Continuous venous infusion of doxorubicin in advanced sarcomas

Seventeen patients with advanced sarcoma were treated with continuous venous infusion of doxorubicin for a mean of 118 days, achieving total doses up to 1097 mg/m2. Three partial responses and one minor response were obtained. Major toxic effects were stomatitis and hand-foot syndrome. There was a low incidence of leukopenia (18%) and clinical cardiotoxicity (11%). Continuous venous infusion is a safe means of administering doxorubicin, with a response rate similar to that observed with bolus doxorubicin in metastatic sarcoma.     

Gastroduodenal tolerability of indomethacin and acetaminophen. A comparative endoscopic study in healthy subjects

The effect of a 5- and 10-day treatment with indometacin and acemetacin (Rantudil) on the gastroduodenal mucosa was endoscopically evaluated in 16 healthy volunteers. In a randomised double-blind cross-over fashion the volunteers received 50 mg t.i.d. indometacin as well as 60 mg t.i.d. acemetacin. Acemetacin evoked after 5 and 10 days significantly less gastroduodenal lesions than indometacin. Possible reasons for this apparently better tolerability of acemetacin in man are discussed.     

Malignant histiocytosis. Complete remission in two pediatric patients

The experience with the treatment of malignant histiocytosis has been disappointing. Despite modest treatment success with a combination of cyclophosphamide, Adriamycin (doxorubicin), vincristine and prednisone, the overall prognosis remains poor. There are only a few reports of prolonged complete remissions in pediatric patients. The following report describes two children who have had long-term remission with an aggressive combination chemotherapy program that included intrathecal prophylaxis. The chemotherapeutic regimen described merits further evaluation in a larger number of patients.     

High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain.

The mitochondrial theory of aging proposes that mitochondrial DNA (mtDNA) accumulates mutations with age, and that these mutations contribute to physiological decline in aging and degenerative diseases. Although a great deal of indirect evidence supports this hypothesis, the aggregate burden of mtDNA mutations, particularly point mutations, has not been systematically quantified in aging or neurodegenerative disorders. Therefore, we directly assessed the aggregate burden of brain mtDNA point mutations in 17 subjects with Alzheimer's disease (AD), 10 elderly control subjects and 14 younger control subjects, using a PCR-cloning-sequencing strategy. We found that brain mtDNA from elderly subjects had a higher aggregate burden of mutations than brain mtDNA from younger subjects. The average aggregate mutational burden in elderly subjects was 2 x 10(-4) mutations/bp. The bulk of these mutations were individually rare point mutations, 60% of which changed an amino acid. Control experiments ensure that these results were not due to artifacts arising from PCR error, mistaken identification of nuclear pseudogenes or ex vivo oxidation. Cytochrome oxidase activity correlated negatively with increasing mutational burden. These findings significantly bolster the mitochondrial theory of aging.     

Heat shock protein hsp72 induction in cortical and striatal astrocytes and neurons following infarction

Transient global and transient focal ischemia induced the 72 kDa heat shock protein (hsp72) in neurons in cortex, striatum, and other regions known to be injured during transient ischemia. A novel finding was the induction of hsp72 in islands (cylinders in three dimensions) of cells composed of astrocytes around the perimeter and neurons in the interior. Since histology showed pale staining in these regions, it is proposed that these islands represent areas of focal infarction in the distribution of small cortical and lenticulostriate arteries. Although the factors responsible for hsp72 induction during ischemia and infarction are unknown, these results suggest differences in mechanisms of hsp72 induction in astrocytes compared to neurons.     

Nonaromatizable androgens may stimulate a male mouse reproductive behavior by binding estrogen receptors

Castrated DBA/2J male mice emitted 70 kHz vocalizations to female stimuli in response to 10 days of treatment with either testosterone (T, 300 micrograms/day), diethylstilbestrol (DES, 1 or 3 micrograms/day) or methyltrienolone (R1881, 900 micrograms/day). Lower dosages of R1881 (300 and 600 micrograms/day) and the oil vehicle were relatively ineffective in restoring vocalizations. The effects of these hormones on restoring seminal vesicle weight did not always parallel their effects upon behavior. In general T and R1881 (600 and 900 micrograms/day) were effective in restoring seminal vesicles while DES, the lowest dose of R1881 (300 micrograms/day), and the oil vehicle were ineffective. In receptor competition studies, R1881 pretreatment significantly reduced estrogen binding in hypothalamic-preoptic cytosol. In fact the most effective dose for restoring vocalizations (900 micrograms/day) reduced available estrogen binding sites by 91%. We propose that the male-typical vocalizations of mice may normally be stimulated through the activation of estrogen receptors following androgen aromatization and that the ability of a pharmacological dosage of R1881 (900 micrograms/day) to restore behavior may be due to interaction with estrogen receptors in the brain.     

Delineating the sites and progression of in vivo atrophy in multiple system atrophy using fluid-registered MRI.

We describe the pattern and progression of atrophy delineated using fluid registration of serial magnetic resonance imaging scans in a case of multiple system atrophy (MSA). The in vivo findings were consistent with those found at postmortem, including significant supratentorial atrophy concurrent with an unusual degree of cognitive impairment for MSA.