Circulating carcinoembryonic antigen in pancreatic carcinoma.

Circulating CEA levels were determined in 102 patients wtih histologically proven pancreatic carcinoma and 26 patients with chronic pancreatitis. In the group with pancreatic carcinoma eleven patients had resectable tumors, the mean CEA in the nonjaundiced patients was 10 +/- 5 ng/ml while the mean value in jaundiced patients in this group was 27 +/- 40. Thirty-four patients with nonmetastatic locally unresectable disease had a mean serum CEA of 25 +/- 52 with a range of 1 to 250 ng/ml. Twenty-one percent had values of 5 ng/ml or less. The mean value in 57 patients with metastatic disease was 97 +/- 194 with a range of 0.05 to 1000 ng/ml and 19 percent had values of 5 ng/ml or less. Survival of patients with locally unresectable or metastatic carcinoma was significantly longer in those patients who had a normal CEA at the time of diagnosis. Circulating CEA in the metastatic group was much lower in patients with nonhepatic metastases as well as in those with well differentiated adenocarcinoma histology. Twenty-three patients with chronic pancreatitis and normal serum bilirubin had a mean CEA value of 5.3 +/- 4 ng/ml with 65% of values being 5 ng/ml or less but the CEA ranged from 4.6 to 27 in three who were jaundiced.


Initial levels of CEA and their rate of change in pancreatic carcinoma following surgery chemotherapy and radiation therapy.

CEA levels and their rate of change in 41 patients with pancreatic carcinoma following surgery, chemotherapy and radiation therapy were determined. Surgical resection, though not curative, was associated with a decrease in CEA level, with approximately half these levels returned to normal. No correlation with survival was noted. CEA levels are increased by obstructive jaundice. Radiation alone or in combination with 5-Fluorouracil did not change CEA levels in patients with locally unresectable pancreatic carcinoma. CEA levels progressively increased in patients with widespread metastatic pancreatic carcinoma, who expired from their disease.


Measurement of carcinoembryonic antigen in patients with bronchogenic carcinoma.

Estimation of CEA levels by the Z-gel method indicates that smokers, patients with limited lung cancer and patients with extensive lung cancer have higher values than nonsmoking controls. The CEA levels within each group are significantly different from one another. Use of CEA estimation for diagnostic purposes is limited because of the considerable overlap between normal controls and patients with cancer, the relatively low incidence of elevated values in patients with limited disease and the high incidence of false negatives (20%) even in patients with extensive disease. Elevated CEA values are associated with a poor prognosis and could be of clinical value as an addition to clinical staging to determine survival particularly for patients with extra-thoracic disease. Persistently high values in patients deemed clinically disease-free postoperatively are indicative of residual disease and a poor prognosis. If and when effective therapy for bronchogenic carcinoma becomes available, monitoring of CEA values may be useful in some patients as an early indication of release. Further studies are required to determine if the extraordinarily poor prognosis associated with marked elevations of CEA may be used as an additional criterion of inoperability in such patients.


CEA levels in patients with carcinoma of the esophagus.

Serum CEA levels were determined serially by the Hansen Z gel technique on 41 patients with carcinoma of the esophagus and compared to 276 controls. Seventy percent of patients with carcinomas of the esophagus had elevated CEA levels. CEA levels greater than 10.0 ng/ml after therapy correlated with significantly shortened survival. CEA appears promising as an indicator of tumor presence in patients with carcinoma of the esophagus.


The detection of elevated plasma levels of carcinoembryonic antigen in patients with suspected or established medullary thyroid carcinoma.

Plasma levels of carcinoembryonic antigen (CEA) and calcitonin (CT) were measured in 35 normal control subjects and in 37 patients with suspected or established medullary thyroid carcinoma (MTC). None of the normal control subjects had elevated basal plasma levels of either CEA (greater than 5 ng/ml) or CT (greater than 0.25 ng/ml). However, of the 37 patients with suspected or established MTC, 23 (62%) had elevated basal plasma levels of CEA (range 9.8--7,000 ng/ml) and 27 (73%) had elevated basal plasma CT values (range 0.30--500 ng/ml). Generally, patients with clinically apparent MTC, either primary or metastatic, had higher plasma CEA and CT levels than those with occult disease. A positive correlation was found (r = 0.785, p less than 0.01) when comparing basal plasma CEA and stimulated plasma CT levels in 20 patients. A marked increase above the basal plasma level of CT but not CEA was detected in each of six MTC patients following intravenous calcium or pentagastrin. These data demonstrate that basal plasma levels of CEA and CT were increased in a large percentage of patients with MTC. Plasma calcitonin levels unlike plasma CEA levels were more often elevated in patients with occult disease and were increased above basal following the intravenous administration of either calcium gluconate or pentagastrin.


Clinical correlation between CEA and breast cancer.

Elevated plasma CEA levels were observed in 14.2% (2/14) of preoperative patients, 7.9% (3/38) of postoperative patients, and 70.9% (83/117) of patients with metastatic disease. Within these respective groups the simultaneous measurement of hCG, three polyamines and three minor nucleosides further enhanced the detection rates to 69.2%, 54.2%, and 98.6%. It was observed that in patients with at least one elevated CEA, measurement of sequential CEA levels paralleled the clinical course of metastatic disease in 25 patients. Prior to therapy for metastatic disease CEA levels greater than 5 ng/ml were associated with lower response rates and a shorter time to treatment failure than were levels less than or equal to 5 ng/ml. This effect was enhanced in patients also having an elevated hCG level. Hepatic and osseous involvement were associated with a greater incidence of CEA elevations than were pulmonary or soft tissue sites of involvement.


Evaluation of carcinoembryonic antigen as a plasma monitor for human breast carcinoma.

Plasma CEA levels have been determined in 92 normal women and 768 women with benign or malignant breast diseases. Only one of 92 normal women had a CEA level above 5 ng/ml. Of 253 women with benign breast diseases (gross cystic disease, adenofibroma, fibrosis, etc.) only one had a CEA level above 5 ng/ml. Ninety-four percent of the above two groups of women had CEA levels below 3 ng/ml. Of 164 women operated upon for Columbia Clinical Classification Stage A or B breast carcinoma, preoperative CEA levels were above 5 ng/ml in seven (4%). Patients with a preoperative CEA level above 3 ng/ml seemed to have an increased incidence of tumor recurrence. Elevated CEA levels (greater than 10 ng/ml) in our postmastectomy population of 288 patients have correlated with development of metastases in 14 of 46 subjects. Of 216 patients under treatment for metastatic breast carcinoma, CEA levels above 10 ng/ml have been detected in 15 percent of patients with soft tissue metastases, 38% of patients with visceral metastases and 50% of patients with osseous metastases. Of metastatic breast carcinoma patients with CEA levels above 10 ng/ml serial measurements have correlated with the patients response to therapy, progressively increasing in treatment failures and decreasing in treatment responders.


Carcinoembryonic antigen in breast cancer.

Carcinoembryonic antigen (CEA) levels were determined in 742 postoperative patients with breast cancer. Within this group the percentage of elevated (greater than or equal to 4.0 ng/ml) assays increased with UICC clinical stage and was 14.8% (12/81), 23.7% (27/114), 73.1% (190/260) and 20.0% (49/245) for stages I, II, III, IV and X (unstagable due to insufficient data) patients. We have now followed the above 482 stages I, II, III and X patients in whom CEA was performed less than or equal to 3 months after initial surgery at a time when there was no evidence of residual disease, for an average interval of 255 days from date of diagnosis. At present 16.2% (17/105) of patients with elevated CEA values compared to only 4.8% (18/377) of patients with normal values have developed recurrent disease (p less than .0005). There is an association of elevation of CEA postoperatively with different clinical stages of breast cancer. Elevated CEA levels postoperatively are associated with an increased risk of development of recurrent disease in breast cancer patients.


Carcinoembryonic antigen (CEA) in the cancer family syndrome.

We present findings on plasma CEA in relatives and spouses from six kindreds manifesting the Cancer Family syndrome. The CEA distributions per se were transformed to square root CEA to correct for skewness and kurtosis. Significant effects of age and duration of smoking were adjusted for by linear regression. Relatives were classified as: 1) cancer patients, 2) individuals at high genetic cancer risk (one or more first-degree relatives affected, and 3) individuals at low genetic cancer risk (no first-degree relatives affected) for statistical comparisons. Unrelated spouses were also classified into corresponding groups according to their directline mate's status. Cancer patients and relatives at high genetic risk had significantly greater mean square root CEA than relatives at low genetic risk, and, surprisingly, unrelated spouses had mean levels of square root CEA which were similar to that in the corresponding cancer risk class of their direct-line mates. Our results suggest the existence of both a genetic and connubial effect on CEA, presumably due to a common environmental agent acting in concert with the degree of genetic predisposition to oncogenesis in this syndrome.


Present status of the zinc glycinate marker (ZGM).

ZGM was purified from both primary and metastatic colonic carcinomas demonstrably positive for ZGM by immunofluorescence microscopy. ZGM purification included preparative Pevikon electrophoresis, Sepharose 4B molecular exclusion chromatography and Con A-Sepharose affinity chromatography. ZGM had an alpha2 electrophoretic mobility, an estimated molecular weight by Sepharose 4B equal to or greater than 2 x 10(6), and did not bind to Con A-Sepharose, although having determinants with CEA-like activity. Its immunologic activity was resistant to trypsin or phospholipase A but not to neuraminidase. Antisera prepared to ZGM and absorbed with saliva, when tested by double immunodiffusion, formed a single precipitation line with saline extracts of colon tumors and did not cross-react with CEA, AFP, normal tissue extracts, ferritin, NCA, NCA-2, CSAp, blood groups A, B, H, Lewis antigen, or buffy coat, alpha-2 macroglobulin, saliva or ovarian cyst fluid. Immunofluorescence microscopy confirmed the presence of ZGM in 40 out of 45 adenocarcinomas of the GI tract staining primarily in tumors, the apical cytoplasm, and in grossly nonmalignant tissues, the deep crypts of the villi, while all of 22 non-GI tumors in the study were ZGM negative.


Comparative evaluation of carcinoembryonic antigen and gross cystic disease fluid protein as plasma markers for human breast carcinoma.

