Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.     

Molecular size characterization of Haemophilus influenzae type b polysaccharide-protein conjugate vaccines

Current vaccines against Haemophilus influenzae type b (Hib) consist of capsular polysaccharide, polyribosylribitol phosphate (PRP), chemically conjugated to a carrier protein. The stability of the conjugate is essential for vaccine efficacy, as the target population for this vaccine includes infants, who do not mount an immune response to free polysaccharide vaccines. A method has been developed for determining structural stability and batch-to-batch consistency of Hib vaccines by the application of fast protein liquid chromatography (FPLC). This FPLC method is fast, reproducible, and can be used to evaluate single human doses of Hib vaccines. We have shown that the FPLC elution profiles provide a suitable indicator of vaccine stability under normal and degradative conditions. The method may also be applicable to other conjugate vaccines such as meningococcal and pneumococcal protein-polysaccharide conjugates.     

Alterations of lidocaine and pentylenetetrazol-induced convulsions by manipulation of brain monoamines

The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.     

Fibular transport in conjunction with Hoffman external fixation of the tibia

Tibiofibular synostosis is a salvage procedure commonly used for difficult nonunions of the tibia. It may be carried out by means of transfixion screws, a bone graft, or fibular transfer using Ilizarov (Smith and Nephews Richards, Memphis, Tennessee) or Monticelli-Spinelli (Howmedica Inc, Rutherford, New Jersey) devices. This paper describes fibular transfer employing the Hoffmann external fixator, which is commonly used in the management of tibial fractures or nonunions.     

Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart

BACKGROUND: The basic pharmacology of the third-generation beta-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical beta-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure. METHODS AND RESULTS: The effects of carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating comparable degrees of beta-blockade. Compared with metoprolol, carvedilol was associated with greater improvement in New York Heart Association functional class. Although there were no significant differences in hemodynamic effects between the carvedilol and metoprolol active-treatment groups, carvedilol tended to produce relatively greater improvements in left ventricular ejection fraction, stroke volume, and stroke work compared with changes in the respective placebo groups. Carvedilol selectively lowered coronary sinus norepinephrine levels, an index of cardiac adrenergic activity, whereas metoprolol did not lower coronary sinus norepinephrine and actually increased central venous norepinephrine levels. Finally, metoprolol was associated with an increase in cardiac beta-receptor density, whereas carvedilol did not change cardiac beta-receptor expression. CONCLUSIONS: The third-generation beta-blocking agent carvedilol has substantially different effects on left ventricular function, hemodynamics, adrenergic activity, and beta-receptor expression than dose the second-generation compound metoprolol. Some or all of these differences may explain the apparent differences in clinical results between the two compounds.     

Evidence for transcriptional modulation but not acid phosphatase expression during programmed cell death in the colonial tunicate Botryllus schlosseri

Botryllus schlosseri is a clonally modular ascidian in which asexually derived adults (zooids) exhibit developmental synchrony. At the conclusion of the blastogenic (asexual) cycle every 5 days at 21 degrees C, all zooids within a colony die simultaneously in 24 hours and are replaced by a new asexual generation of zooids. This cyclical process, called takeover, involves the selective destruction of the zooid's visceral tissues which include the pharynx, esophagus, stomach, intestine, endostyle, neural complex and heart, whereas bud tissues and mesenchymal components (muscle and blood cells) remain unaffected. Ultrastructural analysis indicates that the most prevalent form of cell death occurs by apoptosis, although necrotic changes are also observed in several tissues (i.e., stomach and intestine). Blood-derived macrophages and neighboring cells subsequently engulf visceral tissues, reducing the zooid to the size of a small vesicle. Here, we have tested the possibility that acid phosphatase, a hydrolase whose presence is associated with cell death in several invertebrate systems, could account for some of the regressive changes observed during takeover. Our observations indicate that acid phosphatase (AP) activity was selectively localized in the gut of parent zooids during the growth phase of the cycle, with the stomach exhibiting the most intense histochemical staining on tissue sections. As zooid regression progressed during takeover, stomach AP staining gradually disappeared. Other visceral tissues never became AP-positive. Therefore, this hydrolase appears to play a minimal role in zooid death. In order to characterize genes whose expression pattern was selectively altered during takeover, we have carried out differential mRNA display analysis. We report on two genes, 790.3 and 790.4, that are down- and upregulated, respectively, during this process. Collectively, these findings indicate that the takeover phase of blastogenesis in Botryllus involves modulated gene expression.     

Benign neoplasms in the parotid gland in the county of Copenhagen 1986-1995

In a ten year period from 1986-95 433 patients were submitted to operation due to benign tumours in the parotid gland in Copenhagen County. In this study we made a retrospective analysis of the surgical outcome. The incidence was calculated to be 6.8 benign tumours in the parotid gland per 100,000 persons per year. The histological distribution showed a frequency of 54% pleomorphic adenomas, 28% adenolymphomas and 18% other tumours. In the observation period there was a 3% recurrence rate in our material, most frequently the pleomorphic adenoma. The risk of permanent damage to the facial nerve was 1% for severe injury and 3% for affection of the ramus marginalis. Frey's syndrome was present in 50% of the patients, moreover the syndrome was observed many years after surgery. The frequency rate reached its highest level about five years postoperatively.