Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient Xpa mice.

Chronic use of phenacetin-containing analgesics has been associated with the development of renal cancer. To establish genotoxicity as a possible cause for the carcinogenic effect of phenacetin, we exposed wild type and DNA repair deficient Xpa-/- and Xpa-/-/Trp53+/- mice (further referred as Xpa and Xpa/p53 mice, respectively), carrying a reporter lacZ gene, to 0.75% (w/w) phenacetin mixed in feed. Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds. Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice. A minor response was found in liver, whereas no lacZ mutation induction was observed in the spleen of these animals. Interestingly, the observed phenacetin-induced mutant frequencies were higher in male than those found in female mice. This gender difference is probably due to a difference in metabolic rate. Phenacetin-induced mutations mainly consisted of point mutations rather than deletions. The mutational spectra in the kidney of treated WT and Xpa mice were quite similar. Taken together, these results demonstrate that the human carcinogen phenacetin acts as a weak genotoxic agent in an in vivo mouse model system.

A prospective evaluation of anorectal function after total mesorectal excision in patients with a rectal carcinoma.

BACKGROUND: Rectum resection with total mesorectal excision (TME) and neorectal anastomosis often compromises anorectal function. Insight into the underlying mechanisms is lacking. Therefore, a prospective study was designed to investigate the relationship between clinical and functional outcomes preoperatively and postoperatively. METHODS: Eleven patients with rectal cancer were examined before and 4 and 12 months after surgery and compared with 11 healthy volunteers (HVs). Anorectal (neorectal) function was examined by clinical outcome questionnaire, anal manometry, rectal compliance, and sensation. Six HVs also underwent barostat measurements in the sigmoid colon. RESULTS: Clinical parameters of soiling and passive incontinence (loss of stool without sensation) increased significantly until 12 months postoperatively, whereas urgency and tenesmus increased temporarily, returning to preoperative values at 12 months. In anorectal measurements, anal sphincter function was grossly preserved; however, rectal-anal inhibitory reflex (RAIR) was decreased at 4 months but recovered after 1 year. Neorectal compliance was similar to that of HV sigmoid, increasing slightly after 12 months but still significantly lower than that of normal rectum. Neorectal sensation to pressure distention was similar to that of normal rectum, however accompanied by smaller volumes. Neorectal distention induced contractions of large amplitude at 4 months, returning to normal after 12 months. CONCLUSIONS: Our results suggest that the transient increase in urgency and tenesmus after surgery results from a temporary increase in neorectal "irritability" accompanied by some adaptation of compliance in time. In contrast, episodes of incontinence and soiling are increased after 1 year most likely because of reduced neorectal capacity and RAIR recovery in the presence of a low basal anal sphincter pressure.

Exploring sources of heterogeneity in systematic reviews of diagnostic tests.

It is indispensable for any meta-analysis that potential sources of heterogeneity are examined, before one considers pooling the results of primary studies into summary estimates with enhanced precision. In reviews of studies on the diagnostic accuracy of tests, variability beyond chance can be attributed to between-study differences in the selected cutpoint for positivity, in patient selection and clinical setting, in the type of test used, in the type of reference standard, or any combination of these factors. In addition, heterogeneity in study results can also be caused by flaws in study design. This paper critically examines some of the potential reasons for heterogeneity and the methods to explore them. Empirical support for the existence of different sources of variation is reviewed. Incorporation of sources of variability explicitly into systematic reviews on diagnostic accuracy is demonstrated with data from a recent review. Application of regression techniques in meta-analysis of diagnostic tests can provide relevant additional information. Results of such analyses will help understand problems with the transferability of diagnostic tests and to point out flaws in primary studies. As such, they can guide the design of future studies.

Artemisinin or chloroquine for blood stage Plasmodium vivax malaria in Vietnam.

Chloroquine-resistant Plasmodium vivax has not yet occurred in Vietnam. The efficacy of artemisinin for P. vivax was not established. We conducted a double-blind randomized study involving 240 inpatients with P. vivax malaria who received artemisinin (40 mg/kg over 3 days) plus placebo chloroquine (Art) or chloroquine (25 mg/kg over 3 days) plus placebo artemisinin (Chl). Patients were followed up with weekly blood smears for 28 days. In each group 113 cases were analysed. All patients recovered rapidly. The median (range) parasite clearance time of regimen Art was 24 h (8-72) and of Chl 24 h (8-64; P = 0.3). Parasites reappeared in two cases in each group on day 14, in eight cases in each group (7%) on day 16 and in 25 (23%) and 18 (16%) cases, respectively, at the end of 4-week follow-up (P = 0.3). The population parasite clearance curve followed a mono-exponential decline. The parasite reduction ratio per 48 h reproduction cycle was 2.3 x 104 for both regimens. We conclude that artemisinin and chloroquine are equally effective in the treatment of P. vivax infections in Vietnam. Reappearance of parasites before day 16 (7%) suggests the emergence of chloroquine resistance. Three days of artemisinin monotherapy does not prevent recrudescence.

Facial disfigurement: is it in the eye of the beholder? A study in patients with Graves' ophthalmopathy.

OBJECTIVES: The importance of facial disfigurement in many diseases necessitates a reliable and valid measure of disfigurement severity for clinical studies. The hypothesis is that a universal concept of disfigurement exists and can be measured in a reliable way. The objectives of this study were to investigate if persons, in particular patients and physicians, can agree on facial disfigurement severity; and to determine the relative contribution of predefined clinical characteristics of patients with Graves' ophthalmopathy (GO) to the overall rating of facial disfigurement severity. DESIGN: A panel study was carried out in four different panels, each consisting of four members. PATIENTS: We randomly selected 100 slide pairs of GO patients from four available study populations, involving mild, moderate and severe GO patients (mean age 49 years, 76% female) who were treated with either radiotherapy, sham-irradiation, prednisone or orbital decompression. MEASUREMENTS: All panel members individually scored the disfigurement severity of 100 GO patients shown on standardized slides on a Visual Analog Scale. In total, 1600 ratings were collected. We calculated within- and between-panel agreement of disfigurement severity and identified determinants of disfigurement. RESULTS: Agreement within a panel varied from 0.65 to 0.79 and was highest within the panel of ophthalmologists. Between-panel agreement was 0.67 and was highest between ophthalmologists and laypersons. Compared with the global average, patients overrated and endocrinologists underrated disfigurement severity. Female panellists rated the patients, on average, more disfigured than male panellists. Important determinants of disfigurement were eyelid retraction, severe eyelid swelling and proptosis. Their relative importance was consistent across panels and in contrast to current measures of GO severity. CONCLUSION: Facial disfigurement severity can be measured in a reliable way using panels of panellists. Except for some systematic differences between panellists, facial disfigurement does not seem to be in the eye of the beholder.