A comparative evaluation of carcinoembryonic antigen (CEA) and gross cystic disease fluid protein (GCDFP) as plasma markers for human breast carcinoma has been performed. Both assays appear to be useful in patients with metastatic breast carcinoma. Of 216 patients under treatment for metastatic disease, 111 (51%) had abnormal plasma levels of CEA and/or GCDFP. Abnormal plasma levels of CEA were present in 73 patients whereas abnormal GCDFP levels were present in 67. Twenty-nine patients had increased plasma levels of both markers simultaneously, 44 patients had increased CEA levels only and 38 patients had increased GCDFP levels only. Thus, of the 111 patients with elevated levels of either CEA or GCDFP, the two markers varied independently of each other in 74%. Utilizing both assays, abnormal plasma levels were present in 79% of patients with osseous metastasis, 53% of patients with visceral metastasis and 26% with soft tissue metastasis. Both assays, when performed serially in patients treated for metastatic breast carcinoma, were found to have utility in monitoring responsiveness; and increasing CEA or GCDFP plasma level indicated disease progression and a decreasing plasma level indicated regression.


The value of adriamycin in the treatment of diffuse malignant pleural mesothelioma.

Thirty-six patients with diffuse malignant pleural mesothelioma were seen over a period of 15 years. The median age was 60 years (range, 21 to 75 years), and the male to female ratio was 2.3 to 1. The most common symptoms were chest pain and shortness of breath and all patients presented with pleural effusion on chest x-ray. The diagnosis was established by tissue biopsy in all cases. The median survival time for all patients was 12.5 months. Twenty-one patients were treated with an adriamycin-containing regimen and in this group, the median survival time from histological diagnosis was 14 months. In contrast, the median survival time for the 15 patients, who did not receive adriamycin, was 6 months (p = 0.009). The median survival time from the initiation of chemotherapy was 9 months for the adriamycin group and 2 months for patients treated with other type of chemotherapy (p = 0.001). Adriamycin appears to be of benefit in the treatment of diffuse malignant pleural mesothelioma.


Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols: a clinical-pathologic study of 33 patients.

Sequential chemotherapeutic regimens, primarily used in the treatment of hematopoietic malignancies, and employing ara-C as a basic antineoplastic agent induce mucosal alterations in the entire gastrointestinal tract. These are characterized by surface and glandular epithelial atypia, immaturity, and necrosis. Glandular regeneration is characteristically delayed leading to a state of intestinal aproliferative cytopenia. Other toxic intestinal changes include telangiectasia of blood vessels and the formation of intramural hematomas. Intestinal infections develop frequently and are complicated by peritonitis, liver abscesses, pneumatosis cystoides in testinalis and sepsis. These intestinal lesions are accompanied by a predictable clinical syndrome which begins concomitantly with ara-C infusions and is characterized by diarrhea, ileus, abdominal pain, hematemesis and melena, severe hypokalemia, hypocalcemia and a protein-losing enteropathy. Additional toxic manifestations induced by ara-C include transient weight gains, fever elevations and severe bone marrow depression. The genesis of the intestinal lesions is linked to the three day dose schedule of ara-C infusions which insures both arrest of the cycling intestinal cells in the S-phase and a high cytotoxic index. The severity of these lesions is markedly augmented by prior treatment with ara-C and cyclophosphamide which causes synchronization and probable recruitment of intestinal stem cells, respectively.


Pituitary oncocytic tumor with Cushing's disease.

Pituitary adenomas composed of oncocytes are rare. We report a young female with an atypical oncocytic tumor of the pituitary. The histology was unusual because the oncocytic cells--in addition to an abundance of abnormal mitochondria--contained a conspicuous smooth endoplasmic reticulum. The tumor grew invasively and the patient developed adrenal hypercorticism.


Adenosquamous carcinoma of skin appendages (adenoid squamous cell carcinoma, pseudoglandular squamous cell carcinoma, adenocanthoma of sweat gland of Lever) of the vulva: a clinical and ultrastructural study.

History and clinical findings of 18 cases of adenosquamous carcinoma of the skin appendages found among 135 cases of primary carcinoma of the vulva seen at the University of Minnesota Hospital between 1951 and 1970 were analyzed. In addition, two recent cases of this tumor were studied with conventional transmission electron microscopy. Adenosquamous carcinoma of the vulva showed poorer survival and a higher rate of lymph node metastases than squamous cell carcinoma of the corresponding stages (carcinoma in situ excluded). In four out of thirteen cases, the metastatic lesions in the lymph nodes retained glandular pattern. The ultrastructure showed mucin-producing columnar cells lining glandular lumina, and poorly differentiated squamous cells elsewhere; further, cells of the intermediate type between the two were present. This study indicates that adenosquamous carcinoma of the vulva is a distinctively separate entity from squamous cell carcinoma of the vulva, and possibly arises from mucin-producing cells of the skin appendages as suggested by Johnson and Helwig.


Intraoral papillary squamous cell tumor of the soft palate with features of sialadenoma papilliferum-? malignant sialadenoma papilliferum.

An unusual, recurring, squamous papillary tumor involving and possibly arising from minor salivary gland excretory ducts in the palate is presented. Similarity to sialadenoma papilliferum and upper respiratory tract papillomatosis is noted. A paraglandular cystic mass with some resemblance to the palatal lesion, and a solitary lymph node with papillary squamous epithelial deposits was found in a radical neck dissection. We suggest that the lymph node lesion represents a metastasis which may have arisen from the palatal lesion, and therefore propose the concept of a possible malignant analogue of sialadenoma papilliferum.


Immunoblastic lymphadenopathy and adenocarcinoma of the pancreas: a case report.

Immunoblastic lymphadenopathy developed 5 months before the clinical manifestation of an anaplastic adenocarcinoma of the pancreas in a 53-year-old male. The possible association and significance of this relationship, which has not been hitherto reported, is discussed.


Anaplastic dysgerminoma.

A rare case of rapidly evolving dysgerminoma produced death by tumor in less than two months after onset of symptoms. It is important to recall that dysgerminoma possesses considerable malignant potential, which infrequently is manifested by rapidly progressive disease. Certain risk factors, present in the pathological specimen, serve to indicate the aggressive potential of such neoplasms.


A preliminary study of intralesional, intralymph node, intravenous and intraperitoneal Corynebacterium parvum treatments in patients with advanced cancer.

Twenty-one patients with squamous cell carcinoma of oral cavity and/or cervical lymph node and four patients with soft tissue sarcomas were given intralesional (2-4 mg/m2) and intralymph node (2-4 mg/m2) C. parvum injections followed by 5 intravenous (2-4 mg/m2) C. parvum treatments and conventional therapies. Seven patients with Stage III ovarian carcinomas were given intraperitoneal (2-4 mg/m2) C. parvum injections followed by conventional therapies. The local and systemic effects of the C. parvum treatments were described and the anti-tumor effects were evaluated in this series of patients.


Value of serum copper levels and erythrocyte sedimentation rates as indicators of disease activity in children with Hodgkin's disease.

Initial and serial serum copper levels (SCL) and erythrocyte sedimentation rates (ESR) of 29 children with Hodgkin's disease were reviewed to determine the relationship of these features to disease activity. Only six of 10 patients who relapsed had SCL greater than adult upper normal levels. Although correction for age increased this to 7, it also increased the number of patients with false positive results to 9 of 19. Although 9 of the 10 patients at relapse had an increase in SCL over the preceding value, almost one-fifth of patients in remission had increases in consecutive SCL greater than the average increase of patients who relapsed. We conclude that SCL, even when age corrected and consecutively followed, are not useful as indicators of disease activity in children with Hodgkin's disease. Although the ESR increased to greater than 20 mm/hour in 9 of 10 patients who relapsed, this determination could not be considered a useful early indicator of disease recurrence since it was so frequently elevated in patients who were free of disease (62 of 109 determinations). The extremely nonspecific nature of SCL and ESR in childhood renders these tests unreliable, particularly in the individual child.


Cancer and total mortality among active Mormons.

Based on Church records for 15,500 California Mormons during 1968 to 1975 and for 55,000 Utah Mormons during 1970 and 1975, the ratio of age-adjusted death rates for religiously active Mormon males compared with U.S. white males is 38% for ages 35 to 64 years and 50% for ages 35 years and above. The remaining life expectancy for active Mormon men at age 35 is about 44 years, over 7 years greater than for U.S. white males. Their standardized mortality ratio is 50% for all cancer, being 23% for smoking-related cancer sites and 68% for all other sites. Active Mormons, defined here to be High Priests and Seventies, abstain almost completely from the use of tobacco, alcohol, coffee, and tea, but appear to be fairly similar to other white males with regard to socioeconomic status, urbanization, and diet. Active Mormons are healthier than Mormons as a whole and rank among the lowest in mortality when compared with other groups of healthy males.


Relative high frequency of childhood Hodgkin's disease in the north of Portugal.

Sex, age and histopathologic pattern of 322 cases of Hodgkin's disease diagnosed at the Laboratory of Pathology of Oporto Medical School between 1930 and 1974 are presented. 35 (10.9%) of the 322 patients were less than 10 years old. The male/female ratio of childhood Hodgkin's disease was 2.9:1 and the histologic observation revealed mixed cellularity in 18 (51.4%) and nodular sclerosis in 10 (28.6%) of the 35 cases. Childhood Hodgkin's disease relative frequency has abruptly decreased in the last five years of the study period. Most of the children belonged to large families living under poor socioeconomic conditions and the majority of them presented in advanced clinical stages. These findings are similar to those previously described in some developing countries of tropical and subtropical regions and reinforce the advanced relationship between under-development and the geographic variations in childhood Hodgkin's disease frequency and pattern.


Systematic restaging in patients with Hodgkin's disease: a Southwest Oncology Group Study.

Eighty-two patients with advanced Hodgkin's disease who were in apparent complete remission (CR) after receiving 10 courses of combination chemotherapy were systematically reevaluated for persisting disease. Occult Hodgkin's disease was found in 10 (12%) of these patients and was predominantly present in nodal sites (91%) which were known to have been involved at initial staging (100%). Repeat chest radiography, Gallium-67 tumor scanning and lymphography were the most helpful procedures for detecting residual disease. Nine of the 72 (13%) patients felt to be free of disease after negative restaging subsequently relapsed within 8 months. Sites of early relapse, like the sites of disease found at restaging, occurred almost always in previously involved nodal areas. We conclude that systematic restaging should be incorporated into subsequent lymphoma trials in order to define more clearly complete remission and that every patient treated for lymphoma should undergo a careful restaging evaluation before therapy is discontinued.


