the epidemiological information on its causation. The data strongly suggest the factors associated with poverty and specific limitations of dietary intake increase susceptibility for this disease.


Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden.

Sideropenic anemia with epithelial lesions (Plummer-Vinson syndrome) was previously very common among women in northern Sweden. The incidence of this condition is decreasing, however, because of better nutrition and improved health care. Plummer-Vinson syndrome as a sequela of previous sideropenic anemia still influences the pattern of hypopharyngeal and oral cancer in northern Sweden where the female/male ratio in these diseases is remarkably high and where cancer in the postcricoid part of the hypopharynx is relatively common. In Sweden as a whole, a decreasing trend in the incidence of hypopharyngeal cancer in women can be demonstrated, which is probably due to diminished prevalence of Plummer-Vinson syndrome.


Alcohol and alcohol-related deficiencies as carcinogens.

From the available evidence, alsohol ingestion per se does not appear to be carcinogenic. While alcoholism constitutes a major and serious social problem, it is not clear to what extent it constitutes a major health problem. We suggest that excessive alcohol ingestion coupled with a nutritional deficiency or some other insult (e.g., smoking) may be carcinogenic. Alcohol and/or several nutritional deficiencies usually associated with alcoholism have been shown to be immunosuppressive. The relationship between immunoincompetency and neoplasia has long been appreciated, and the exact role that alcohol and/or nutritional insults have in this relationship requires further investigation.


The epidemiology of large bowel cancer.

Results from epidemiogical studies have provided clues as to etiological factors involved in the development of large bowel cancer. Overnutrition, especially in terms of dietary fat consumed, appears to be a key etiological variable affecting the rate of colon cancer. Epidemiologists can provide the leads for chemists and bacteriologists to pursue in population groups and for experimentalists to test in laboratory animals. Coordination of and cooperation between many disciplines is necessary in order to contribute to the prevention of this man-made disease.


Comments on the epidemiology of large bowel cancer.

Available evidence strongly suggests that there are at least two epidemiological subentities of large bowel cancer. Tumors of the intermediate portions display a socioeconomic gradient not observed for cancer of the cecum or lower rectum. Dietary factors are the most plausible etiological candidates. High-fat intake may be a prominent factor, but other dietary constituents could be relevant and may be studied in populations in which stomach and large bowel cancer are infrequent. The eqidemiological usefulness of precursor lesions is emphasized.


Fecal bacteriology of colonic polyp patients and control patients.

Feces from 25 subjects with colonic polyps (multiple adenomatous, large single, or single with atypia) and from 25 matched control subjects were studied by detailed quantitative aerobic and anaerobic techniques, using a large battery of culture media and several atmospheric conditions. Over 55% of organisms detected on microscopic count were recovered anaerobically. In several cases, there were significantly different numbers of organisms of specific types recovered from the two different populations studied. However, these differed from organisms with "statistical significance" noted in a previous study from this laboratory involving two different diet groups (Japanese Americans on either a Japanese or a Western diet). Specific differences in bacteriology between groups with different risks of bowel cancer, noted in earlier British studies, were not noted in our present or previous study.


Animal models for the study of dietary factors and cancer of the large bowel.

Studies in metabolic epidemiology have shown a strong association between dietary fat intake, level of fecal anaerobic bacteria, fecal acid, and neutral sterols and the risk of colon cancer among different populations. Current concepts visualize that colonic bile acids and cholesterol metabolites play a modifying role in large bowel carcinogenesis, that these compounds are derived from dietary factors (directly or indirectly), and that they subsequently are modified by the intestinal bacteria. In the animal model, 2 bile acids (lithocholic and taurodeoxycholic) acted as colon tumor promoters. Rats fed a high-fat diet were more susceptible to colon tumor induction by 1,2-dimethylhydrazine compared to animals fed a normal-fat diet. The intestinal microflora also played a modifying role in enhancing colon tumor production by 1,2-dimethylhydrazine.


The diet, nutrition, and cancer program of the NCI National Cancer Program.

In November 1974, in response to a mandate in the revised National Cancer Act of 1974, a plan was introduced for the formation of a Diet, Nutrition, and Cancer Program. Dr. Frank J. Rauscher, Director of the National Cancer Institute, selected a group of scientists who defined the goals of the program and recommended the appointment of a program director and of an advisory committee. These recommendations were accepted, and an Advisory Committee, reflecting a cross-section of scientific expertise, has been selected. To recommend a well-balanced program, it will be necessary for the Advisory Committee to assess the current state of the art of nutrition in cancer etiology and therapy and to be apprised of current opportunities, needs, and resources. Toward this end, a literature survey project has been initiated and two specialized workshops have been held.


Epidemiology of cancer of the stomach with special reference to its recent decrease in Japan.

Statistics showing a significant decline in stomach cancer death rate in Japan are presented. The decline was most striking in cancer of the pylorus, compared to other anatomical sites, and in metropolitan areas, compared to rural areas. A striking dietary change, especially of milk and milk products, was considered to be the possible reason for such decline, although some of the decrease must be attributed to the active nationwide program of early detection of stomach cancer.


Future inquiries into the epidemiology of gastric cancer.

The fact that gastric cancer has been shown in many studies to be strongly related to a large number of social factors, ethnic background, occupation, socioeconomic status, and the like, suggests the importance of exogenous factors in its etiology. Past studies show a variety of relationships that furnish leads requiring elucidation to further understanding of this disease, e.g., higher risks related to exposures to asbestos, metals dusts, purgatives, and poor dental hygiene. Diet inquiries have steadily improved and negative relationships have been discovered with ingestion of vegetables in studies in Wales, Liverpool, Buffalo, Honolulu, Japan, and Norway. Positive relationships with starch have been found in many of these same places as well as in Israel. These leads need further investigation, as do better methods of diet research, studies of diet and histological type of gastric cancer, diet in its relationship to familial aggregation of gastric cancer, and studies of consistencies in relationships among the various sites in the digestive tract. Because diet is so heterogeneous in modern societies, multivariate analysis is needed in addition to simpler traditional modes.


Dietary factors and the etiology of gastric cancer.

We have developed the working hypothesis that gastric cancer in man may result from the in vivo nitrosation in the stomach of as yet unknown substrates, with the production of alkylinitrosamides. We have established that a source of the nitrite required for the nitrosation was the reduction of nitrate in foods. Nitrate could be derived from its deliberate addition to food as a preservative, from drinking water, and from foods grown in nitrate-rich soils. The reduction of nitrate does not occur at 2-4 degrees, accounting for the decline in gastric cancer in countries and regions where means of refrigerated food storage have been introduced. Future research includes the search for the substrates, presumably in the form of alkylamides, in some foods typically consumed in high-risk regions.


Dietary factors and cancer in Israel.

