High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.     

Increased abdominal pain during final examinations

Anecdotes and animal experiments alike suggest that physiological and psychological stress can profoundly alter gastrointestinal function. However, few studies have examined, in humans, real-world stress to see if free-living persons exhibit gut alterations similar to those produced in the laboratory. To investigate this possibility, we studied 16 medical and premedical students during final written examinations. As compared to a control day, the examination created a classic stress response: elevated serum cortisol (16±1 to 21±3 µg/dl;P<0.05), ACTH (31±1 to 33±1 pg/ml;P<0.05), heart rate (72±3 to 79±3 beats/min;P<0.05), arterial blood pressure (systolic pressure 106±2 to 120±2 torr;P<0.05; diastolic pressure 72±2 to 77±1 torr;P<0.05), and subjective anxiety (raw score 28±2 to 47±3;P<0.0001). In contrast, subjects displayed identical orocecal liquid transit time (of 0.36 g/kg lactulose in a 240-ml, 250-kcal liquid meal) under control (103±8 min) and examination conditions (106±8 min;P=NS). Mean subjective reports of gas, diarrhea, and borborygmi were unchanged on the day of the experiment, although the examination did increase reported abdominal pain (from 0.5±0.4 to 2.1±0.5 on a 0–5 analog scale;P<0.05). We conclude that examination stress in humans can increase gastrointestinal symptoms without altering orocecal transit.     

You can't ask if you don't know what to ask: a survey of the information needs and resources of hospital outpatients.

OBJECTIVES: to test public demand for health and sickness information and identify sources of information used by the public. METHODS: using a questionnaire as the basis of a highly structured interview, 274 outpatients or their caregivers from nine clinics in Wellington Hospital, attending for the second or subsequent time, were asked whether they felt they knew enough about their illness and treatment, and where they had obtained their information. RESULTS: almost half expressed a wish for more illness information and two-fifths wanted to know more about their treatment. Respondents were significantly more satisfied with treatment than illness information. Outpatient comments further indicated dissatisfaction with information. Sixteen sources of information were each used by four or more people, almost 20% of the sample using more than six sources. Health professionals, the hospital doctor in particular, were the most important source of information; informal personal contacts were also widely used. CONCLUSIONS: the results highlight the difficulties of communication between health professionals and clients. The possibility of cooperation between health and information professionals in providing patients with more information is raised.     

Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases.

The spontaneous reaction of 110 microM chlorambucil (4-[p-[bis(2-chloroethyl)amino]phenyl]-butanoic acid; CHB) with 5 mM GSH at 37 degrees C in physiological phosphate-buffered saline for 35 min gave primarily the monoglutathionyl derivative, 4-[p-[N-2-chloroethyl,N-2-S-glutathionylethyl]amino]phenyl]-butano ic acid; CHBSG) and the diglutathionyl derivative, 4-[p-[bis(2-S-glutathionylethyl]amino]phenyl]-butanoic acid (CHBSG2) with small amounts of the hydroxy-derivatives: 4-[p-[N-2-chloroethyl,N-2-hydroxy-ethyl]amino] phenyl-butanoic acid (CHBOH) and 4-[p-[N-2-S-glutathionylethyl-2-hydroxyethyl]amino]phenyl]-butanoi c acid (CHBSGOH). The inclusion of approximately physiological amounts of human glutathione S-transferases (GSTs) A1-1, A2-2, P1-1, M1a-1a M3-3 or P1-1 (for nomenclature see Mannervik et al., 1992, Biochem. J., 282, 305) had little or no catalytic effect on these reactions as determined by loss of CHB. However, GTSs A1-1 and A2-2 were associated with a significant increase of CHBSG at the expense of CHBSG2 + CHBSGOH suggesting that these GTs sequestered CHBSG at the active site. This interpretation was supported by inhibition studies which showed that CHBSG was a pure competitive inhibitor of the activity of GSTs A1-1 and A2-2 towards 1-chloro-2,4-dinitrobenzene with Ki's of 1.3 and 1.2 microM respectively. GSH transferases P1-1 and M1a-1a were inhibited by CHBSG above 10 microM. Incubation of 2 microM CHB, a concentration which may be of more significance for chemotherapy, in the presence or absence of GST A1-2 (20-50 microM) showed catalysis of GSH monoconjugation equivalent to 18% of the spontaneous rate. However, the dominant effect again was the sequestration of CHBSG which reached 74.3 +/- 1.5 (SEM)% of the total reactants at 60 min compared to 28.9 +/- 0.3(SEM)% in controls. CHBSG, although possessing a potential electrophilic centre, showed no detectable alkylation of plasmid DNA but indirect evidence was obtained that it alkylated other cellular macromolecules. It is concluded that the contribution of GSTs to catalysis of CHB detoxication will depend on factors not previously considered, namely the relative molarities of CHB, CHBSG and GSTs, and the cellular capacity to excrete CHBSG to relieve product inhibition.     

Is it advantageous to strengthen the cement-metal interface and use a collar for cemented femoral components of total hip replacements?

The mechanism of initiation of loosening of cemented femoral components is now known. It is debonding at the cement-metal interface. Current data strongly support the concept that a collar and improvement of the cement-metal interface are valuable. Precoating and having a roughened surface proximally and distally on the stem contribute to extended longevity of the cement-metal interface. Using contemporary instrumentation, collar-calcar contact can be achieved regularly and, once achieved, is well maintained for years.     

Book Reviews

Book reviews in this article:
Biopsy Pathology of Melanocytic Disorders . W.J. M oor and T. K rausz (1992).
Topical Corticosteroids . Edited by H.I.M aibach and C.S urber (1992).     

Construction and validation of a Parkinson's disease mutation genotyping array for the Parkin gene.

Parkin mutations account for the majority of familial and sporadic early onset Parkinson's disease (EOPD) cases with a known genetic association. More than 100 mutations have been described in the Parkin gene that includes homozygous, compound heterozygous, and single heterozygous mutations. We have designed a Parkin mutation genotyping array (gene chip) that includes published Parkin sequence variants and allows their simultaneous detection. The chip was validated by screening 85 PD cases and 47 controls previously tested for Parkin mutations. Similar genotyping microarrays have been developed for other genetically heterogeneous diseases including age-related macular degeneration. Here, we show the utility of a genotyping array for Parkinson's disease by analysis of 60 subjects from the Genetic Epidemiology of Parkinson Disease (GEPD) study that includes 15 early-onset PD case probands and 45 relatives.     

Distal radial fractures Injectable calcium phosphate bone cement versus conventional treatment

AMEDLINEsearchwasconductedtoidentifystudiespublishedfromJanuary1999toMarch2004thatcom-paredinjectablecalciumphosphatebone(NorianSRS)cementwithconventionaltreatmentindistalradialfrac-tures.Fromalistof13articlesidentifiedfromthesearchstrategy,fourarticleswe…