Mediastinal rhabdomyoma.

An 80-year-old black male with gastric adenocarcinoma, liver metastases, and parathyroid adenomas also had a rhabdomyoma of the anterior-superior mediastinum. This appears to be the first reported case of mediastinal rhabdomyoma in the literature. The ultrastructural demonstration of haphazardly arranged myofilaments with prominent Z bands and the absence of demosomes indicates that it is of extra-cardiac type. The probable origin of this tumor from the myoid cells of the thymus is discussed.


Lymphangioma circumscriptum following radical mastectomy and radiation therapy.

Lymphangioma circumscriptum, a rare long-term complication of chronic lymphedema, has been described only twice following radical mastectomy. The case discussed in this report developed 25 years after radical mastectomy and radiation therapy. Both this condition and lymphangiosarcoma, its malignant counterpart, may arise in lymphedematous extremities regardless of the etiology of the lymphatic obstruction.


Major peripheral arterial occlusion due to malignant tumor embolism: histologic recognition and surgical management.

Four cases of major peripheral arterial occlusion due to malignant tumor emboli are reported. All of the emboli originated from primary lung carcinomas, three following resection of the lung tumor, and the fourth occurring spontaneously before discovery of the lung primary. Each patient underwent successful embolectomy and was discharged without any related deficits. Their survival ranged from three to seven months. These cases emphasize the possibility of tumor embolism either spontaneously or following surgical manipulation. Early pulmonary vein ligation and, if indicated, intrapericardial ligation should be performed at the time of resection to try to prevent this complication.


Recognition and successful management in pulmonary aspergillosis in leukemia.

Invasive pulmonary aspergillosis is a common fungal infection in the compromised host. The outcome has been generally poor and, until recently, most reports are derived from autopsy series. We report nine patients with leukemia and the characteristic clinical presentation of pulmonary infarction. There is histological evidence that infarction is due to fungal invasion of the pulmonary arterial system with distal hemorrhagic infarction, cavitation, and mycetoma formation. This complete evolution was detected in six patients, none of whom had previous cavitary pulmonary disease. Therapy included amphotericin B (9 patients), aerosolized nystatin (6 patients), and 5-fluorocytosine (5 patients). Complete resolution of the pulmonary lesions occurred in six patients with a subsequent median survival of 13.5 months (range: 5-32+ months). Three patients died with continuing pulmonary infiltrate. Despite the antifungal chemotherapy, resolution seemed to correlate best with recovery of circulating neutrophils.


Sister chromatid exchanges in lymphocyte cultures of patients receiving chemotherapy for malignant disorders.

The frequency of sister chromatid exchange (SCE) was studied in peripheral lymphocytes of patients receiving chemotherapy for various malignant disorders. Significantly increased SCE frequencies were recorded in six patients 2-7 weeks after CCNU treatment and in one patient 2 weeks after melphalan treatment. One patient treated with prednimustine and one treated with DTIC had SCE frequencies just within the upper limit of the control range 1-2 weeks after therapy. Normal SCE frequencies were recorded in nine patients studied at times varying from 3 days to several weeks after administration of cytostatic courses involving 5-fluorouracil, vincristine, adriamycin, cyclophosphamide, bleomycin, thioTEPA, methotrexate, and prednimustine. Radiotherapy could not be causally related to increased SCE frequencies in any of the patients. The results indicate that CCNU and melphalan, in contrast to several other chemotherapeutic agents, induce very long-lived DNA lesions, which may be of crucial importance for the development of secondary neoplasms.


Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy.

A mammary adenocarcinoma (16/C) was isolated and maintained in serial passage by transplantation of metastatic lung foci. This tumor originated as a spontaneous mammary adenocarcinoma in a C3H/He female mouse. It was selected as a model from greater than 50 mammary tumors studied because it was highly metastatic and because it responded to most of the agents reported to be active against breast cancer in women. Sc implanted 16/C tumors (in the 300--1000-mg range) metastasized to the lungs in greater than 75% of the mice and to the axillary lymph nodes in greater than 30%. This tumor has been tested for sensitivity to greater than 40 clinically used agents. Adriamycin was the most active single agent. Other active agents included cyclophosphamide, 5-fluorouracil, vincristine, melphalan, dibromodulcitol, maytansine, neocarzinostatin, palmO-ara-C, vinblastine, and VP-16-213. Agents most active against 40--1000-mg tumours were also most active against micrometastatic disease (eg, adriamycin). The converse was also true; agents inactive or marginally active against 40--1000-mg tumors were at best marginally active against micrometastatic disease (eg, BCNU). Tumors greater than 20 mg were not curable by chemotherapy alone, although adriamycin treatment caused complete regressions of 100--400-mg tumors in greater than 80% of the mice. Surgical removal of 300--1000-mg tumors plus therapy with adriamycin resulted in 40%--72% cures as compared to 0--26% cures with surgery only. Data resulting from treatment with other agents, singly and in combination, are presented.


Protective effect of hyperthermia against the cytotoxicity of actinomycin D on Chinese hamster cells.

Hyperthermia is being tested as an adjuvant to chemotherapy for clinical use. We elected to study the interaction of heat at 43 degrees C with actinomycin D (AMD) (0.5 microgram/ml) in tissue culture using plateau phase Chinese hamster cells. The simultaneous administration of 43 degrees C and AMD produces more than additive cytotoxicity if the duration of exposure is less than 30 minutes; however, this is quickly reversed with longer exposures with the cells developing resistance to further cytotoxicity of AMD. If heat (43 degrees C) is applied before AMD exposure, the cells also are rendered insensitive, with a greater protection observed for longer periods of heating. For example, for cells heated for 2 hours at 43 degrees C and then exposed to AMD (0.5 microgram/ml for 2 hours), cytotoxicity to AMD is decreased by a factor of 10. Heat-induced resistance to AMD persists for at least 18 hours before full recovery of AMD effect returns. The application of heat following AMD exposure also protects against the cytotoxicity of AMD. Studies using 3H-AMD demonstrate that the resistance does not correlate with reduced membrane permeability to AMD of heated cells. Attention must be given to the timing of hyperthermia when used clinically as adjuvant therapy in patients receiving AMD.


Hepatic arterial BCNU: a pilot clinical-pharmacologic study in patients with liver tumors.

BCNU at a dose of 200 mg/m2 was administered in a 60-minute hepatic arterial (HA) infusion to three patients with liver-predominant neoplastic disease. Nitrosourea blood levels were measured during the 60-minute infusion and for 30 minutes after completion of the infusion in samples obtained simultaneously from a hepatic venous (HV) catheter and a peripheral venous (PV) site. Direct extraction of blood with diethyl ether was used in order to remove quantitatively the nitrosourea from blood and thereby stabilize it against in vitro breakdown in blood prior to colorimetric analysis. As determined by blood levels, steady-state was achieved within 50 minutes of infusion. Mean HV levels at steady-state were 2.5-fold higher in the HV compared to PV samples. The higher HV compared to PV levels must reflect higher tumor exposure to nitrosourea with HA compared to the usual iv route of administration. No drug-related hepatic toxicity was noted. Myelosuppression was noted in only one patient in whom reversible leukopenia (granulocyte nadir, 500/mm3) and thrombocytopenia (platelet nadir, 20,000/mm3) developed.


Evaluation of single-dose vincristine, actinomycin D, and cyclophosphamide in childhood solid tumors.

Bolus chemotherapy with vincristine, actinomycin D, and cyclophosphamide was administered to 31 patients with solid tumors. Among 12 patients with measurable disease who had not received prior treatment, a complete response was achieved in one with Ewing's sarcoma and a partial response was achieved in another with rhabdomyosarcoma. The dose-limiting toxicity was granulocytopenia.


Treatment of advanced colorectal cancer with methyl-CCNU plus 5-day 5-fluorouracil infusion.

Thirty-six patients with advanced colorectal carcinoma who had not received prior chemotherapy and had tumor sites measurable or evaluable for response received methyl-CCNU at a dose of 175 mg/m2 orally on Day 1 plus 5-fluorouracil at a dose of 30 mg/kg/24 hours by continuous iv infusion for 120 hours (Days 1-5). Doses were chosen to approach the maximum which could be administered in combination. The cycle was repeated 6 weeks later. Objective partial responses occurred in six patients (17%), with five responses apparent after the first cycle and one additional response after the second cycle. The response duration ranged from 1.5 to 18+ months (median, 5 months). Dose-limiting toxic effects included mucositis in 18 patients (50%) and dermatitis in nine patients (25%), while leukopenia (less than 4000 cells/mm3) and thrombocytopenia (less than 100,000 platelets/mm3) were observed on at least one occasion during therapy in 52% and 46% of patients, respectively. 5-Fluorouracil administration by infusion avoided overlapping myelosuppression and allowed a higher total dose to be given with methyl-CCNU. However, the response to the combination did not exceed the results anticipated for the use of either drug alone.


In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia.

A subline of P388 leukemia resistant to adriamycin (P388/ADR) was developed by exposure to the drug in vivo. Resistance to adriamycin proved to be a stable characteristic of P388/ADR. There was no significant inhibition of nucleic acid synthesis in P388/ADR cells in vivo following a dose of 10 mg/kg of adriamycin in contrast to a prolonged and complete inhibition, particularly of DNA synthesis, observed in parental sensitive P388 leukemia cells. P388/ADR proved to be completely cross-resistant to a spectrum of anthracycline derivatives. Cross-resistance was observed to nonanthracycline DNA intercalating agents (with the exception of anthramycin), to agents which interfere with mitotic spindle function, and to antineoplastic inhibitors of protein biosynthesis (with the exception of bruceantin). P388/ADR was sensitive to antimetabolites and alkylating agents. Cross-resistance was also observed to several agents (ICRF-159, a terephthalanilide, taxol, lymphosarcin, bouvardin, and a crude extract of Ervatamia hyneana) whose mechanisms of action have not yet been clearly defined. This observation has proved useful in providing a lead for determination of mechanism of action of some of these drugs. The pattern of cross-resistance of a subline of P388 leukemia resistant to daunorubicin, though not studied extensively, appears to be similar to that of P388/ADR.


Chemotherapy for colorectal cancer with a combination of 5-fluorouracil, mitomycin C, adriamycin, and cytosine arabinoside: a pilot study.