The risk of developing cancer is relatively higher in the European-born Israeli population than in those originating from the Middle Eastern or North African countries. The majority of cancer sites with a higher risk in the European groups involve the gastrointestinal and reproductive systems. Certain leads suggest that at least some of these differences may be attributed to diet. Data based on case-control studies are provided; they indicate a high consomption of starches among gastric cancer patients and a lower fiber consumption in patients with cancer of the colon. The latter observations may be extended to cancer of the breast, ovary, and corpus uteri, assuming an interplay between the concentration of bile degradation products and hormone metabolism. Although a low fiber consumption seems a more likely mechanism, a higher fat consumption is also compatible with this model. However, due to the complexity of human nutrition, it seems unwarranted to incriminate any single dietary factor in carcinogenesis. A better understanding of the metabolic pathways, coupled with consistent observations from distinct populations, should be looked for.


Cancer in United States Jews.

The published studies of cancer of United States Jews are reviewed. Despite the lack of religious designation on death certificates, case reports, and census returns, a number of indirect methods for measuring the problem have been devised, which produce fairly consistent findings. In general, for American Jews, these show deficits in cancer mortality, among males, for the buccal cavity and pharynx and prostate and, among females, for the breast, uterine cervix and corpus, and bladder. Excesses in mortality, noted for both sexes, are esophagus, stomach, colon, pancreas, lymphomas, and leukemia and, in females, the lung and the ovary. The standardized mortality ratios for cancer of selected sites for Russian-born residents of upstate New York, 1969 through 1971, are presented as an indirect measure of the problem in the United States Jews. Statistically significant excesses were found in males for stomach and colon, with a striking deficit in cancer of the buccal cavity and pharynx. Among females, excesses were noted for stomach, pancreas, and lung with a sharp deficit in the uterine cervix. On the basis of the religious affiliation of the cemetery of burial, estimates of the Jewish and non-Jewish components of the 800 deaths in Russian-born residents were determined. Expected deaths in these two subgroups by sex, for each cancer site, were then calculated by use of the site-specific proportionate mortality of upstate New York for these years. This revealed a significant excess among Jewish males for colon cancer, with a deficit in lung cancer, while among the non-Jewish male components stomach cancer mortality was the only site significantly in excess. Among Jewish females, stomach and lung cancers were in excess, with a deficit in cancers of the breast and cervix uteri. In non-Jewish Russian-born females, the only site significantly in excess was stomach, with breast cancer showing a deficit.


Role of life-style and dietary habits in risk of cancer among seventh-day adventists.

The Seventh-Day Adventist population abstains from smoking and drinking; about 50% follow a lacto-ovo-vegetarian diet; and most avoid the use of coffee, tea, hot condiments, and spices. Existing data on cancer mortality in Seventh-Day Adventists clearly document mortality rates that are 50 to 70% of general population rates for most cancer sites that are unrelated to smoking and drinking. Several approaches to determining whether this reduced risk is due to the unique Seventh-Day Adventist life-style or selective factors related to who choses to become and remain a Seventh-Day Adventist are described. A comparison of the mortality experience of Seventh-Day Adventist and non-Seventh-Day Adventist physicians shows equal cancer mortality, which is consistent with the hypothesis that the apparent reduced risk of cancer death in all Adventists may be due to selective factors. However, the results of a small case-control study of colon and breast cancer among Adventists show statistically significant relative risks for colon cancer of 2.8 for past use of meat. For current food use, the significant relative risks are 2.3 for beef, 2.7 for lamb, and 2.1 for a combined group og highly saturated fat foods. This strongly suggests that the lacto-ovo-vegetarian diet may protect against colon cancer. However, the evidence linking diet to breast cancer is less clear. Because of the marked variability in dietary habits within the Seventh-Day Adventist population, they will be a productive group for further study of diet and cancer.


Incidence of cancer in United States blacks.

Incidence rates for the black population of six Standard Metropolitan Statistical Areas in the United States are examined using data collected in the Third National Cancer Survey, 1969 to 1971. For all sites combined, black males had the highest rates among the four major race-sex groups; black females had the lowest rates. For fourteen common sites accounting for 80% of the cancers among blacks, black/white ratios, survival data, trends between 1935 and 1969, and geographic variation are presented. United States black data adjusted to an African Standard are compared with similar data from Nigeria, Rhodesia, and South Africa.


Relevance of animal studies to human disease.

Increasing restrictions on the experimental use of human subjects and the difficulties of either evaluating or controlling human subjects over long periods of time suggest the need for increasing use of experimental animals, especially in the study of chronic disease. Experience appears to provide the only guideline for the selection of the most useful species in any particular field. It should be recognized that the species that are most susceptible or those that most nearly approximate the lesion found in man are not necessarily the only useful species. Differences in susceptibility or metabolism provide opportunities for identifying significant parameters in man. We tend to be locked into the use of a few experimental species for no obvious logical reason and have not yet begun to utilize the potential of the diverse species available. Whatever the experiment, diet remains an environmental variable that should be considered in the design and evaluation.


Metabolism of benzo(a)pyrene by human epithelial cells in vitro.

Primary cell cultures derived from human skin epithelium metabolized benzo(a)pyrene to three classes of compounds: phenols, quinones, and dihydrodiols. The relative proportions of metabolites varied according to the skin donor but differed from the pattern of metabolites in rat liver microsome preparations. While appreciable amounts of 7,8- and 9,10-dihydrodiol; 1,6-, 3,6-, and 6,12-quinone; and 3- and 9-hydroxy derivatives were found in the medium, no 4,5 (K-region)-dihydrodiol or epoxide was detected. Reduced amounts of quinones were produced when the cultures were pretreated with hydrocortisone before exposure to the hydrocarbon. The cultures did not require a period of enzyme induction for efficient metabolism of the hydrocarbon. Cultures of fibroblasts derived from the same skin samples as the epithelial cells metabolized the hydrocarbon but to a much different extent. Preexposure of the epithelial cell cultures to mixtures of polycyclic hydrocarbons resulted in a decrease in the amounts of carcinogen metabolized to phenols and dihydrodiols. These findings suggest that the prevalence of carcinomatous disease in humans is due to the differential capacity of the epithelial cells to metabolize potential carcinogens to active forms, a capacity reduced in fibroblasts or other nonepithelial cells. This suggestion is supported by the observations that supposedly normal prostate cells also efficiently metabolize polycyclic hydrocarbons in a manner similar to that of epidermal cells. No evidence of neoplastic transformation was seen in cytological preparations of cells exfoliated into the medium.


Microcytotoxicity assays of tumor immunity in patients with bronchogenic carcinoma correlated with clinical status.

Peripheral blood lymphocytes from patients with bronchogenic carcinoma were tested in microcytotoxicity assays against cultured bronchogenic cancer cells, other types of tumor cells, and skin fibroblasts. Lymphocytes from patients who were postresection with no clinical evidence of residual or recurrent tumor were more frequently toxic against bronchogenic carcinoma than were lymphocytes from normal donors or from patients with clinically evident disease. Lymphocytes from patients with minimal or no tumor  were more frequently toxic against bronchogenic cancer than against skin fibroblasts. Serum samples from a few patients rendered lymphocytes toxic for bronchogenic cancer cells, but this serum activity could not be correlated with the patient's clinical status.


