Phase I study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762, PNU 152243) administered on a daily x3 schedule

Background:3-Deamino-3-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762,PNU 152243) is a highly lipophilic doxorubicin derivative which possessespotent in vitro and in vivo antitumor activity. Previous phase I studies hadbeen conducted using a single bolus every 28 days.Patients and methods: We conducted a phase I study of FCE 23762 on adaily ×3 every 28 days schedule. Thirty patients received 68 cycles oftherapy at 5 dose levels (200–600 µg/m²/d).Results: Prolonged neutropenia and thrombocytopenia were thedose-limiting toxicities. Other nonhematological toxicities included nauseaand vomiting, anorexia, fatigue and transient elevations of serum creatinineand hepatic transaminases. No cardiac toxicity was demonstrated. There wereno partial or complete antitumor responses.Conclusion: The recommended phase II dose using the schedule defined inthis study is 500 µg/m²/d × 3.     

Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring.

Food restriction during pregnancy in rats induces intrauterine growth retardation with consequences persisting into adulthood. In the present study we have investigated the hypothesis that malnutrition in pregnant rats may lead to altered cardiovascular function in adult female offspring. Perinatal growth retardation was induced by a 50% reduction of normal dietary intake in rats during the second half of pregnancy. Systolic and diastolic blood pressure values and heart rate were recorded in conscious female offspring (100 d old) using a femoral artery probe. No significant differences in heart rate, or in systolic and diastolic blood pressures were recorded between control offspring and offspring of nutritionally deprived rats. In order to ascertain whether cardiovascular variables in the offspring were influenced by lactation, subgroups of offspring from food-restricted dams were fostered with lactating dams fed on a normal diet. Blood pressure and heart rate were also found to be normal in these offspring. The rise in blood pressure associated with NO inhibition was similar in all groups. Isolated resistance artery function was assessed in vitro in offspring (100-120 d old) of a second group of semi-starved dams. Small mesenteric arteries from these animals showed reduced endothelium-dependent relaxation (to acetylcholine and bradykinin), but enhanced sensitivity to exogenous NO (sodium nitroprusside). We conclude that food restriction during the second half of pregnancy and/or lactation does not induce hypertension in adult offspring, but may effect subtle changes in vascular function.     

The effects of in vitro hemodilution with gelatin, hydroxyethyl starch, and lactated Ringer's solution on markers of coagulation: an analysis using SONOCLOT

Blood-saving strategies have recently been established to avoid allogeneic transfusion during surgery or after trauma. This includes an expanding use of crystalloids and colloids. These solutions interfere with coagulation systems, but quantitative measurements are still lacking. The SONOCLOT (Sienco Company, Morrison, CO) analysis (SCT), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation, system. To quantify hemodilutional effects on in vitro coagulation, we studied gelatin (G), hydroxyethyl starch 6% (HES; molecular weight 450,000), and lactated Ringer's solution (RL) in 33% and 66% dilutions measuring routines laboratory and SCT variables. Hemodilution with RL tended to increase in vitro coagulability. Among the tested colloids, G had the least impact on markers of coagulation. G33% did not differ significantly from the undiluted control group. HES had the largest impact on markers of coagulation compared with G and RL. In conclusion, SCT provides a fast and easy to perform bedside test to quantify in vitro hemodilution. IMPLICATIONS: The effects of progressive hemodilution on coagulation are difficult to measure. SONOCLOT analyses provide an easy to perform test with fast information on cellular and plasmatic coagulation properties. Among colloids, hydroxyethyl starch has the largest impact on markers of coagulation compared with gelatin or lactated Ringer's solution.     

Measuring client satisfaction with assertive community treatment

OBJECTIVE: A mailed survey was used to measure satisfaction of seriously mentally ill clients with services provided by an assertive community treatment team. METHODS: A detailed 35-item questionnaire was mailed in 1995 to all 174 clients of the Brockville (Ontario) Psychiatric Hospital's assertive community rehabilitation program. RESULTS: The rate of return was 51 percent. Compared with clients who did not return the survey, the respondent group had significantly fewer males and fewer clients with a diagnosis of schizophrenia; respondents had been associated with the program for less time. Factor analysis of the survey responses revealed three principal components accounting for 46 percent of the total variance in responses. The factors were interpersonal aspects of care, client involvement in treatment, and medication and treatment issues. Respondents were generally satisfied with service from the program, but they were dissatisfied with side effects of medication and the amount of medication they were taking. CONCLUSIONS: A mailed survey appears to be an efficient and nonintrusive way to collect satisfaction data anonymously from persons with serious mental illness who are clients of an assertive community treatment team. The results highlight areas of need that the team can address.     

