Cerebellar toxicity with high-dose cytosine arabinoside

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.     

Selachyl alcohol as an oral antihypertensive agent: a preliminary note

Selachyl alcohol (SA) is a mono-oleyl glyceryl ether. It has certain biologic activities similar to those of the antihypertensive neutral renomedullary lipid (ANRL) derived from the renal papilla and its renomedullary interstitial cells (RIC). These include a vaso-depressor effect following bolus injection and a requirement for hepatic activation for the development of biological activity. In view of this similarity to ANRL, it appeared worthwhile to test the antihypertensive action of SA when given via the GI tract. Accordingly, pure SA was given either by gavage or by tube into the stomach or duodenum of one-kidney, one-clip hypertensive rats (5-10 mg per dose). The role of hepatic activation was demonstrated by comparing the BP response to bolus injection of SA and ANRL with and without the presence of an intact circulation to the liver. Administration of SA via the GI tract resulted in a significant decline in BP without tachycardia or weight loss. In the absence of a circulation to the liver, neither SA nor ANRL was active. SA appears to be an effective antihypertensive agent when given via the GI tract.     

Social support, stress, and health: a comparison of expectant mothers and fathers

The influence of social support and stress on expectant mothers' and fathers' health was determined by testing and comparing different predictive models. Instruments used were the Support Behaviors Inventory, Stress Amount Checklist, and Health Responses Scale. Regression analyses were performed on data from questionnaires completed by 313 couples in the second half of pregnancy to predict health, using the same independent variables for women and men. The regression analyses began with a model that included the variables of stress, satisfaction with partner support, satisfaction with other persons' support, history of chronic illness, education, age, employment status, military status, and family income. The effects of four variables, satisfaction with partner support, satisfaction with others' support, stress, and chronic illness, were tested separately for men and women. Subsets of these variables were deleted to create a series of nested comparisons. Results indicated that social support and stress were useful in predicting health. Partner support appeared to be the most important variable in understanding expectant fathers' health, but social support for mothers included a larger domain and social networks contributed to their health in the same way as partner support. Both stress and chronic illness were more important explanatory variables for pregnant women's health than for their partners' health. These data suggest that nursing interventions targeted at reducing stress and improving expectant parents' satisfaction with their partner support might enhance their health.     

Microtubule dynamics in axons and dendrites.

We have investigated the stability, alpha-tubulin composition, and polarity orientation of microtubules (MTs) in the axons and dendrites of cultured sympathetic neurons. MT stability was evaluated in terms of sensitivity to nocodazole, a potent anti-MT drug. Nocodazole sensitivity was assayed by quantifying the loss of MT polymer as a function of time in 2 micrograms/ml of the drug. MTs in the axon and the dendrite exhibit striking similarities in their drug sensitivity. In both types of neurites, the kinetics of MT loss are biphasic, and are consistent with the existence of two types of MT polymer that depolymerize with half-times of MT polymer that depolymerize with half-times of approximately 3.5 min and approximately 130 min. We define the more rapidly depolymerizing polymer as drug-labile and the more slowly depolymerizing polymer as drug-stable. The proportion of MT polymer that is drug-stable is greater in axons (58%) than in dendrites (25%). On the basis of current understanding of the mechanism of action of nocodazole, we suggest that the drug-labile and drug-stable polymer observed in both axons and dendrites correspond to two distinct types of polymer that differ in their relative rates of turnover in vivo. In a previous study, we established that in the axon, these drug-stable and drug-labile types of MT polymer exist in the form of distinct domains on individual MTs, with the labile domain situated at the plus end of the stable domain (Baas and Black, J Cell Biol 111:495-509, 1990). Because of the great difference in drug sensitivity between the drug-labile and drug-stable MT polymer, we were able to dissect them apart by appropriate treatments with nocodazole. This permitted us to evaluate the drug-labile and drug-stable polymer in terms of polarity orientation and relative content of alpha-tubulin variants generated by posttranslational detyrosination or acetylation. In both the axon and the dendrite, the modified as well as unmodified alpha-tubulins are present in both drug-labile and drug-stable polymer, but at different levels. Specifically, the modified forms of alpha-tubulin are enriched in the drug-stable MT polymer compared to the drug-labile MT polymer. In studies on MT polarity orientation, we demonstrate that in axons, MTs are uniformly plus-end-distal, whereas in dendrites, MTs are non uniform in their polarity orientation, with roughly equal levels of the MTs having each orientation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Swallowing food without chewing; a simple way to reduce postprandial glycaemia

1. The degree to which disruption by mastication affects the glycaemic response to four different carbohydrate foods was investigated in healthy human volunteers; each food was eaten by six subjects. 2. Subjects ate meals of sweetcorn, white rice, diced apple or potato on two occasions; on one occasion they chewed the food thoroughly, on the other occasion they swallowed each mouthful without chewing it. 3. When the foods were chewed the postprandial blood glucose levels rose to levels which varied according to the food ingested. 4. Swallowing without chewing reduced the glycaemic response to each food, achieving a similar effect as administration of viscous polysaccharides or 'slow-release' carbohydrates.     

Anti-idiotypes in B-cell tumor therapy

Thirteen patients with B-cell lymphomas were treated with mouse monoclonal anti-idiotype antibodies. All but 1 of the patients in this study had received extensive prior treatment with conventional therapy for lymphoma. The treatment protocol initially included an escalating dose schedule which was intended to help us evaluate toxicity and pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last 4 patients received substantial initial doses. Tumor sampling was performed before and during therapy for evaluation of tissue penetration by antibody. Patients received antibodies of gamma 1, 2a, or 2b isotype. None of the patients had serum paraproteins by routine clinical testing, but 6 had an idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/ml, two of which were greater than 200 micrograms/ml. These levels were temporarily reduced by plasma-pheresis. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig that occurred in 5 of the 13 patients. Once an immune response had begun, further infusions of antibody failed to reach the tumor or induce tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 50 months after receiving antibody. Six of 12 additional patients have had objective remissions which also were clinically significant. However, these remissions were not complete. This therapy shows promise as an alternative modality for the treatment of B-cell lymphoma. We will need further studies to determine the mechanisms of the antitumor effect and to improve the clinical results.