Excision of pyrimidine dimers from epidermal DNA and nonsemiconservative epidermal DNA synthesis following ultraviolet irradiation of mouse skin.

Pyrimidine dimer production and excision in epidermal DNA were studied at five different dose levels of ultraviolet light in the skin of intact mice. Dimer production increased with dose up to 50,400 ergs/sq mm. Approximately 30% of the thymine-containing dimers were excised by 24 hr after irradiation at three lower dose levels of ultraviolet light. Nonsemiconservative DNA replication in ultraviolet-irradiated mouse skin was shown to continue for at least 18 hr. The rate of nonsemiconservative replication decreased with time, but did so slowly. The initial rates of nonsemiconservative replication increased uith ultraviolet light dose level up to about 4,200 ergs/sq mm, after which the initial rates were decreased. Semiconservative epidermal DNA synthesis was shown to be inhibited by hydroxyurea, but hydroxyurea had no effect on ultraviolet light-induced nonsemiconservative DNA replication. The observed pyrimidine dimer excision and nonsemiconservative DNA replication suggest that in the intact mouse the cells of the epidermis are capable of DNA excision repair after ultraviolet irradiation of mouse skin.


Replication of an avian myxovirus in tumor cell cultures obtained from effusions of mammary carcinoma patients.

In view of the possible use of viruses for the immunotherapy of breast cancer, the replication of a strain of fowl plaque virus was studied in the tumor cells of 11 mammary carcinoma patients with malignant effusions. The tumor cells were obtained by centrifugation on iodamide solutions, then cultured in vitro, and infected by a fowl plaque virus previously adapted to grow in a mammary carcinoma cell line. Virus multiplication was observed in all cases, a prerequisite for the use of autologous viral oncolysates for immunotherapy in mammary carcinoma patients.


Cytogenetic, cytological, and virological characteristics of a bovine fibrosarcoma.

The features of a bovine tumor with typical histopathological characteristics of a malignant fibrosarcoma are described. Direct karyotype preparations from the tumor tissue showed two populations of cells with bizarre karyotypes. An in vitro cell culture, designated BS-2, derived from the tumor had a normal diploid karyotype. This culture formed syncytia and produced a virus morphologically indistinguishable from the ubiquitous bovine syncytial virus. BS-2 cells reacted strongly in immunofluorescent tests with both bovine syncytial virus reference serum and serum from the tumorous cow. The virus was also demonstrated by immunofluorescence and mixed culture techniques in the buffy coat cells of the same cow.


Kinetic analysis of the metabolism of benzo(a)pyrene to phenols, dihydrodiols, and quinones by high-pressure chromatography compared to analysis by aryl hydrocarbon hydroxylase assay, and the effect of enzyme induction.

High-pressure liquid chromatography was used to analyze the rate of benzo(a)pyrene metabolite formation by liver microsomes from control and 3-methylcholanthrene-treated rats. The relative amounts of each metabolite formed were determined with several concentrations of microsomal mixed-function oxidases. The specific activity, i.e., amount formed per mg protein per min, was found to be constant for the formation of 3-hydroxybenzo(a)pyrene and 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene. The specific activity for the formation of 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene was higher at high microsomal enzyme concentration. The formation of 9-hydroxybenzo(a)pyrene, however, did not increase with greater amounts of microsomes. The data indicate that 9-hydroxybenzo(a)pyrene is a nonenzymatic product derived from a reactive intermediate, probably benzo(a)pyrene-9,10-oxide. The relatively constant specific activity for the formation of 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene with several enzyme concentrations suggests that the K-region epoxide, benzo(a)pyrene-4,5-oxide, is the most stable of the benzo(a)pyrene epoxide intermediates. The relative percentages of each metabolite fraction found are as follows: 3-hydroxybenzo(a)pyrene, 36; 9-hydroxybenzo(a)pyrene, 3 to 13; 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene, 15 to 25; 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene, 8; 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, 12 to 14; benzo(a)pyrene quinones, 14 to 17. Induction of the enzyme system by 3-methylcholanthrene increases the amount of each metabolite formed to a different extent. The amount of 9,10-dihydro-9,10-dihydroxy- and 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene formed are markedly increased relative to the increase in the other metabolites. Thus the induction of the enzyme may specifically alter pathways of metabolism relevant to carcinogenesis. This study also makes a detailed comparison between the results obtained by high-pressure liquid chromatography analysis and the standard aryl hydrocarbon hydroxylase assay and further develops the chromatographic analysis of benzo(a)pyrene metabolites.


In vitro metabolism of benzo(a)pyrene by human liver microsomes and lymphocytes.

The metabolism of benzo(a)pyrene by human liver microsomes and human lymphocytes has been analyzed by high-pressure liquid chromatography. Human liver forms seven known metabolites and at least five additional unidentified metabolites that migrate as distinct peaks. Lymphocytes incubated with benzo(a)pyrene for 30 min do not form dihydrodiols. Lymphocytes incubated for 24 hr with benzo(a)pyrene form all of the metabolites produced by liver including dihydrodiols as well as additional metabolites. The ratios of phenols formed by liver and lymphocytes are different, and preparations from humans form a different profile of metabolites than that formed by rat liver.


Dimethylnitrosamine-induced inhibition of hepatic protein synthesis in vitro and the effect of pretreatment with cystamine or pregnenolone-16alpha-carbonitrile.

Hepatic protein synthesis was investigated using a postmitochondrial supernatant system derived from the livers of rats that were given injections of a single dose of dimethylnitrosamine (DMN), 30 mg/kg. The time course and extent of DMN-induced inhibition in vitro were identical to those reported for the incorporation of amino acids into liver proteins in vivo, maximum inhibition being about 70% at 5 hr. Addition of specific inhibitors of chain initiation (polyinosinic acid and aurin tricarboxylic acid) to the postmitochrondrial supernatant system from DMN-treated rats caused only a slight additional inhibition, indicating that DMN predominantly affects translation by a block of initiation. Treatment with cystamine prior to DMN administration completely abolished the depression of protein synthesis and reduced by more than 90% the methylation by [14C]DMN of purine bases in liver DNA. Pretreatment with pregnenolone-16alpha-carbonitrile stimulated protein synthesis in controls but had no preventive effect in DMN-treated rats and did not reduce the extent of DNA alkylation in vivo.


The effect of estrone-progesterone treatment on cell proliferation kinetics of hormone-dependent GR mouse mammary tumors.

