Insertion of the DNA for the 163-171 peptide of IL1beta enables a DNA vaccine encoding p185(neu) to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice.

An assessment was made of the effectiveness of DNA vaccination in prevention of the mammary adenocarcinomas of BALB/c female mice transgenic for the activated rat Her-2/neu oncogene. Atypical hyperplasia is evident in their mammary glands when they are 6 weeks old and in situ carcinoma by the 13th week. Palpable invasive carcinomas appear around the 17th week and are always evident in all 10 glands by the 33rd week. Intramuscular vaccinations with 100 microg plasmid DNA encoding the extracellular domain of the Her-2/neu p185 (ECD) performed at the 6th, 12th, 18th and 24th week provided no significant protection, whereas those ECD plasmids in which the DNA coding for the immunomodulatory 163-171 (VQGEESNDK) nonapeptide of human IL1beta (ECD-IL1betap) had been inserted both delayed carcinogenesis and reduced tumor multiplicity. This reduction was associated with a marked immune-inflammatory reaction and a conspicuous leukocyte infiltrate located in the stroma surrounding the hyperplastic mammary ductul-alveolar structures. It was also directly correlated with a high anti-p185(neu) antibody production and an immunoglobulin switch to IgG2a and IgA. No anti-p185(neu) cytotoxic response was found. No significant protection was obtained when the DNA coding for the non-active peptide 189-197 of IL1beta was inserted.

DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice.

The ability of vaccination with plasmids coding for the extracellular and the transmembrane domain of the product of transforming rat Her-2/neu oncogene (r-p185) to protect against r-p185(+) transplantable carcinoma (TUBO) cells and mammary carcinogenesis was evaluated. In normal BALB/c mice, DNA vaccination elicits anti-r-p185 Ab, but only a marginal CTL reactivity, and protects against a TUBO cell challenge. Massive reactive infiltration is associated with TUBO cell rejection. In BALB/c mice transgenic for the rat Her-2/neu gene (BALB-neuT), DNA vaccination elicits a lower anti-r-p185 Ab response, no CTL activity and only incompletely protects against TUBO cells, but markedly hampers the progression of carcinogenesis. At 33 wk of age, when control BALB-neuT mice display palpable tumors in all mammary glands, about 60% of immunized mice are tumor free, and tumor multiplicity is markedly reduced. Tumor-free mammary glands still display the atypical hyperplasia of the early stages of carcinogenesis, and a marked down-modulation of r-p185, along with a massive reactive infiltrate. However, BALB-neuT mice protected against mammary carcinogenesis fail to efficiently reject a TUBO cell challenge. This suggests that the mechanisms required for the rejection of transplantable tumors may not coincide with those that inhibit the slow progression of carcinogenesis.

Evidence for the involvement of chromaffin cells in the stimulatory effect of tachykinins on corticosteroid secretion by the frog adrenal gland.

The adrenal gland of the frog is innervated by a network of fibers containing two tachykinins (ranakinin and [Leu3,Ile7]neurokinin A), which both stimulate corticosteroid secretion from frog adrenal tissue. The aim of the present study was to determine the mode of action of tachykinins on the frog adrenal gland. Double immunolabeling of tissue sections with a monoclonal antibody to tyrosine hydroxylase and an antiserum to substance P showed that tachykinin-containing fibers are preferentially apposed onto chromaffin cells. Immunocytochemical labeling at the electron microscope level revealed that tachykinin-immunoreactive fibers establish close contacts only with adrenochromaffin cells. Ranakinin stimulated corticosterone and aldosterone secretion from perifused adrenal slices, but had no stimulative effect on dispersed adrenal cells. Cytoautoradiographic labeling of frog adrenal cells in primary culture with [3H]substance P revealed the existence of specific binding sites located exclusively on chromaffin cells. Microfluorimetric measurement of cytosolic calcium concentrations ([Ca2+]i) in cultured adrenal cells showed that ranakinin induced a dose-dependent increase in [Ca2+]i in chromaffin cells (ED50 = 2 x 10(-7) M). In contrast, ranakinin did not affect [Ca2+]i in adrenocortical cells. The present results indicate that in the frog adrenal gland, tachykinin-containing fibers make preferential contacts with chromaffin cells, and tachykinins directly activate chromaffin cells. These data suggest that the stimulative effect of tachykinins on corticosteroid secretion is mediated via presynaptic activation of adrenochromaffin cells.

Predicting mortality and length of stay of geriatric patients in an acute care general hospital.

Three-hundred-eight geriatric patients (mean age = 76.7 yr, range = 70-94 yr) consecutively admitted to an acute care general hospital were followed up to identify the predictors of in-hospital mortality and long stay. Sociodemographic, medical, and functional data were collected within 24 hours from admission and their correlation with the outcomes assessed by logistic regression analysis. The following variables were shown to be independent predictors of death: use of more than 6 drugs (odds ratio = 3.04, confidence limits = 1.05-8.76); abnormal Mini-Mental State score (o.r. = 1.72, c.l. = 1.05-1.83); low ADL score (o.r. = 2.4, c.l. = 1.07-5.56). Extended stay was significantly and independently predicted by polypharmacy (o.r. = 1.94, c.l. = 1.18-3.2) and comorbidity (o.r. = 2.06, c.l. = 1.24-3.38). The mortality rates of patients with cognitive impairment and polypharmacy with or without functional impairment were 40% and 22%, respectively. The proposed method allows identification of high-risk geriatric inpatients by a simple medical and functional assessment on admission.

A simple method of recognizing geriatric patients at risk for death and disability.

OBJECTIVE: To identify prognostic indicators for geriatric patients discharged from an acute care hospital. DESIGN: Prospective observational study. SETTING: Base line assessment at discharge from an acute care hospital; reassessment after 1 year at home. PATIENTS: One hundred-seventy-eight consecutive patients over 70 years of age (mean age +/- SD = 75.6 +/- 13.1 years, range 70-95 years, 52% males); 56% were dependent in one or more Activities of Daily Living, 21% had abnormal Mini Mental State Scores. MAIN OUTCOME MEASURES: mortality, increasing physical dependence, health care utilization. RESULTS: Mortality was directly related to a low ADL score at hospital discharges (Odds Ratio = 3.31, Confidence Limits = 1.91-5.75), neoplastic disease (OR = 3.59, CL = 2.01-6.43), cardiovascular disease (OR = 2.47, CL = 1.40-4.36), and drug use, expressed as the total number of individual preparations prescribed at discharge (OR = 1.72, CL = 1.05-2.83). Low ADL score, cardiovascular and neoplastic disease were also predictive of increasing physical dependency. The use of health care services, quantified by an appropriately designed score, did not correlate with any of the baseline variables, with the implication that the use of the health care services was not proportional to the need for care. CONCLUSIONS: Elderly subjects at major risk of death and disability can be easily identified at discharge by a simple assessment of their medical and functional state.