Fifty-four patients with clinical evidence of residual colorectal adenocarcinoma following surgical removal of the primary tumor were treated with a combination of 5-fluorouracil, mitomycin C, adriamycin, and cytosine arabinoside. The objective response rate in these patients was 17%. Bone marrow suppression was the major toxic effect. These data fail to show an advantage of this combination therapy over previously described chemotherapeutic regimens.


Amphotericin B and combination chemotherapy in the treatment of refractory metastatic breast carcinoma and sarcoma.

Nineteen patients resistant to an adriamycin-containing regimen were treated with 4 days of amphotericin B and the same adriamycin-containing chemotherapy regimen that had been given without amphotericin B. Of the 14 evaluable patients (11 with breast carcinoma and three with sarcoma), one patient with breast carcinoma achieved a partial remission and a second patient with breast carcinoma remained stable. All other patients developed progressive disease. Both hematologic and nonhematologic toxicity were significantly increased when amphotericin B was added to chemotherapy.


Antitumor activity of fungal metabolites: verrucarin beta-9, 10-epoxides.

Verrucarins A (4) and B (5) and verrucarin A acetate, in vivo antileukemic inactive fungal metabolites, have been oxidized with m-chloroperoxybenzoic acid to give verrucarin beta-9,10-epoxides which show high in vivo activity against P388 mouse leukemia.


Ophthalmologic toxicity after cis-dichlorodiammineplatinum(II) therapy.

Two cases of apparent ophthalmologic toxicity which occurred during treatment with cis-dichlorodiammineplatinum(II) (DDP) are described. In the first case, a patient with testicular carcinoma developed papilledema after three courses of DDP and adriamycin therapy. In the second case, a patient with breast cancer developed retrobulbar neuritis after three courses of DDP therapy. The differential diagnosis and possible explanation for these toxic effects are discussed.


Specific conversion of D-galactose into D-galacturonic acid residues in glycoproteins: a facile method for carbohydrate linkage-analysis.

The terminal D-galactopyranosyl residues of asialoglycopeptides isolated from human alpha1-acid glycoprotein were oxidized in nearly quantitative yield to the corresponding uronic acid residues by a two-step sequence employing D-galactose oxidase followed by treatment with Tollens reagent, Ag(NH3)+2. Mild acid hydrolysis of the oxidized glycopeptides led to the isolation of the corresponding aldobiuronic acid(s). Structural and colorimetric analysis revealed that only one aldobiuronic acid 2-amino-2-deoxy-4-O-(beta-D-galactopyranosyluronic acid)-D-glucose, was isolated from the oxidized glycopeptides of alpha1-acid glycoprotein. This method can readily distinguish between the (1 leads to 3), (1 leads to 4), and (1 leads to 6) isomers of the corresponding aldobiuronic acids.


Exercise testing in children and young adults: an overview.

This chapter has demonstrated the diagnostic capability and feasibility of documenting functional abnormalities during dynamic stress in a pediatric population. The overview confirms that a controlled exercise procedure can be performed routinely in ambulatory children with or without cardiovascular disease and should be included in the clinical evaluation of specific lesions. It now appears that the primary indications for noninvasive exercise testing in the pediatric population include the following disorders: 1. Left ventricular outflow obstructions, a. Subvalvar obstructions, b. Valvar obstructions, c. Supravalvar obstructions, d. Idiopathic hypertrophic subaortic stenosis, e. Coarctation of the aorta; 2. Chronic left or right ventricular volume overload, a. Atrioventricular or semilunar valve incompetence, b. Left-to-right shunts; 3. Rhythm and conduction disturbances, a. Postoperative ventriculotomy, b. Bradytachyarrhythmias, c. Arrhythmias in patients with or without symptoms. The role of the exercise procedure is not yet established in the following areas: 1. Patients with family history of premature atherosclerosis or Type II hyperlipoproteinemia; 2. Patients with elevated blood pressure; 3. The evaluation of syncope, chest pain, or atypical findings on physical examinations (especially in athletes). Consequent upon increased interest and improved technology, the role of this technique will soon be established in the invasive and noninvasive evaluation of pediatric patients with or without overt cardiovascular disease.


Purification and partial characterization of protein 35/7.7 a cytosol protein that is abundant in rapidly growing hepatomas.

Protein 35/7.7 is an abundant cytosol protein of Morris hepatoma 3924A and Novikoff hepatoma which was not found in normal liver. Protein 35/7.7 was isolated from the cytosol of Novikoff hepatoma ascites cells by ammonium sulfate precipitation and DEAE-cellulose chromatography. It migrated as a single major spot on two-dimensional isoelectric focusing-SDS polyacrylamide gels. The N-terminal hexapeptide is Val-Asx-Pro-Thr-Val-Phe and its carboxyl-terminal amino acid is phenylalanine.


Preparation of membrane-depleted polygonal coat structures from isolated coated vesicles.

When coated vesicles isolated from porcine brain are treated with buffers containing 2 M urea and subjected to ultracentrifugation, pellets are obtained which consist of largely smooth-surfaced, i.e. coat-free, vesicles. On dialysis of the urea from the supernatant solution spheroidal particles can be pelleted which are of similar size to the coated vesicles and show the typical polygonal lattice arrays but do not reveal any vesicle membrane profiles. Gel electrophoresis of these membrane-depleted polygonal arrangements demonstrates the predominance, if not exclusive occurrence, of the polypeptide band component with an apparent molecular weight of about 180,000. This suggests that the polygonal coat structure contains only clathrin.


A three-dimensional study of organelle interrelationships in regenerating rat liver. 1. The Gerl-system.

Arguments are put together indicating that the GERL-system, or at least its thick membrane and part of its content are derived from the mature Golgi cisterna. Just like every Golgi cisterna does, the GERL shows direct continuities with ER, from which a complement of products may be supplied. Rigid lamellae are interpreted as intermediate forms in the transformation of the mature Golgi cisterna into the GERL-system. In hepatocytes the GERL produces two types of lysosomes: dense bodies, which may either contain lipoprotein granules or not, and small coated vesicles. The probable meaning of lipoprotein digestion (crinophagy) is discussed.


A three-dimensional study of organelle interrelationships in regenerating rat liver. 2. Transient connections with luminal continuity between thin- and thick-membraned organelles.

Luminal continuities can be established between thin- and thick-membraned structures, and serve the transfer of their contents. The abrupt change in membrane thickness at the site of connection suggests that exchange of membrane constituents is very limited. This enables retrograde separation of the connected organelles. sER (endoplasmic space) makes up such continuities with exoplasmic structures (mature Golgi cisterna, GERL-system, occasionally MVB). Transfer tubules, possessing a thiny membrane but nevertheless belonging to the exoplasmic space, take up endocytized material from large coated vesicles or from coated plasma membrane loops and carry it to MVB. They offer the possibility to recycle the internalized plasma membrane.


[Immunocytology and immunohistology of malignant lymphomas].

Two methods of immunological tests used in haematology were assessed with fairly positive results. However, the authors have some considerable reservations as regards the practical significance of the two methods insofar as practice independent of research is concerned. Their pessimism is substantiated by the demanding complexities of immunological methods, but also by the relatively rare essential diagnostic significance of these findings and by the vulnerability of result interpretation.


[Prognosis of hematopoietic-system tumors as based on structural properties].

Comparisons were made in a series of 43 orofacial biopsies and 91 necropsies as regards the survival rate in patients with histological types of malignant lymphoma and other tumours of the haematopoietic system. Results listed in tables are, on the whole, in agreement with literary data. Problems were only encountered in the group of immunoblastomas where the nodular and angiofollicular varieties were repeatedly seen in association with a survival time of as much as 3 years as opposed to 1 year survival time in the diffuse variety.


[Angiofollicular hyperplasia of lymph nodes (Castleman's hyperplasia)].

Intrathoracic angiofollicular enlarged nodes illustrating two histological types according to Flendrig and Keller were removed in a 36- and an 18-year old man. Clinical symptomatology was absent in one of the patients, and disappeared in the other after resection. The histological pictures featured in particular: protein penetration from the hyperplastic vascular bed, regressive changes in the follicles, and plasmocytic hyperplasia. Vascular as well as interfollicular fibrosis were seen as one of the causes of visualization of normal follicular vascularization, which is normally poorly visible. The whole process, however, revealed increased interfollicular vascularization, the significance of which is the subject of discussion.


[Myxoma of the external nose].

A male bus-driver aged 45 had a proboscoid mass on the tip of his nose removed after three year's duration of the disease. Microscopically, the tumour appeared to be a myxoma with marked mucus accumulation extending subepidermally and leading to the formation of lacunes lined with fibroblasts.


[Sclerosing lipogranuloma (with lipid pseudocysts)].

A case of sclerosing lipogranuloma (with oil pseudocysts) in a 38-year old woman is described. The disease started at the age of 16 as extensive foci with local inflammatory manifestations on the legs. Later on, it took the form of relapsing disseminations of tiny fibrous nodules with no inflammatory manifestations. Judging from literary data and his own observations, the author describes sclerotizing lipogranuloma as an independent pathological involvement of the subcutis quite distinct from histologically identical lesions caused by exogenous lipids (paraffinomas).


Arabinosyl nucleosides. XII. Influence of arabino-furanosylthymine on growth of L5178y cells.

The antibiotic 1-beta-D-arabinofuranosylthymine (araThd) is a potent inhibitor of the growth of mouse lymphoma cells (L5178y). The ED50 concentration was found to be 9.8 muM. The cells die as a consequence of an unbalanced growth. The cytostatic activity of araThd can be abolished by coincubation with dThd and dUrd but not with Urd. At cytostatic concentrations araThd selectively blocks DNA synthesis; RNA- and protein synthesis are unaffected. Intracellularly araThd is rapidly phosphorylated to araTTP. This enzymic phosphorylation does not influence the synthesis of the naturally occuring, related triphosphate dTTP. AraTMP is incorporated into DNA during DNA synthesis; 1 mol of ara-TMP is incorporated/19,500 molecules of dTMP.


Arabinosyl nucleosides. XIII. Influence of arabinofuranosylthymine on DNA-, RNA- and protein-synthesizing systems in vitro.