Hormone-dependent mammary tumors were induced in virgin GR mice by treatment with estrone and progesterone. Discontinuation of hormonal treatment was followed by regression of the tumor. This response to hormone treatment was also observed in the first transplant generation in inbred syngeneic hosts, but after several transplantations the tumor growth became hormone independent. The hormone dependence of the primary tumors and tumors after a single transplantation was demonstrated by growth curves. Furthermore, the cell proliferation kinetics has been investigated in a growing as well as in a regressing hormone-dependent tumor after a single transplantation from the same primary tumor. The experimental data consist of growth curves, percentage-labeled mitoses curves, and labeling indices. Since these data do not contain information concerning the localization of the cell loss in the cell cycle, they were analyzed by a computer method based on three mathematical models differing in respect to the mode of cell loss. All three models gave approximately the same estimates of the cell kinetic parameters in the growing as well as the regressing tumor. The results for the growing, hormone-dependent tumor showed a growth fraction of 62%, a cell production rate of 3.4%/hr, and a cell loss rate of 2.3%/hr. Regression of the tumor after hormonal deprivation was accompanied by a decrease in growth fraction to 18% and a decrease in the cell production rate to 0.9%/hr, while the cell loss rate was unchanged at 2.8%/hr. Furthermore, the discontinuation of hormonal treatment introduced an increase in the mean transit time of the cell cycle, particularly in the mean transit time of the G1 phase. The results might indicate that estrone and progesterone treatment stimulated growth of hormone-dependent GR mouse mammary tumors mainly by an increase of growth fraction and cell production rate.


Altered glucose metabolism in metastatic carcinoma.

To evaluate the possible role of altered glucose metabolism in malignant cachexia, metabolic parameters including total glucose turnover, glucose oxidation, and Cori cycle activity were measured in fourteen patients with metastatic carcinoma. Eight patients with progressive weight loss (PWL) were compared to 6 without (controls). Cori cycle activity was significantly increased (p less than 0.02) in PWL patients, 90 mg/kg/hr (range, 22 to 193) compared to 18 mg/kg/hr (range, 13 to 24) in controls. Total glucose turnover was moderately increased in PWL patients, 196 mg/kg/hr compared to 110 mg/kg/hr in controls. Glucose oxidation was 62 mg/kg/hr versus 48 mg/kg/hr, and total caloric expenditure was 36 kcal/sq m/hr compared to 33 Kcal/sq m/hr. PWL patients were metabolically heterogenous and mean values are skewed by four patients with increased glucose turnover, oxidation, and markedly high recycling rates that were equivalent to total endogenous glucose turnover of a normal subject. Total caloric expenditure was greatest in three of the four patients with a marked increase in Cori cycle activity. Energy loss associated with a high rate of gluconeogenesis from lactate has been suggested as an explanation for increased energy expenditure in some cancer patients, thus contributing to mechanisms that promote weight loss.


Variables and specificity of in vitro lymphocyte-mediated cytotoxicity in human melanoma.

In vitro cell-mediated cytotoxicity (CMC) assays have been carried out in human melanoma system with blood effector lymphocytes on [3H]proline-labeled target cells in a 48-hr microcytotoxicity technique. Three lymphocyte purification procedures (Ficoll:Hypaque gradient, plasma gel sedimentation followed by nylon column incubation, and plasma gel sedimentation followed by separation with nylon powder and glass beads) are compared in parallel experiments for characteristic effector cell composition and cytotoxic potential against target cells of dissimilar histology. The cytotoxicity is defined by the loss of target cell 3H cpm as measured by residual target cell 3H cpm in individual microwell following incubation with lymphocytes. Target cell 3H cpm loss by test lymphocytes is compared with target cell 3H cpm loss by several age and sex matched control lymphocytes (from normal donors and unrelated cancer patients); further comparison between the various control lymphocytes is also made in each assay. As control for target cells, autologous fibroblasts and homologous tumor cells of dissimilar histology are always included in each assay. Specific cytotoxicity is defined as statistically significant and selective destruction of only melanoma cells by the test lymphocytes as compared to the control lymphocytes. Significant but nonselective destruction of 2 or more target cells of unrelated histology is regarded as nonspecific cytotoxicity, while no destruction of any target cells signifies no cytotoxicity. The Ficoll:Hypaque preparations consistently exhibit the highest nonlymphocytic cell contamination (8 to 16%); the nonlymphocytic cells are, almost exclusively, monocytes. They also produce relatively high percentage of thymus independent (B) cells (8 to 15%). The ultimate cell composition of the 2 plasma gel-nylon preparations is essentially identical. In either plasma gel-nylon preparations, the nonlymphocytic contamination is minimal (0 to 4%) and thymus-dependent (T) cell percentage is considerably higher (92 to 99%) with none or few B cells.


Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor.

Pyran (divinyl ether-maleic anhydride) copolymer (NSC 46015) is a polyanion with interferon-inducing and macrophage-stimulating properties, and therefore it has been studied as a possible antitumor agent. Extensive studies using pyran as an adjuvant to chemotherapy against the LSTRA murine leukemia and the Lewis lung carcinoma were performed. Pyran was effective over a dose range of 0.1 to 100 mg/kg/day. Single and multiple dose schedules were both capable of producing significant numbers of cures or increasing life-span, but pyran was ineffective if used without remission inducing chemotherapy. Various molecular weights of pyran copolymer were compared against NSC 46015 for adjuvant activity as well. In general, NSC 46015 tended to be the most efficacious, but all the pyran sizes that were tested possessed significant activity.


Autoradiographic analysis of proliferative activity in rat kidney epithelial and mesenchymal cell subpopulations following a carcinogenic dose of dimethylnitrosamine.

In a system that yields 100% incidence of renal mesenchymal tumors and a 30 to 40% incidence of renal cortical epithelial neoplasms, the proliferative activity of renal epithelial and mesenchymal cell subpopulations following a single dose of dimethylnitrosamine (DMN) was traced by autoradiographic analysis of [methyl-3H]thymidine uptake during the 3 weeks immediately posttreatment. The initial response to DMN was a depression in DNA synthesis and mitosis to near 0 levels in all segments of the nephron and in attendant mesenchymal cells for a period of 1 to 3 days. Following the period of inhibition, increased DNA synthetic activity was observed in certain subpopulations of both epithelium and mesenchyme and these patterns were matched by equivalent mitotic activity. A stimulation of DNA synthesis was observed in cells of the proximal and distal tubules of Zones 1 and 2 but in no other epithelial segments. The increased activity was most intense in Zone 1 epithelium reaching a peak at the 10th day after DMN injection 4 days after epithelial cell necrosis had commenced. In renal mesenchyme, the major response involved only the interstitial cells of Zones 1 and 2. At Day 3, there was a wave of increased DNA-synthetic and mitotic activity in the free interstitial cells of the cortex, followed by a 2nd, more intense peak of activity at Day 6. The cells responding at Day 3 appeared to involve the resident population of cortical fibrocytes while the major contribution to the Day 6 peak came from infiltrating mononuclear inflammatory cells, although resident fibrocytes and capillary endothelium also contributed. A significant wave of increased activity involved the intestitial cells of Zone 2, but the peak, although of equivalent intensity to the response in Zone 1, was single and occurred 3 days later at Day 9. Apart from a small, brief, and variable wave of activity in interstitial cells of Zone 3 from Days 8 to 10, no toerh mesenchymal cell populations in the kidney were stimulated by the injection of DMN.