Characterization of lymphoma-derived cell lines: comparison of cell lines positive and negative for Epstein-Barr virus nuclear antigen. I. Physical, cytogenetic, and growth characteristics

Sixteen lymphoid cell lines were derived from patients with undifferentiated lymphoma of Burkitt's or non-Burkitt's type. They were obtained directly from tumor biopsies, from serous effusions, or from bone marrow. In 10 of the cell lines, the Epstein-Barr virus (EBV) nuclear antigen (EBNA) was undetectable; the remaining 6 lines were EBNA-positive (EB-pos). Of the 16 lines, 15 were aneuploid, with detectable chromosome "14q+ markers (11 had +8;14 translocations). These 15 lines, which included the EBNA-negative (EB-neg) lines, were believed to be of tumor cell origin. The remaining line consisted predominantly of diploid cells derived from normal lymphocytes, but some cells of tumor origin were present. Four EB-pos cell lines derived from EB-neg tumors had an aneuploid karyotype consistent with an origin from tumor cells (including no.8;14 translocation in two), which suggested that either tumor cells were infected with EBV in vitro or a tiny fraction of EB-pos tumor cells (or potential tumor cells) present in vivo gave rise to the predominant cell of the line. EB-neg B-cell lines and EB-pos cell lines established from undifferentiated lymphomas differed greatly. EB-neg lines had consistently smaller electronic mean cell volumes and narrow-angle light scatter than did EB-pos lines. This finding correlated with a lower nuclear:cytoplasmic ratio in EB-pos lines. EB-neg lines also had higher saturation cell densities than did EB-pos lines under standard culture conditions. The data indicate either that EBV influences the morphologic and physiologic characteristics of lymphoid cell lines or that EB-neg B-cell lines and EB-pos cell lines are derived ultimately from different lymphocyte subpopulations or that both may apply.     

Enzyme pattern and marker antigens in nodular "regenerative" hyperplasia of the liver

Characteristic alterations of marker enzymes and tumor-associated antigens have been detected in the preneoplastic lesions of experimental hepatocarcinogenesis. An identical pattern of enzyme activity (increased gammaglutamyl transferase, loss of glucose-6-phosphatase, and canalicular adenosine triphosphatase) was demonstrated in a case of nodular "regenerative" hyperplasia of liver. The lack of marker antigens (alphafetoprotein, carcinoembryonic antigen, alpha 1-antitrypsin) in the hyperplastic nodules in this patient may be related to the discontinuation of oral contraceptive steroids four years earlier. The phenotypic changes of enzyme activity suggest that nodular "regenerative" hyperplasia of the liver in man is preneoplastic.     

Effect of age and pregnancy on the antibody and cell-mediated immune responses of horses to equine herpesvirus 1.

The cell-mediated immune response and antibody response of horses of varying ages and of pregnant horses to equine herpesvirus 1 antigen were examined. Six to eight month old horses showed either no increase or slight increases in anti-equine herpesvirus 1 serum neutralizing antibody following vaccination and revaccination with a modified live equine herpesvirus 1 vaccine. However, these same horses showed a marked increase in the cell-mediated immune response to equine herpesvirus 1 as measured by the lymphocyte transformation test. Eighteen to 21 month old horses showed four to 64-fold increases in anti-equine herpesvirus 1 serum neutralizing antibody titer following vaccination, but the cell-mediated immune response to equine herpesvirus 1 was low or absent. Only after revaccination did they show an increased cell-mediated immune response to equine herpesvirus 1. The cell-mediated immune response of mares in the latter stages of pregnancy to equine herpesivurs 1 was suppressed although antibody titers increased as much as 16-fold following exposure to virulent equine herpesvirus 1.