The natural metabolite of the sponge Cryptotethya crypta, arabinofuranosylthymine (araThd), is intracellularly phosphorylated to araTTP. The present study demonstrates that araTTP inhibits both isolated DNA polymerases alpha and the DNA polymerase beta from L5178y cells competitively with respect to the analogous substrate dTTP. The affinity of araTTP is higher to the DNA polymerase alpha than to the DNA polymerase beta. The activity of mammalian DNA-dependent RNA polymerases I, II and III as well as the incorporation rate of a protein cellfree system is not affected by high doses of araTTP.


Effects of carcinogenic and non-carcinogenic chemicals on plasma esterases in BALB/c mice.

Esterase profiles of plasma from female BALB/c mice treated with a variety of carcinogenic and weakly- or non-carcinogenic chemicals were analyzed. Mice treated with the potent carcinogens diethylnitrosamine, dinitrosopiperazine, dipropylnitrosamine, dimethylhydrazine, urethane, and dimethyldinitrosopiperazine had similarly altered plasma esterase profiles after 7 days' exposure to the chemicals. The alterations consisted of increased activity in 4 esterase bands. The increased activity persisted in some of the bands after cessation of carcinogen exposure. Exposure to high concentrations of the weakly- or non-carcinogenic compounds nitrosohydroxyproline, nitrosomethoxymethylamine, 1-nitroso-4methylpiperazine,nitroso-2,6dimethylpiperidine, and ethyl methanesulfonate caused no obvious plasma esterase alterations. Ingestion of carbon tetrachloride resulted in increased activity in one esterase band with concomitant decrease in a second band. Analysis of serum from test mice for levels of serum glutamic oxaloacetic transaminase, alkaline phosphatase, lactate dehydrogenase-lactate substrate, and D-gamma-glutamyl transpeptidase did not differentiate between mice treated with selected carcinogens and those treated with non-carcinogens and/or carbon tetrachloride.


Benzo(a)pyrene 7,8-dihydrodiol-9,10-oxide modification of DNA: relation to chromatin structure and reconstitution.

Purified duck reticulocyte DNA was incubated in vitro with a 7,8-dihydrodiol-9,10-oxide derivative of benzo(a)pyrene (BPDE). The carcinogen-modified DNA was somewhat more susceptible to partial digestion by the single strand specific endonuclease S1 than unmodified DNA, suggesting slight denaturation of the helix at sites of modification. Chromatin was reconstituted in vitro utilizing this carcinogen-modified DNA and unmodified-chromatin associated proteins. This reconstituted chromatin showed the same kinetics and extent of digestion by Staphylococcal nuclease, and similar nucleosome profiles on sucrose density gradient centrifugation, as those obtained with native chromatin or chromatin reconstituted with unmodified DNA. Moreover, polyacrylamide gel electrophoresis of DNA fragments obtained from nuclease digests gel electrophoresis of DNA fragments obtained from nuclease digests of the reconstituted chromatins suggested that the chromatin containing carcinogen-modified DNA had the same subnucleosome structure as that reconstituted with unmodified DNA. In a separate set of studies intact duck reticulocyte chromatin was reacted directly with BPDE. Nuclease digestion studies indicated that 65% of the carcinogen was bound to the 'open' regions of chromatin, and 35% to 'closed' regions. These results indicate that although convalent binding of a benzo(a)pyrene (BP) derivative to DNA produces local distortions in conformation of the helix, this modification does not appear to interfere with the ability of the DNA to associate with histones to form nucleosome structures. In addition, although DNA in the open regions of chromatin is more susceptible to reaction with the BP derivative, there is appreciable reaction with the DNA associated with histones.


Heavy metal complexation in polluted molluscs. III. Periwinkles (Littorina littorea), cockles (Cardium edule) and scallops (Chlamys opercularis).

The accumulation of cadmium, zinc and copper by environmentally contaminated periwinkles, cockles and scallops has been studied by gel permeation chromatography of water-soluble extracts of the shellfish. Three distinct low mol. wt. (less than 3000) zinc complexes were separated from periwinkle extracts. Copper and cadmium were present as a single low mol. wt. species which is apparently responsible for the elevated copper levels in Littorina littorea.


The glutathione-linked metabolism of 2-allyl-2-isopropy-lacetamide in rats. Further evidence for the formation of a reactive metabolite.

2-Allyl-2-isopropylacetamide (AIA) causes a depletion of liver glutathione in rats only if the animals have been pretreated with phenobarbitone. Phenobarbitone stimulates the excretion in bile of a component derived from AIA and glutathione which is apparently not the same as the conjugate formed by reaction of the two components in simple solutions. The significance of these findings are considered in relation to the suggestion that AIA is metabolised to an epoxide by the microsomal enzyme system; in addition several differences between AIA and the non-porphyrogenic compound, acrylamide, are discussed.


Inhibition of the alkylation of nucleic acids and of the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile.

Pretreatment of rats with aminoacetonitrile inhibited the metabolism of [14C]1,2-dimethylhydrazine to 14CO2 and increased the expiration of [14C]-azomethane. Alkylation of nucleic acids following administration of 1,2-dimethylhydrazine was reduced by aminoacetonitrile to 5% of control levels in liver, 11% of control levels in kidney and 43% of control levels in colon.


Isolation and purification of Lea blood-group active and related glycolipids from human plasma of blood-group A Lea individuals.

From 81 of human plasma of blood-group A Lea nonsecretors three different Lea blood-group active ceramide pentasaccharides (a total of 4.65 mg) have been isolated, all revealing glucose, galactose, N-acetylglucosamine and fucose in molar ratios of 1 : 2 : 1 : 1 as determined by gas liquid chromatography. A fourth blood-group active fraction (0.72 mg) represents a mixture of a Lea active ceramide pentasaccharide and an A active ceramide hexasaccharide (molar ration 7.7 : 2.3 as calculated from the content of different aminosugars). Additionally, two different globosides, two different hematosides and a new N-acetylglucosamine containing ceramide tetrasaccharide were obtained. All 9 glycolipid fractions demonstrated homogeneity in analytical high performance thin layer chromatography (HPTLC) using 4 different solvent systems. 0.2 microgram of each Lea active glycolipid completely inhibited the agglutination of O Le(a+b-) erythrocytes by 50 microliter of 4 hemagglutinating units of caprine anti Lea serum. At least 0.04 microgram of each Lea antigen are sufficient for incubation to convert 9 x 10(7) O Le(a-b-) erythrocytes into Lea-positive cells. Mainly due to the relatively low content of the blood-group A glycolipid in plasma (0.17 mg/81), previously negative erythrocytes readily become agglutinable by anti Lea sera and not by anti A sera after incubation with appropriate plasma.


[Pyogenic infections of the sacro iliac joint in children (author's transl)].

The authors report 13 pyogenic infections of the sacro-iliac joint in children. They emphasize the difficulties of the diagnosis. The disease is sometimes recognised only at a late stage because the sign must be misleading. The radiological appearance of the sacro-iliac joint is usually sufficient to diagnose the condition. The germ was most often a staphylococcus aureus. Healing is always obtained by rest or immobilisation on a plaster and antibiotics active against staphylococcus. Surgery is only indicated in presence of an abcess or in cases of diagnostic uncertainty.


[Personal experience of Cotrel's method in the surgical treatment of scoliosis and kyphosis (author's transl)].

This current report of our experience of Cotrel's method falls within the context of continuing the developments in our treatment of scoliosis. Our follow-up for Harrington's operation is 13 years, 281 patients having undergone surgery. On other words, having known the beginnings of this surgery, we are in a position to measure the progress represented by Berckoise's technique (7, 6, 8).


[Future of the remaining rectum after treatment of familial polyposis (author's transl)].

In the treatment of familial polyposis the conservation of the rectum is essential to assure a convenient control and rhythm of defecation. Meanwhile the future of resting polyps deserves the attention of the surgeon. Certain authors are optimistic and claim that spontaneous regression of the polyps is possible. Our experience illustrates that the rectal mucosa tends to fabricate new crops of polyps. The prolonged post operative observation of more than 4 years of polyposis in one family has permitted us to follow the evolution of the rectal mucosa and to deduce that gravity of the lesion is quite variable. The polypotique character of the rectal mucosa must influence the choice of certain surgical technic  specially that nine of them achieve entire satisfaction yet.


[Rectal agenesis with absent bladder in a female newborn (author's transl)].

This paper reports a very unusual variety of female ano-rectal agenesis without fistula associated with severe urogenital malformations. The patient died of renal failure and, at autopsy, both ureters draining dysplastic ectopic kidneys and two vaginas, either with its corresponding uterus and annexa were found opening to s single perineal orifice through a very narrow conduit. Bladder and urachus were absent and a single left umbilical artery was found. This infant had also thoracic vertebral anomalies.


[The resection of lumbosacral hemivertebrae (author's transl)].

The spinal deformities due to lumbo sacral hemivertebrae are difficult to correct: The orthopedic treatment is not effective. Surgical correction of the lumbar compensatory curve is of no use as it does not correct the oblique take off. The resection of the hemivertebra is actually the more efficient way. The surgical technique used in 2 cases is described. The results depend mainly upon the age of operation, which should be performed in the first years of life, in order to correct the oblique take off before the lumbar compensatory curve become a structural one.


[Correction of subcoronal and high penile hypospadias].

The authors present a surgical procedure for the treatment of subcoronal and high penile hypospadias. According to this technique, the urethra is elongated to the extremity of the glans penis, so the anatomic and functional reestablishment of the malformation is absolutely normal. They applied this technique to twenty two cases. The results were very satisfactory.


[Segmental replacement of thoracic aorta with autologous pericardium during growth (author's transl)].

Surgical treatment of coarctation of the aorta in the newborn often recurs during childhood. As a means of avoiding this complication segmental replacement of the thoracic aorta with autologous pericardium was evaluated. The isthmic aorta of seven mongrel puppies was replaced by a tubular live pericardial autograft. Between 5 and 36 months (average 15) after surgery, the status of the graft was evaluated by hemodynamic, angiographic, macroscopical and histological studies. Growth of the graft was appreciated by comparing its diameter to that of the descending aorta DG/DA. No pressure gradient across the graft was noted. No significant structure of the graft was observed. The internal surface of the graft was smooth, and the wall, slightly thinner than that of the aorta showed no aneurysm. The diameter of the graft was increased (DG mean 37 %) proportionally to the increase of the aorta (DA mean 36 %). Histologically the graft was endothelialized, the wall was thickened and made up of concentric collagen fibers, live fibroblasts and muscular cells. These results show that during the first months of life, the isthmus of the aorta can be replaced by an autologous pericardial graft which will follow the growth of the normal aorta and adapt to its hemodynamic regimen.