Bladder calculi and urothelial hyperplasia with papillomatosis in the rat following insertion of chalk powder in the bladder cavity with subsequent trauma of the bladder wall.

A suspension of chalk powder was injected into the cavity of the urinary bladder of Fischer 344 rats. Three weeks later rats were divided into 4 major groups and were given a submucosal injection. One group received a suspension of viable Chapman 4909 tumor cells, the 2nd group received a suspension of frozen-killed 4909 tumor cells, the 3rd group received a suspension of normal rat spleen cells, and the 4th group received cell-free fresh tissue culture medium. After 3 additional weeks urolithiasis was recognized in each experimental group. The incidence of calculi in the groups as listed above was 14 of 17, 6 of 11, 6 of 11, and 2 of 15, respectively. In control studies inocula consisted of tumor alone, i.e., without chalk powder. Inoculation of the 4909 rat bladder cancer cell line into the lumen of urinary bladders of rats did not result in any calculi after 3 weeks but did produce intramural tumor nodules and hyperplastic changes in adjacent host urothelium in 2 of 10 rats. The tumor inoculated in the submucosa of the bladder produced calculi and papillomas in 2 of 7 rats, and it produced intramural tumor nodules with adjacent hyperplasia of urothelium in all 7 rats.


Carcinoembryonic antigen in human ovarian neoplasms.

The presence and location of carcinoembryonic antigen (CEA) was examined in tissue sections of 14 mucinous and 13 serous cystadenomas and cystadenocarcinomas of the ovary. CEA was demonstrated in the mucinous tumors but was not present in the serous tumors. In the mucinous tumors, CEA was located in the glycocalyx and apical portions of the absorptive-type epithelium, with only trace quantities in goblet cells, a pattern identical to that seen in colonic neoplasms. Endocervical-type epithelium in the mucinous tumors contained little or no CEA.


The synthesis of glycopeptide fragments of human plasma alpha1-acid glycoproteins by sequential elongation at the terminal-amino group.

Glycopeptides corresponding to sequences 27--28, 48--49, and 58--59 of human plasma alpha1-acid glycoproteins have been synthesized by sequential elongation of the peptide chain at the terminal amino group. 2-Acetamido-3,4,6-tri-O-acetyl-1-N-(L-aspart-4-oyl)-2-deoxy-beta-D-glucopyranosylamine was condensed with the p-nitrophenyl esters of protected amino acids to give the corresponding protected glycodipeptides having the sequences Gly-(GlcNAc-4-)Asn, Pro-(GlcNAc-4-)Asn, Val-(GlcNAc-4-)Asn, Leu-(GlcNAc-4-)Asn, Glu-(GlcNAc-4-)Asn, Tyr-(GlcNAc-4-)Asn, Ser-(GlcNAc-4-)Asn, and Cys-(GlcNAc-4-)Asn. Deprotection of the carbohydrate and of the peptide residues of these compounds was achieved, except for those having N-tert-butyloxycarbonyl protective groups, to give the corresponding free glycopeptides. The glycotripeptide 2-acetamido-1-N-(2-N-[N-(tert-butyloxycarbonyl)-L-glutam-1-oyl-L-tyrosyl]-L-aspart-4-oxy)-2-deoxy-beta-D-glucopyranosylamine, having the amino acid sequence 10--12 of human plasma alpha1-acid glycoprotein, was prepared by condensation of 2-acetamido 3,4,6-tri-O-acetyl-2-deoxy-1-N-[2-N-(L-tyrosyl)-L-aspart-4-oyl[-beta-D-glucopyranosylamine with 5-benzyl 1-p-nitrophenyl N-(tert-butyloxycarbonyl)-L-glutamate, followed by removal of the ester groups.


Synthesis of p-nitrophenyl 2-acetamido-2-deoxy-O-beta-D-galactopyranosyl-beta-D-glucopyranosides.

Reaction of p-nitrophenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-beta-D-glucopyranoside (2) with 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide (3) under the usual conditions, followed by removal of the p-methoxybenzylidene group and O-deacylation, produced crystalline p-nitrophenyl 2-acetamido-2-deoxy-3-O-beta-D-galactopyranosyl-beta-D-glucopyranoside (6). Starting from p-nitrophenyl 2-acetamido 3,4-di-O-acetyl-2-deoxy-beta-D-glucopyranoside, the synthesis of p-nitrophenyl 2-acetamido-2-deoxy-6-O-beta-D-galactopyranosyl-beta-D-glucopyranoside was also accomplished.


Isolation, purification, and structure of components from acidic polysaccharides of Pleurotus ostreatus (Fr.) Quél.

Isolation of an antitumor component from polysaccharide fraction A5 of some Basidiomyces was achieved by column chromatography on Sephadex G-200. A detection method based on the specific rotatory characteristics of the polysaccharide was applied to estimate components in effluent fractions from the chromatography, and it was confirmed that a series of eluates having similar specific rotation was made up of homogeneous polysaccharide. Three components (H51, H52, and H53) were isolated, in chromatographically pure state, from fraction A5. Component H51 consisted of a skeleton of beta-(1 leads to 3)-linked glucose residues, probably having branches of galactose and mannose residues, and also containing acidic sugars. Component H53 had a main structure similarly consisting of beta-(1 leads to 3)-linked glucose residues and a larger proportion of acidic sugar than H51. Component H52 was a heteropolysaccharide made up of alpha-linked galactose and mannose residues. Components H51 and H53 had a higher and a lower molecular weight, respectively, than H52. The only antitumor-active component was H51.


Structures of the oligosaccharides from the enzymic hydrolysis of hemicellulose by a hemicellulase of Ceratocystis paradoxa.

And endo-hemicellulase (HC-II) of Ceratocystis paradoxa degraded spear-grass hemicellulose B to a series of mixed oligosaccharides. Four neutral oligosaccharides (AraXyl2, AraXyl3, Xyl2, and Xyl3), isolated by preparative paper chromatography, were shown by enzymic and methylation techniques to constitute a series of beta-(1 leats to 4)-D-xylose and O-alpha-L-arabinofuranosyl-(1 leads to 3)-O-beta-D-xylopyranosyl-(1 leads to 4)-O-beta-D-xylopyranosyl-(1 leads to 4)-D-xylose, respectively, the latter being a new compound.


5,6-unsaturated hexofuranosyl glycosides and 5',6'-unsaturated hexofuranosyl nucleosides.

Methyl 5,6-dideoxy-2,3-O-isopropylidene-alpha-D-lyxo-hex-5-enofuranoside, prepared from methyl 2,3-O-isopropylidene-5,6-di-O-methylsulfonyl-alpha-D-mannofuranoside with sodium iodide in 2-butanone, was acetolyzed and the product coupled with 6-benzamidochloromercuripurine by the titanium tetrachloride method. Removal of the N-benzoyl group with pictic acid afforded 9-(2,3-di-O-acetyl-5,6-dideoxy-beta-D-xylo-hex-5-enofuranosyl)adenine. In a similar manner, methyl 5,6-dideoxy-2,3-O-isopropylidene-alpha-L-lyxo-hex-5-enofuranoside was prepared from L-mannose and converted into 9-(2,3-di-O-acetyl-5,6-dideoxy-beta-L-xylo-hex-5-enofuranosyl)adenine, further de-esterified to give the free nucleoside. 2,3:5,6-Di-O-isopropylidene-alpha-L-mannofuranosyl chloride, prepared from L-mannose, gave 9-(2,3-O-isopropylidene-alpha-L-mannofuranosyl)adenine, hydrolyzed into 9-alpha-L-mannofuranosyladenine. Treatment with methanesulfonyl chloride gave the 5',6'-dimethanesulfonate, which gave with sodium iodide in acetone the 5',6'-unsaturated nucleoside, further hydrolyzed into 9-(5,6-dideoxy-alpha-L-lyxo-hex-5-enofuranosyl)adenine.


[Social status of pathologists].

The authors discuss basic problems of pathology in district institutes of national health as well as social aspects of the work of pathologtsts. Social activity and correctly conceived health education are an essential part of the activities of pathologists.


[Lambliasis in enterobiopsy].

The authors describe relations between lamblia and the intestinal mucosa of the host and some rare ultrastructural characteristics of the parasites as revealed in a tissue specimen obtained by enterobiopsy. Lambliae were found in one clinically asymptomatic case, by using an electron microscope and optical microscope, in the intestinal lumen and intestinal mucosa.


[Differentiation of spondylitis ankylopoietica and spondylitis hyperostotica].

Changes in the bodies of vertebrae in ancylopoetic spondylitis (Bekhterev's disease) and in hyperostotic spondylitis (Forestier's disease) may be very similar, in particular as regards the ancylotic connection of the bodies of the vertebrae and syndesmophytes. In the differential diagnosis the following differences are important: Syndesmophytes in Bekhterev's disease are symetrical and continuous, there is ossification of the intervertebral discs, and ancylosis affects always sacroiliac, intervertebral and costovertebral joints. In hyperostotic spondylosis the sclerotic syndesmophytes bulge in a lateral direction, mainly to the right. The inveretebral discs do not ossify, the sacroilliac and other above mentioned joints are not affected.


[Carcinoma of the thyroid gland].

A series of 172 surgical cases of thyroid carcinoma accumulated in apprximately 21 years have been classified according to their microscopical patterns as follows: papillary carcinoma, follicular carcinoma, medullary carcinoma with amyloid and anaplastic carcinoma. The author briefly mentions the significance of scintigraphy and of the so-called cold nodules as well as the interrelationship between thyroiditis and thyroid carcinoma. Attention is drawn to the sequelae of cervical irradiation, particularly in young individuals with respect to the possibility of development of thyroid carcinoma within this region.


Inactivation of bacteriophages with cis-platinum(II) diamminedichloride.

The ability of the cis-plantinum(II) diamminedichloride and its hydrolytic products to inactive DNA bacteriophages was examined on the models T2, T4, T4BO1, T3, and lambda. The inactivation of all bacteriophages under study increases gradually during the first 40-90 min of the action of neutral cis-Pt(II) and later passes into an exponential phase. The extent of the region of slower inactviation is larger for osmotically sensitive strains T2 and T4. Inactivation with the hydrolytic products for cis-Pt(II) proceeds exponentially starting from the very beginning and their inactivating effect is higher by 40-80 times than for a comparable concentration of the original complex. The extent of inactivation is not affected with the HCR marker of the host bacteria. The sensitivity to cis-Pt(II) is higher for bacteriophages with a head permeable to salts. An additional inactivation ("after-effect") was observed after dilution of the complex; it can be removed by adding S-aminoisothiuronium dihydrobromide (AET). The results obtained are in good accord with the assumption that inactivation is due to the hydrolytic products arising in the head of bacteriophage.


Acute biochemical and morphological effects of N-nitrosomorpholine in comparison to dimethyl- and diethylnitrosamine.

Some biochemical and ultrastructural changes induced in the livers of rats treated with N-nitrosomorpholine are described and compared with parallel observations in rats given dimethyl- or diethylnitrosamine. Hepatotoxic doses of the nitrosamines caused inhibition of incorporation of [14C]leucine into hepatic proteins, accompanied by progressive disaggregation of polysomes which paralleled the known time course of metabolism of each compound. Dimethylnitrosamine (DMN) and N-nitrosomorpholine (NM) inhibited incorporation of [14C]orotate into liver RNA but diethylnitrosamine (DEN) caused a slight stimulation of orotate incorporation. Electron microscopy revealed similar hepatic cytoplasmic changed induced by each nitrosamine, including dilation and degranulation of the rough surfaced endoplasmic reticulum and subsequent increase of the smooth endoplasmic reticulum. Nuclear changes differed with each compound, N-nitrosomorpholine having more marked effects than either dialkyl compound. The results are discussed with particular reference to the metabolism of N-nitrosomorpholine in the liver.


fMet-tRNA F Met binding and peptidyl transferase function in free and bound ribosomes from normal and puromycin aminonucleoside-treated rats.

Treatment of rats with the aminonucleoside of puromycin, which increases the incorporation of labelled phenylalanyl-tRNA into polypeptide chains in liver ribosome preparations studied in vitro, did not change the factor-dependent binding of fMet-tRNA f Met to ribosomes nor the peptidyl transferase function of the ribosomes. Peptidyl transferase function, as measured by fMet-tRNA f Met-puromycin formation, was comparable in the free and bound ribosome preparations. Similarly, the factor-dependent binding of fMet-tRNA f Met to ribosomes was the same in free ribosome preparations obtained from rat liver as it was in bound ribosome preparations that had been freed of membranes by puromycin incubation and high salt wash.


The use of high pressure liquid chromatography to study chemically induced alterations in the pattern of benzo[a]pyrene metabolism.

The metabolism of radiolabeled benzo[a]pyrene (BP) by control, 3-methyl-cholanthrene (3-MC) induced, and 1,1,1-trichloropropene-2,3-oxide (TCPO)-inhibited rat liver microsomes was measured using fluorescence, radiometric, and high-pressure liquid chromatographic (HPLC) assays. Significant differences in the total measurable metabolism of BP by the three microsomal enzyme incubations resulted from the use of the three assay procedures. Appreciable differences in the concentration of the metabolite fractions after 3-MC induction and TCPO inhibition are clearly demonstrated. NMR analysis revealed that while the 3-hydroxy-BP fraction is greater than 90% pure, the 9-hydroxy fraction contains a number of metabolites having essentially identical retention times.


Inhibition of hepatic aryl hydrocarbon hydroxylase by 3-methylcholanthrene, 7,8-benzoflavone and other inducers added in vitro.