[Stress ulcer by hypovolemic shock in pregnant and normal rabbits and in the fetuses (author's transl)].

The purpose of this experimental  work was to study the possibility of stress ulcer in fetal Surgery. Firstly an experimental model of production of stress ulcer by hypovolemic shock was worked out: by removing a volume of blood equivalent to 2% of body weight out of the femoral artery, a stress ulcer was was regularly induced in 25 female rabbits in the fundic area within 3 hours. In 10 pregnant rabbits and in the fetuses a stress ulcer could not be produced by the same method. This observation suggests the hypothesis that the reactions of the gastric wall are modified by the specific hormonal situation of the pregnant rabbit. This assumption ought to be elucidated by further investigations.


[Mediastinoscopy in children].

This technique enables the exploration of the mediastinum by the cervical way, but remains an unfrequent examination in children. Among almost 1000 mediastinoscopies made by the authors, the indication concerned only 20 children aged less than 17. Made in a prognostical purpose in most of the cases (16 patients) it gave the diagnosis 14 times. In four cases the mediastinoscopy was carried out as a prognosis during a pre-therapeutics of some hematosarcomas. This method requires a general anaesthesia with intubation, but doesn't differ much from the technic for adults. Besides the supra-sternal way leading to the axial mediastinum (Carlens's technic) other ways are used, particularly the anterior mediastinoscopy--exploring the thymic lodge--and the antero-lateral way through an intercostal space. The mediastinoscope enable the visual control of the lesions, completed with biopsies of the tissues for an histological examination and puncture with a needle for the cytology study. The diagnosis was made in 90% of the cases, sometimes after repeat mediastinoscopy. The failures are due most often to an incertitude in the interpretation of the samples than a badly directed biopsy. There was no surgical incident in our serie. The general morbidity of the examination is 1,5% and the mortality is 0,1% according to the authors. But two anesthetic incidents were observed in children with malignant lymphomas and required the use of reanimation technics. The mediastinoscopy is useful in the tumors of the thymus (10 times), the tumors of the lateral mediastinum (8 times) an hematosarcomas or Hodgkin's disease.


[Vascular traumatic injuries of the limbs in children (author's transl)].

The authors review 66 case reports of trauma involving major vessels of the limbs in children and confirm the seriousness of these lesions. It becomes apparent that iatrogenic lesions are quite frequent especially after arterial punctures and arteriographies in general. They stress the  importance of clinical diagnosis in vascular blocks. Arteriography should be exceptionally used for infants. Management should aim at restoring vascular continuity by deobstruction, suture or vein grafting. The ideal solution is often easily obtained when repair is undertaken quickly. Normal blood flow was satisfactorily obtained in only 36 patients whereas poor results in the remaining cases was explained because of delayed action. Sequellae are severe and more frequently encountered when blood flow is not restored. On the other hand, the repercussions on growth and development of the limb after chronic ischemia is still not a proven fact. Finally, the authors underline the severe consequences of thromboses after arteriographies by femoral puncture in infants.


[Gastroschisis. Analysis of 19 cases (author's transl)].

Since 10 years, 19 cases of gastroschisis have been observed in the surgical paediatric unit of Rouen. 12 children are alive and 7 died. It is possible to classify the lesions of the alimentary tract in four groups of increasing gravity. For the first two groups, survival is probable when the treatment is correct. The third group, including bowel resections and risk of short bowel is more difficult to treat. The last group, with necrosis of the main part of the bowel is uncurable. Surgical treatment of choice is immediate closure with small enlargement of the initial parietat defect. It was possible without complication in 8 cases (9 trials). Delayed closure is now employed when immediate closure is impossible. Post-operative treatment is marked by risks of infectious problems and chronic subocclusion. In this last occurence, reintervention must not be too much delayed. Parenteral feeding, with occasionnal continuous enteral feeding must be sufficient.


[Osteoid osteoma in childhood (author's transl)].

15 cases of osteoïd osteoma are studied and the various investigations are considered. The authors underline the specific characters of this bony tumour of which early diagnosis is difficult for the X-ray signs often delay. They emphasize a complet pathologic investigation of all the specimens. The prognosis is evaluated and possibility of relapse. So the rules of the surgical treatment of the osteoïd osteoma are stated.


[Osteoarticular tuberculosis in children (author's transl)].

A group of sixteen children suffering from osteoarticular tuberculosis were seen over the past five years in the Belgrade Paediatric Surgery Clinic. This disease is now extremely rare and effects chiefly children born outside maternity departments and not receiving BCG vaccination at birth for different reasons. The osteoarticular tuberculosis rate in the Socialist Republic of Serbia over this period was thus one in 500,000 children. The disease is three times as common in male children, most often affecting the hip and presenting above all at about the age of nine. At the time of admission, eight children had tuberculosis lesions affecting the lungs, visible and active or latent, partially or completely. In five children, one of the parents was receiving treatment for active pulmonary tuberculosis at the time of onset of the disease. Conservative treatment (immobilisation, tuberculous bacteriostatic therapy and general measures) was used in fifteen children and only one underwent surgery, in addition to the standard treatment described. In only one child, there was ankylosis of the hip and the end of treatment, the others having less sequelae of returning completely to normal. In one girl, osteoarticular tuberculosis was complicated by exsudative tuberculosis pericarditis.


[The lungs in congenital diaphragmatic hernias (author's transl)].

In congenital diaphragmatic hernias, the presence of abdominal viscera in the thoracic cavity will arrest the development of the ipsilateral lung, and occasionally of the controlateral lung also. The lung may thus be either compressed or hypoplastic in varying degrees. Its state of development conditions the prognosis of this disease. In severe forms, known as "High Risk" forms, presenting in the 3 first days of life with respiratory distress, the lung is very often hypoplastic, the number of bronchial, bronichiolar and vascular generations is diminished. The airways pulmonary function in medium and long term has been studied in 10 children over a period of 3 to 15 years. The clinical radiological, scannery and fonctional lung study results present not unfrequently signs of overdistention, of obstructive disease, and pulmonary bronchectasis on the side of the hernia. The evolution could be explained by the normal post natal multiplication of airways as well as by an increase of their size in such a manner as to occupy the whole thoracic cavity.


[Towards reasoned early surgical treatment for hiatal hernia in the infant (author's transl)].

The authors report 2 cases of HH and MCT in newborn of 1 1/2 and 5 months old who quickly develop a peptic stenosis despite a good medical treatment. Reviewing 51 cases of early surgical treatment (29 cases operated on before 2 months of age), they estimate legitimal an early surgical treatment for HH and MCT in newborn. They insist on the necessity to begin with a rigourous medical treatment, which cannot exceed one month if an oesophagitis persist (documented by a good and acurate endoscopic examination). This examination is the guide line for the surgical indication and is more acurate than the clinical and radiological informations. They point out the absence of mortality and the improvement of the results if the patients are operated on before 2 months old. In the literature ones can observe that the incidence of recurrence and peptic stenosis is decreased when the patients are operated on early.


[Orthopedic problems in fibrous dysplasia in infant's bones. A report on 23 cases (author's transl)].

The authors report on 23 cases of fibrons in infants who had been treated surgically, and review the therapeutic problem which arise from this particular type of bone fragility. When located in the diaphysis they had been treated by screw fixation, isolated grafts being constantly unsuccessful. Various procedures had been used in 9 cases with localization in the proximal end of the femur, and they are reviewed critically.


[Segmentary growth of the lower limb after surgical lengthening in the children (author's transl)].

The authors review their results after continuous and increasing distraction of either the tibia or femur and attempt to formulate grow the patterns of the lower extremity. To do this, they plotted 23 growth curves of 27 segmentary lengthenings. All measurements were taken on telemetric x-rays and developmental status determined according to the Greulich and Pyle Atlas. Length gain of the elongated segment and limb were analysed in each case. Findings clearly show that growth of the lower extremity depends on the amount of lengthening obtained by distraction. It appears that growth may be normal or accelerated after moderate lengthening (less than 5 cm), reduced or momentarily halted after significant gain. Growth appears to be more favorable when weight bearing is begun early. On the contrary, neither distraction rate, age nor aetology of length discrepancy seem to modify the final outcome. The other segments are equally influenced by distraction. The authors were surprised to find that growth rate here is either exaggerated or reduced in such a way as to result in an over-all lengthening or shortening with regards to the opposite side. They feel that such unexpected variations should promote caution before predicting final status.


[Fibrosis of the rectus femoris muscle (author's transl)].

The author presents seven cases of isolated fibrosis of the rectus femoris muscle. The retraction of the rectus femoris muscle is characterized clinically by limping and the blocking of the knee flexion in the movement of the hip articulation in fixed in extension. The hip flexion immediately permits the knee flexion. The tenomiotomy of the proximal insertions of the muscle led in all cases to the disparition of the limping and to complete freedom of movement of the knee flexion.


[Congenital tracheobiliary fistula. Report of a case with choledocal hypoplasia (author's transl)].

The authors describe a new observation of a congenital aerobiliar fistula in a newborn infant showing choleptysies associated with a pulmonary obstruction. The most remarkable facts are the presence of a radiological pneumogallbladder, and the existence of a real trifurcation of the trachea on the bronchography, associated with a choledocal hypoplasia. The death having occured before the operation, the autopsy  allowed the confirmation of the termination on the left hepatical duct and the duality of conformation of the fistula, respiratory and biliary. On the occurence of this 9th case, a review of the literature shows the stereotyped nature of the clinical signs and the course of the fistula which seems invariable. The different aspects of the malformation are considered as well as the treatment which necessitates an exeresis by thoracic pathway.


[Aortic reposition of the anormal subclavian artery (case report of 3 infants) (author's transl)].

The most common anomaly of the aortic arches is retro-oesophageal position of the right subclavian artery. Most often this malposition does not exhibit any clinical manifestation. In some rare cases, eso-tracheal compression is therefore observed. In these cases, a reposition of the subclavian artery in the ascending aorta was performed according to the technique presented. This surgical procedure, suppresses all symptoms without decreasing the vascularisation of the upper extremity as well as of the vertebral and basilarian territories. Long-term follow-up studies were carried out using ultra-sonic flow-metry.


[The anomalies of limbs obtained by injections of cyclophosphamid to the pregnant rabbit (author's transl)].

By injections of cyclophosphamid to pregnant rabbits, we obtained different sorts of agenesis. These anomalies are the consequence of a lack of the quantity of mesenchyme necessary to the formation of the limbs. The final malformation depends on the date, the dose and the period of action of the cyclophosphamid.


Pericardial tamponade-induced myocardial ischemic injury.

Cats of either sex anesthetized with sodium pentobarbital (30 mg/kg, IV) were subjected to sham pericardial tamponade or pericardial tamponade for five hours. Five cats underwent sham pericardial tamponade and six cats were subjected to pericardial tamponade which reduced the mean arterial blood pressure to approximately 40 mm Hg. Pericardial tamponade produced a 44-51% and a 28-38% decrease in the myocardial activities of cathepsin D and creatine phosphokinase (CPK), respectively. Observation of cellular and subcellular structure of left ventricular tissue of two sham operated cats and two cats after tamponade revealed myocardial injury in cats subjected to tamponade. Tissue stained with hematoxylin-basic fuchsin-picric acid stain showed extensive crimson-red basic fuchsin staining in cats subjected to pericardial tamponade and the absence of staining in cardiac tissue of sham-operated cats. Electron micrographs of cardiac tissue of cats subjected to acute pericardial tamponade revealed extensive vacuolization and extreme contracture. These results indicate ischemic injury with loss of cellular and subcellular enzymes in hearts of cats after five hours of pericardial tamponade sufficient to reduce the mean arterial blood pressure to about 40 mm Hg.


Preserved liver function and leukocyte response in superlethal endotoxic shock.

Recent studies reveal that endotoxin-pretreated awake dogs become markedly leukocytotic and survive superlethal endotoxin challenge without hypoglycemia. The purpose of this study was to determine if an association exists between leukocytosis, liver function, and survival in endotoxin shock. Studies were conducted on awake, conditioned adult dogs, with the experimental group (N= 5) injected intravenously with 1/1,000 LD100 E. coli endotoxin on Days 1 and 2, LD100 on Day 3, and 2 x LD100 on Day 4. A control group (N = 6) received equal volumes of saline on Days 1, 2, and 3, but on Day 4 received 2 x LD100 endotoxin. All saline-pretreated dogs died within seven hours following superlethal endotoxin challenge. Each animal in the experimental group was sacrificed at the time of its paired saline control's death for a comparison of liver pathology, since in parallel studies all endotoxin-pretreated dogs (N = 11) survived for 30 days. Animals in the experimental group exhibited a marked leukocytosis of 39,000/cu mm (mature neutrophils, 28,000/cu mm, immature neutrophils, 8,300/cu mm (P is less than 0.001) on Day 4 compared with saline-pretreated controls. At the time of death the liver enzymes, arginase, and SGPT were significantly elevated in the saline-pretreated controls compared with endotoxin-pretreated dogs (P is less than 0.02). Liver pathology in endotoxin-pretreated dogs consisted of mild necrosis, while saline-pretreated animals demonstrated massive hepatocellular necrosis. Results support the view that increased numbers of neutrophils protect liver function and enhance survival in endotoxin shock.


Adrenal insufficiency secondary to massive corticomedullary junction hemorrhage following hypotension in three anticoagulated patients.

Three patients treated by anticoagulation therapy were found at autopsy to have sustained massive bilateral adrenal hemorrhages. In each instance, an episode of hypotension preceded the onset of the terminal course. In two patients death was regarded in retrospect to have probably been attributable to acute Addisonian crisis. Hypotension commonly produces necrosis of the adrenal corticomedullary junction, which normally heals by fibrosis, but in the anticoagulated patient, this necrosis may be complicated by hemorrhage.


Effects of indomethacin on cardiovascular hemodynamics of goats in hemorrhagic shock.

We examined effects of indomethacin, meclofenamate, and prostaglandin E1 on systemic arterial pressure, heart rate, cardiac output, and systemic vascular resistance of anesthetized juvenile goats in severe hemorrhagic shock. Hemorrhagic shock was characterized by low systemic arterial pressure, decreased vascular resistance, and reduction in cardiac output. In acute experiments, indomethacin (3.4 mg/kg) attenuated the systemic hypotension of hemorrhagic shock. The increase in systemic arterial pressure following treatment with indomethacin was the result of increased systemic vascular resistance. Systemic arterial pressure, heart rate, and cardiac output fell during intravenous prostaglandin E1 infusions (3 micrograms/kg/min for 5 min) in both controls and goats in shock. The effects of prostaglandin E1 were more pronounced and prolonged in goats that had undergone the hemorrhagic-shock-producing procedure followed by indomethacin than in control animals treated with indomethacin but not hemorrhaged. Not only was meclofenamate less effective than indomethacin in increasing the systemic arterial pressures of goats in this type of hemorrhagic shock, but also it attenuated the pressor effects of indomethacin. Substances synthesized via prostaglandin fatty acid cyclo-oxygenase may be involved in the systemic hypotension that is characteristic of hemorrhagic shock.


The effects of heparin pretreatment on plasma histamine following thermal injury in rats and cats.

An elevated plasma histamine level in response to thermal injury is demonstrated in the rat and cat. In cats, the initial elevation of plasma histamine occurred within the first 15 minutes following thermal injury, and this was followed by a second rise between 60 and 120 minutes. Heparin pretreatment markedly reduced the plasma histamine elevating effect of thermal injury in both rats and cats. This suggests that the therapeutic basis for the use of heparin in the treatment of burn shock might conceivable be attributed to its ability to interfere with the elevated histamine levels normally associated with thermal injury.


Sinus node response to premature atrial stimulation in the rabbit studied with multiple microelectrode impalements.

In this study we investigated the response of the isolated rabbit sinus node to ectopic atrial premature beats elicited late in the atrial cycle. In three experiments the response of at least 45 different fibers of the sinus node was recorded, whereas, in other experiments, investigation was less extensive. In this way the spread of activation of the total pacemaker area could be mapped accurately both during spontaneous beating and the induction of ectopic atrial beats of different degrees of prematurity. We found that: (1) The conduction of an impulse from the dominant pacemaker area to the atrium during spontaneous rhythm (antegrade conduction) is slower than the conduction of an ectopic atrial impulse towards the center of the sinus node (retrograde conduction). (2) The action potential of the dominant pacemaker fibers in the sinus node is shortened because of premature activation caused by an ectopic impulse from the atrium. Late premature beats had no effect on diastolic depolarization. If the retrograde activation wave did not reach the area of the dominant pacemaker before the spontaneous discharge of these fibers, there was electrotonic influence demonstrable over a distance of about 0.5 mm. (3) Comparison of the true sinoatrial conduction time with the estimated sinoatrial conduction calculated indirectly from the length of the postextrasystolic atrial cycle revealed that, in the isolated rabbit heart, the calculated value is a serious underestimation of the true antegrade sinoatrial conduction time.


Relationship of aortic wall and baroreceptor properties during development in normotensive and spontaneously hypertensive rats.

We studied the relationship between aortic baroreceptor function and aortic wall properties in normotensive (NTR) and spontaneously hypertensive (SHR) rats 10-20 weeks old. Baroreceptor discharge, static pressure-volume (P-V), and pressure-radius relationships were measured in excised aortic segments. Histological studies of wall thickness and receptor numbers also were made. Circumferential wall stress and strain were calculated, as was the incremental elastic modulus (EINC). EINC in NTR's at 100 mm Hg was similar to values reported for in vivo human, dog, and rat aortas. At 10 weeks, SHR's had significantly elevated blood pressure, but SHR and NTR aortas had similar relationships among pressures, volumes, strains, and EINC's. Differences arose subsequently and, at 20 weeks, NTR aortas had larger volumes, larger strains, and smaller EINC's at equivalent pressures, whereas SHR aortas were unchanged. Thus the reduced distensibility of SHR relative to NTR aortas, rather than being due to retrogressive changes from normal, appeared to result from a failure to pass through a phase of increased distensibility. At 10 weeks, SHR baroreceptors showed resetting in both pressure-response and strain-response curves, and it was concluded that early hypertensive baroreceptor resetting was due to primary changes in the receptors. At 20 weeks, the order of the strain-response curves for NTR and SHR baroreceptors was reversed due to a reduction in strain sensitivity of NTR baroreceptors. Resetting of NTR baroreceptors during development may have important implications as a mechanism of blood pressure control in development.


The distribution of blood rheological parameters in the microvasculature of cat mesentery.

In vivo studies of the rheological behavior of blood in the microcirculation were conducted by direct in situ measurements in cat mesentery. Upstream to downstream pressure drops were measured in unbranched arterioles, capillaries, and venules, with diameters from 7 to 58 micrometer. Simultaneous measurements of red cell velocity and vessel geometry facilitated computation of bulk velocity, pressure gradient, apparent viscosity, wall shear stress, and resistance. Arteriovenous distributions of these parameters revealed the following. Maximum pressure gradient (0.015 cm H20/micrometer) occurs in the true capillaries (7 micrometer in diameter); intravascular wall shear stress averaged 47.1 dynes/cm2 in arterioles and 29.0 dynes/cm2 in venules. Extreme values as great as 200 dynes/cm2 were observed in a few shunting arterioles. Apparent viscosity averaged 3.59 cP in arterioles, 5.15 cP in venules, and 4.22 cP overall. Intravascular resistance per unit length of microvessel varied with luminal diameter as a power law function with exponents of -4.04 for arterioles, -3.94 for venules, and -3.99 for all vessels combined. This apparent maintenance of Poiseuille's law is attributed to the opposing processes of hematocrit reduction and decreasing shear rate as blood is dispersed in successive arteriolar segments, and the converse action of these processes in the venous confluences which lessen the extent of network variations in apparent viscosity. Reductions in bulk velocity from the normal flow state to below 0.5 mm/sec resulted in increases in apparent viscosity by a factor of 2 to 10, which are attributed primarily to obstruction of the lumen by leukocyte-endothelium adhesion.


Effect of changing metabolic rate on local blood flow control in the canine hindlimb.