A close correlation has been observed between the ability of aromatic polycyclic hydrocarbons and 7,8-benzoflavone (7,8-BF) to induce hepatic aryl hydrocarbon hydroxylase (AHH) in vivo and to inhibit the induced enzyme system in vitro. The activity of this mono-oxygenase was measured by the conversion of 14C-labeled dimethylbenz(a)anthracene (DMBA) or benzo(a)pyrene (BP) to water-soluble products by rat liver preparations (8000 X g supernatant). DMBA as substrate had the advantage over BP in giving a wider range of ethyl acetate-soluble metabolites and allowing the observation of changes in the pattern of these products following injection or addition of the inducing agents. This property was used to detect low concentration (0.1 muM) of polycyclic hydrocarbons which are strong AHH inducers and which may also be carcinogenic. The liver preparation was active for several months when stored at --20 degrees. A possible mechanism of action for the in vitro behaviour of polycyclic hydrocarbons and 7,8-BF towards AHH is proposed.


Interaction of sequential stimuli applied during the relative refractory period in relation to determination of fibrillation threshold in the canine ventricle.

An ineffective stimulus applied to cardiac tissue within the relative refractory period can alter the response to an immediately subsequent stimulus. We observed three response patterns that can coexist at different sites of stimulation in the same heart. In the first pattern, a stimulus of two to ten times diastolic threshold, applied too early to elicit a propagated response, becomes effective when a stimulus of equal strength is delivered 10 msec earlier. In the second pattern, a stimulus applied just late enough to evoke a response fails to do so when a stimulus of equal strenght precedes it by as much as 30 msec. Finally, in the third pattern, two stimuli, separated by 10 msec, both of which are late enough to be effective when they are given alone, fail to yield a propagated response when they are applied together. These results have a bearing on the use of trains of stimuli to assess the ventricular fibrillation threshold. Possible interpretations are based on the temporal dispersion of recovery from the refractory state.


Acetylcholine-induced reversal of canine and feline atrial myocardial depression during stretch, cardiac failure, and drug toxicity.

Microelectrode and isometric recording techniques were used to evaluate the effects of acetycholine (ACh) on depressed isolated preparations of dog and cat atrial muscle. Atrial muscles were maintained at 36-37 degrees C with warmed Tyrode's solution and were stimulated at frequencies of 30 or 60/min. Depolarization to resting potentials of approximately -50 mv was noted (1) after excessive stretch was applied, (2) in muscles obtained from cats in overt right heart failure, and (3) during exposure of the muscles to excessive concentrations of acetylstrophanthidin or lidocaine. Depolarized muscles demonstrated action potentials of smaller amplitude and rate of rise. Exposure to ACh (2.7 X 10(-6)M) had a minimal effect on resting potential in normal dog and cat atrial muscle and was accompanied by significant negative inotropic actions. The same concentration of ACh markedly increased resting potential and action potential amplitude and induced positive inotropic effects in depolarized muscles; these effects also occurred during beta-adrenergic blockade. We suggest that the positive inotropic effect of ACh in depressed muscles may result from (1) a more synchronous contraction of cells within each muscle, (2) recruitment of previously quiescent cells in contraction, (3) possibly increased calcium inflow in individual cells during depolarizations of greater magnitude, and (4) an increase in the number of interacting sites between actin and myosin after resting potential is improved.


Pathogenesis of acute renal failure following temporary renal ischemia in the rat.

In this study, we characterized the sequence of several intrarenal events and evaluated their relative importance in the pathogenesis of unilateral oliguric acute renal failure induced experimentally in rats by complete occlusion of a renal artery for 1 hour. Kidneys were studied prior to occlusion and 1-3 hours and 22-26 hours after release of the temporary occlusion. Renal blood flow measured by an electromagnetic flow transducer was reduced to 40-50% of control during both postocclusion periods. Flow of tubular fluid was markedly reduced, and the damaged kidneys were oliguric. Proximal and distal convolutions were filled with fluid and dilated 1-3 hours after occlusion; their pressures were greatly heterogeneous and were elevated, on the average, to 31 and 16 mm Hg, respectively. Glomerular capillary pressure at this time was normal or slightly increased. Histological sections showed extensive tubular obstruction. We conclude that initially the oliguria is primarily due to intraluminal obstruction in the absence of predominant increases in preglomerular vascular resistance. Observations at 22-26 hours after occlusion indicated acute tubular necrosis. Moreover, the combined involvement of preglomerular vasoconstriction, presisting tubular obstruction, and passive backflow of tubular fluid appeared to be important in the maintenance of the oliguria. Glomerular capillary, proximal intratubular, and peritubular capillary hydrostatic pressures were reduced below control values. After acute volume expansion, the reduced pressures and renal blood flow were reversed, yet the experimental kidneys remained oliguric. Thus, it is clear that tubular obstruction is a significant factor responsible for both the genesis and the maintenance of oliguria in this experimental model of ischemia-induced acute renal failure.


Central and peripheral adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats.

The role of the sympathetic nervous system in the development of deoxycorticosterone-sodium chloride (DOCA-saline) hypertension was investigated by measuring plasma levels of norepinephrine, total catecholamines, and dopamine-beta-hydroxylase activity at intervals after the initiation of the DOCA-saline regimen. Plasma norepinephrine was significantly higher in DOCA-saline-treated rats at 4 and 7 weeks and in rats treated with saline alone at 4 weeks compared with that in untreated controls. Total plasma catecholamine levels (epinephrine and norepinephrine) and dopamine-beta-hydroxylase activity were similar in hypertensive rats, untreated controls, and rats that received either DOCA or saline alone. The increases in plasma norepinephrine levels may have resulted from centrally mediated increases in peripheral sympathetic neuronal activity, since the destruction of central catecholaminergic neurons with intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) prevented both the DOCA-saline-induced rise in blood pressure and the increases in plasma norepinephrine. Rats treated with 6-OHDA consistently drank less water or saline than did vehicle-treated controls. The actions of centrally administered 6-OHDA on blood pressure and plasma norepinephrine levels were not secondary to a reduction in salt intake, however, since intact rats given a similar reduced saline intake became hypertensive and demonstrated elevated plasma norepinephrine concentrations. Chronic salt loading may cause a centrally mediated increase in peripheral sympathetic neuronal activity with raised plasma concentrations of norepinephrine. The increased adrenergic activity in the presence of mineralocorticoid-induced sodium retention leads to the development of hypertension.


Active and passive immunization against angiotensin II in the rat and rabbit. Evidence for a normal regulation of the renin-angiotensin system.

Active or passive immunization has been used repeatedly as a tool in studies on the role of the renin-angiotensin system in the control of blood pressure and kidney function. The results are not consistent among each other, and they are also at variance with other studies using different approaches. To evaluate the possible causes of these discrepancies, the biological characteristics of angiotensin antibodies were studied in rats. Following the intravenous injection of angiotensin II antibodies (purified by affinity chromatography), the plasma concentration of the antibodies declined in a two-exponential curve with half times of 11 hours and 7 days, which probably reflect distribution in the extracellular space and elimination, respectively. Plasma angiotensin II levels rose from preinjection levels of 100 pg/ml to 12,000 pg/ml within 10 minutes and then declined concomitantly with the decline in antibody concentration. We calculated that only a samll fraction of the circulating antibody was occupied by angiotensin II. Plasma renin concentrations were initially elevated both in controls and in antibody-injected rats, but they returned to the control level after 30 minutes and remained at that level throughout the rest of the experiment (10 days). This fact indicates that feedback mechanisms which control renin secretion, such as free plasma angiotensin II concentrations, are in the normal range. We therefore concluded that the renin-angiotensin system in antibody-injected rats was regulated at a normal level. Similar conditions seemed to exist in rabbits actively immunized against angiotensin II; these animals exhibited high concentrations of total immunoreactive angiotensin II (up to 200,000 pg/ml) and a small increase in plasma aldosterone and corticosterone concentrations.