This study examined the effect of changing hindlimb metabolic rate on hindlimb blood flow control in anesthetized dogs. The hyperemias induced by graded levels of arterial hypoxia and the degree of steady state autoregulation evoked by changes in blood pressure were measured. Metabolic rate was increased above the resting value by direct electrical stimulation of hindlimb muscles at rates from 0.5 to 1.5 pulses/second, and in three dogs was reduced by cooling. In response to 6 minutes of arterial hypoxia, hindlimb blood flow steadily increased. At rest, and at each level of muscle stimulation, the steepness of the response increased as arterial oxygen saturation (SAO2) decreased. At all levels of SAO2, the response was steeper at increasing stimulation rates. For SAO2 greater than 50%, the relationship between the percentage increase in blood flow from control and SAO2, however, was unaffected by the degree of muscle activity, suggesting that during mild to moderate hypoxia the dynamics of the response were similar whether the muscles were at rest or exercising. The responses to severe hypoxia (SAO2 less than 50%) during stimulation were significantly enhanced compared with those at rest. Autoregulation of blood flow was measured in the steady state by comparing the relative change in blood flow from control with the relative change in blood pressure that produced it. Steady state autoregulation was weak at rest, but improved markedly with increasing muscle stimulation. Conversely, cooling the hindlimb depressed the resting steady state autoregulation. A close correlation was found between the degree of autoregulation and the hindlimb metabolic rate. The results suggest that tissue metabolic rate determines the precision of local blood flow control.


Effects of acetylcholine on the ventricular specialized conducting system of neonatal and adult dogs.

We determined the effects of acetylcholine on automaticity of isolated cardiac Purkinje fibers from neonatal and adult dogs and on the idioventricular rhythm of adult dogs with complete atrioventricular block. Isolated Purkinje fibers were studied with standard microelectrode techniques during superfusion with Tyrode's solution at 37 degrees C. For both age groups, spontaneous rate was decreased by acetylcholine, an effect which was reduced by atropine. The magnitude of the effect is equal in both neonatal and adult dogs. The negative chronotropic effect of acetylcholine was not prevented by phentolamine, indicating that an alpha-adrenergic mechanism was not involved. The idioventricular rate of conscious dogs with formalin-induced heart block was decreased by administration of acetylcholine. The effect was augmented by propranolol and attenuated by atropine. Thus, for both the in vitro and in situ ventricular specialized conducting system, acetylcholine decreases automaticity presumably through combination with a muscarinic receptor.


The circulatory influences of vagal afferents at rest and during coronary occlusion in conscious dogs.

We studied the role of cardiopulmonary vagal afferents in the cardiovascular responses to coronary artery occlusion in conscious dogs with intact carotid sinuses and following functional denervation of the arterial baroreceptors. The contributions of vagal afferents were determined by cold blocking the vagi. In dogs with intact carotid sinuses, coronary artery occlusion produced small decreases in mean cardiac output and arterial pressure, whereas heart rate increased by 35 beats/min. In dogs with intact carotid sinuses, vagal cold block increased mean arterial pressure by 22 +/- 2 (mean +/- SE) mm Hg and heart rate by 90 +/- 6 beats/min. Mean cardiac output increased by 505 +/- 90 ml/min. With the exception of heart rate, responses to coronary occlusion during vagal cold block were similar to the occlusion response prior to vagal cold block. Furthermore, prior occlusion of the coronary artery did not significantly influence the responses to vagal cold block. After arterial baroreceptor denervation, coronary artery occlusion resulted in a substantially greater fall in systemic arterial pressure (-52 mm Hg as compared to -8 mm Hg, with intact carotid sinuses) and peripheral resistance decreased by -0.49 peripheral resistance units (PRU). Vagal cold block following denervation increased the arterial pressure by 49 +/- 10 mm Hg and peripheral resistance by 0.59 +/- 0.13 PRU. Both values were significantly greater than those observed during vagal cold block prior to denervation. In arterial baroreceptor-denervated dogs, vagal blockade significantly attenuated the response to coronary occlusion. Therefore, in conscious dogs, vagal afferents from cardiopulmonary receptors exert a significant inhibitory influence on the peripheral vascular tone. When the carotid sinuses are intact, this inhibitory influence appears to be marked during myocardial ischemia. In the absence of functional arterial baroreflexes, vagal afferent activity contributes to the depressor responses observed during ischemia.


Inotropic and toxic effects of a polar cardiac glycoside derivative in the dog.

It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each drug. Thirteen dogs anesthetized with sodium pentobarbital were given repeated intravenous doses of digoxin or ASI-222. Ventricular tachycardia was elicited at a mean dose of digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for ASI-222 (not significant). Terminal ventricular fibrillation occurred after 0.18 mg/kg of digoxin, a value significantly larger than the ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias. Digoxin produced a 21% increase in LV dP/dt at a plasma digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma digoxin concentration was 88 +/- 16 ng/ml and CSF digoxin concentration was 5.7 +/- 1.6 ng/ml. ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma drug concentrations compared to digoxin, ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.


Direct evidence that the greater contractility of resistance vessels in spontaneously hypertensive rats is associated with a narrowed lumen, a thickened media, and an increased number of smooth muscle cell layers.

The mechanical and morphological properties of segments of certain precisely defined resistance vessels (approximately 150 micrometer lumen diameter) in the mesenteric bed of spontaneously hypertensive (SHR) and normotensive (WKY) rats have been compared in vitro under carefully controlled conditions and also after fixation. At a given transmural pressure, the relaxed SHR vessels (compared with the WKY vessels) would have had a 16% smaller lumen diameter (P less than 0.01) and a 49% thicker media (P less than 0.005), so that the media volume per unit segment length was 31% greater (P less than 0.05). The smooth muscle cells were arranged circumferentially in about four layers in the SHR vessels and in about three layers in the WKY vessels. The SHR active wall tension in response to potassium was 53% greater (P less than 0.02) and to norepinephrine was 50% greater (P less than 0.01) than for WKY. However, the ED50 values for the norepinephrine dose-response curves were similar (approximately 5 micrometer). Activation with potassium plus norepinephrine gave greater responses in both vessel types, than with either agent alone, but the SHR responses were on average only 19% greater than the WKY (P less than 0.10). However, under these conditions, the SHR vessels would have been able to contract against 45% greater transmural pressures (P less than 0.001) because of their smaller lumen. On maximal activation, the mean force developed by each cell (approximately 3.85 micro N) was the same in both vessel types, even though on average (P = 0.10) the SHR cells had a 21% greater cross-sectional area. The results support the Folkow hypothesis that in genetic hypertension the increased peripheral resistance is associated with structural changes in the resistance vessels.


Isometric relaxation of rat myocardium at end-systolic fiber length.

In a "physiologically sequenced" contraction (PSC), which loads the isolated muscle preparation in a manner which approximates that of the intact heart, isometric relaxation precedes isotonic relaxation and occurs at minimum ("end-systolic") length. We studied the effects of inital muscle length, load, temperature, calcium, and isoproterenol on the isometric relaxation phase of physiologically sequenced contractions to define the determinants of the rate of isometric relaxation of rat left ventricular myocardium. At the baseline temperature (28 degrees C), relaxation was found to be nonexponential, and the maximum rate of decline of force (-dF/dtmax) was used to evaluate changes in relaxation. Three factors, shortening, end-systolic length, and total load, were examined as possible mechanical determinants of -dF/dtmax. We found that -dF/dtmax is linearly related to end-systolic muscle length for lengths below 94% of Lmax; -dF/dtmax is also strongly related to total load for lightly loaded contractions, but peaks at loads of approximately 80% of peak developed force and declines thereafter. Shortening is poorly correlated with -dF/dtmax. The slope of the linear portion of the relation between -dF/dtmax and end-systolic length appears to be independent of muscle-loading conditions and sensitive to factors known to alter relaxation.


The relation between arterial viscoelasticity and wave propagation in the canine femoral artery in vivo.

The influence of arterial dimensions and viscoelasticity on pulse wave propagation has been expressed in many theoretical models of blood flow in arteries, but few experimental tests of these theories in vivo have been reported. The measurements required for such tests include not only the arterial viscoelasticity, diameter, and wall thickness, but also the true propagation coefficients and impedances, for comparison with the values "predicted" by solution of the model equations. We made such measurements in 16 experiments on the femoral artery in nine anesthetized dogs. A two-point pressure and flow technique was used to measure wave propagation, and an ultrasonic micrometer was used to measure vessel diameter as a function of time and pressure. Measured attenuation constants ranged from 0.010 at 1.3 Hz to 0.075 at 12.7 Hz, and were more than twice as large as those predicted by two representative linear models. True phase velocity, which increased from 6.71 m/sec at 1.3 Hz to 10.54 m/sec at 12.7 Hz, agreed closely with the values computed by the Cox model but were lower than those given by the Jager model. The resistive, but not the reactive, component of longitudinal impedance was significantly greater than predicted by the models at all frequencies. The experiments do not identify the source of these discrepancies. The use of linear models to calculate pulsatile blood flow from pressure gradients in relatively small vessels, or to calculate attenuation and characteristic impedance from arterial viscoelasticity in vessels of any size, produces significant errors.


A solid angle analysis of the epicardial ischemic TQ-ST deflection in the pig. A theoretical and experimental study.

The solid angle theory has long been applied to the interpretation of the ECG; however, quantitative evaluation of its applicability has been minimal. We applied solid angle analysis to the interpretation of the TQ-ST deflection during acute ischemia. Five anesthetized pigs were studied 1--3 hours after coronary occlusion. Multiple unipolar tracings were recorded from precisely determined positions on the epicardium overlying the ischemic and normal zones. The geometry of the hearts and ischemic zones was preserved, the margins of ischemia being defined as the outer border of Thioflavin S nonfluorescence. Wax replicas of the hearts with ischemic zones removed were constructed. Solid angles subtended at electrode positions on the replicas were calculated. A linear relationship (r = 0.84 - 0.97, P less than 0.001) was shown to exist between the observed TQ-ST deflection and the calculated solid angle. A small but patterned deviation from exact fit of the TQ-ST deflection with the calculated solid angle led us to investigate the possibility that dipole moment strength (phi) is not confined to the ischemic margins. Computations using idealized heart models with ischemic zones cylindrical and transmural in shape allowed us to distribute phi arbitrarily within the ischemic zone, comparing this predicted pattern of TQ-ST deflection with that observed experimentally. The experimental data appear most consistent with the condition in which phi is distributed over a 1-cm border region during the first several hours of ischemia. We conclude that the solid angle theory provides a rational basis for interpretation of the ischemic TQ-ST deflection; however, phi may be distributed over a marginal zone.