Abnormalities of renal perfusion and the renal pressor system in dogs with chronic aortic coarctation.

To clarify the role of the renin-angiotensin system in coarctation hypertension, 2-year-old inbred dogs with chronic neonatally induced thoracic aortic coarctation were subjected to 6 days of rigorous salt restriction. The following parameters were then measured: glomerular filtration rate, renal plasma flow, plasma renin activity, plasma renin concentration, renin reactivity, and renin substrate concentration. Glomerular filtration rate and renal plasma flow were significantly lower in salt-restricted coarcted dogs: 3.0 +/- 0.2 and 9.0 +/- 1.5 ml/min kg-1, respectively, compared with values of 4.0 +/- 0.2 (P less than 0.005) and 13.2 +/- 0.6 (P less than 0.025) ml/min kg-1 in salt-restricted controls. Plasma renin activity was abnormally high in experimental dogs: 13.5 +/- 2.5 vs. 4.5 +/- 1.5 ng angiotensin I/ml hour-1 in controls (P less than 0.005). In addition, a significant elevation of renin reactivity (indicating a relative increase in circulating accelerators or a relative decrease in inhibitors of the renin reaction) was apparent in the plasma of coarcted dogs. Plasma renin concentration was elevated but to an insignificant degree in coarcted dogs, and renin substrate concentration was comparable with that of controls. The impaired renal perfusion and abnormal elevation of plasma renin activity during salt restriction is analogous to clinical and experimental observations in hypertensive states associated with total renal underperfusion and supports a major role for the renal pressor system in the pathogenesis of coarctation hypertension. The insignificant elevation of plasma renin concentration is not incompatible with this view. The demonstration of increased renin reactivity in coarctation hypertension provides additional evidence that acceleration of the renin reaction is common to all hypertensive states.


Influence of potassium ions and osmolality on the resting membrane potential of rabbit ventricular papillary muscle with estimation of the activity and the activity coefficient of internal potassium.

Resting membrane potentials of rabbit right ventricular papillary muscles were measured in modified Tyrode's solutions that were isotonic (1.0 X T), hypertonic (1.58 X T), or hypotonic (0.76 X T) at eight different concentrations of external potassium, [K]o, ranging from 0.78 to 100 mM. The amount of hyperpolarization produced by exposure to the hypertonic solutions was relatively constant with an average of 4.6 mv at all levels of [K]o except 0.78 and 1.56 mM. This potential change is much less than the 10.6 mv which would be predicted if the papillary muscles behaved as nearly perfect osmometers and the activity coefficient of intracellular potassium (K) remained constant. The amount of depolarization produced by exposure to the 0.76 X T hypotonic solutions averaged 6.8 mv at all levels of [K]o except 0.78 mM; this value is close to the predicted value of 6.9 mv. Variations in the activity and the activity coefficient of intracellular K were introduced to explain these discrepancies. We estimated that the activity of intracellular K in 1.58 X T hypertonic solution was increased 15-23% compared with that in isotonic solution. This change is much less than the 58% that would be predicted if the papillary muscle behaved as a nearly perfect osmometer. We also estimated that the activity of intracellular K in 0.76 X T hypotonic solution fell 22-26%, which is very close to the predicted value of 24%. The activity coefficient of intracellular K appeared to fall in 1.58 X T hypertonic solution to about 0.76 of its value in isotonic solution. This decline in the estimated activity coefficient of intracellular K could not be attributed to an increase in Coulombic attractive and repulsive forces as predicted by the Debye-Hückel equation for a univalent electrolyte.


Effect of lidocaine on the early inward transient current in sheep cardiac Purkinje fibers.

We used two experimental techniques to study the effect of lidocaine hydrochloride on the early inward transient (sodium) current as it is reflected by the maximum rate of change of action potential phase 0 (Vmax). We assessed the effect of lidocaine on Vmax as Purkinje fibers were slowly depolarized by increasing the extracellular potassium concentration from 4.0 to 16.0 mM; these voltage-dependent effects were compared with lidocaine's effect on membrane responsiveness (which measures both the time and the voltage dependence of Vmax). We also used a voltage clamp technique to establish the effect of lidocaine on the voltage dependence of Vmax by measuring Vmax 800-1000 msec after transmembrane voltage (Vm) had been changed in small steps. We studied the effect of lidocaine on the time course of early inward transient current reactivation by depolarizing the membrane to -25 +/- 5 mv for 100 msec to inactivate this current, clamping Vm to a repolarized test voltage for various periods, and then measuring phase 0 Vmax of action potentials elicited immediately after termination of the voltage clamp. We showed that lidocaine at 5 mg/liter, but not a 1 mg/liter, shifted the steady-state Vmax- Vm relationship to a more negative position on its voltage axis by about 5 mv and markedly slowed the reactivation of the measure early inward transient current.


Effect of the angiotensin II blocker 1-Sar-8-Ala-angiotensin II on renal artery clip hypertension in the rat.

Twenty-four conscious male Wistar rats with hypertension induced by left renal artery clipping (two-kidney hypertension) were infused intravenously with 1-Sar-8-Ala-angiotensin II a competitive angiotensin II antagonist. The spectrum of responses was wide, ranging from a mild elevation in blood pressure to a marked fall in blood pressure, despite effective and specific angiotensin blockade in all cases. The change in blood pressure during 1-Sar-8-Ala-AII infusion activity showed a significant correlation with the level of plasma renin prevailing immediately before the infusion (r = - 0.78, P less than 0.01) but not with the prevailing blood urea level (r = 0.27, 0.1 greater than P greater than 0.05), the drgree of hypertension (r = 0.42, 0.1 greater than P greater than 0.05), or the time since clipping (r = 0.02, P greater than 0.05). There was no significant correlation between the degree of hypertension and the plasma renin activity (r = 0.42, 0.1 greater than P greater than 0.05). In rats with blood pressure drops greater than 20 mm Hg in response to 1-Sar-8-Ala-AII, the final blood pressure level was still above the normotensive range. Excision of the clipped kidney reduced blood pressure to normal or to near normal within 24 hours in all of the rats tested. It is concluded that the degree of dependence of renal hypertension on the renin-angiotensin system is directly related to the increase in circulating angiotensin itself and not to an increase in sensitivity to angiotensin. Other factors appear to be involved in renal clip hypertension in addition to circulating renin and angiotensin, especially when the measured activity of plasma renin is normal.