Self-inflicted burns: an eight year retrospective study in Finland

The aim of this study was to investigate differences in characteristics of burn patients who had attempted suicide, as compared with other burn patients admitted to the Helsinki Burn Centre during 1989-97. Burn patients were first drawn from a computerised register, after which a psychiatrist examined their medical records and ascertained the suicide attempters. Of the total of 811 burn patients, 46 (5.7%) had attempted suicide. The median total body surface area (TBSA) of suicide attempters (24.0%) was markedly higher than in the other patients (6.0%, P < 0.001). Flame was a much more common cause of burns among suicide attempters (82.1%) than among the remainder (44.5%, P < 0.001). Suicide attempters were also more often unemployed (28.2 versus 12.9%) or on disability pension (30.8 versus 7.1%) before the injury (P < 0.001). Although the proportion with self-inflicted burns among all burn patients was not high, the markedly higher severity of their burns makes them an important clinical subgroup for further study.     

Postnatal development of resistance to short-term high-dose toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in TCDD-resistant and -semiresistant rats

Despite great interspecies differences in adult 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitivity, the toxic potency of TCDD is similar across species in fetal mortality. Han/Wistar (Kuopio; H/W) rats are exceptionally resistant to acute toxicity of TCDD, but show sensitivity to embryotoxicity and teratogenicity. The resistance of adult H/W rats to acute TCDD toxicity is based on a point mutation in the transactivation domain of the aryl hydrocarbon receptor (AHR) and to an unknown gene “B”. This study investigated the time course of postnatal development of resistance to TCDD and the significance of genotypic variation in resistance development. H/W, line A (a new line with the H/W-type mutated AHR), and line B rats (a line with normal AHR but moderately resistant because of gene “B”) were exposed to a single dose of TCDD 2-56 days after birth. H/W and line A rats received 1000 μg/kg; male and female B rats received 200 and 100 μg/kg, respectively. Survival was monitored for 42 days. Interestingly, although TCDD ceased growth and weight gain in all TCDD groups, the younger dosed animals did not seem to reach the body weight of the older dosed animals even in 100 days. The survival results after 42 days showed that line A rats are fairly resistant to TCDD immediately after birth, and their full TCDD resistance develops during the first week of life. The moderate resistance of line B rats develops approximately at the time of weaning. This difference in the time course of resistance development suggests that there are basic differences in pathways mediating resistance in lines A and B rats.     

Developmental toxicity of dioxin to mouse embryonic teeth in vitro: arrest of tooth morphogenesis involves stimulation of apoptotic program in the dental epithelium

Previous studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can arrest molar tooth development in rats after in utero and lactational exposure, and that the sensitive stage is temporally restricted. To define the stage in which TCDD is able to arrest tooth development and the cellular background of the effect, mouse embryonic molar tooth explants including various early developmental stages from initiation to late cap stage were exposed to TCDD in organ culture. TCDD did not inhibit morphogenesis of the first molar teeth including the early bud-staged E12 first molars, but the teeth were smaller than in control cultures. Accordingly, the second molars underwent morphogenesis in the presence of TCDD when explanted at E15 when they were at the bud stage. TCDD arrested their development when explanted at E14 when they had not yet reached the early bud stage. Immunohistochemical localization of incorporated bromodeoxyuridine in cultured E14 teeth showed that TCDD did not affect cell proliferation. Localization of apoptosis by terminal deoxynucleotidyl transferase (TdT)-mediated nick end labeling (TUNEL) method revealed that TCDD enhanced apoptosis of dental epithelial cells, especially in the dental lamina of both the first and second molars, and in the inner dental epithelium at the cusp tips of the first molars. Thus, TCDD can arrest tooth development in vitro if the exposure starts at the initiation stage, whereas exposure at later stages leads to smaller tooth size and deformation of cuspal morphology. TCDD interferes with tooth development by stimulating apoptosis in those cells of the dental epithelium, which are predetermined to undergo apoptosis during normal development.     

Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression during inhaled steroid therapy in adult asthmatic patients

OBJECTIVE: Supraphysiological doses of exogenous glucocorticosteroids cause adrenocortical suppression. Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant adrenal androgen and estrogen precursor. We studied to what extent inhaled glucocorticosteroid therapy for asthma decreases serum DHEA-S concentrations. DESIGN AND METHODS: We measured serum DHEA-S and cortisol concentrations in 101 adult patients with newly detected mild asthma before and after 2 and 12 weeks of treatment with inhaled glucocorticosteroids. The patients were randomized to receive budesonide 200 microg/day (low dose group, n=50) or 800 microg/day (high dose group, n=51) in two parallel groups double-blindly. RESULTS: In the low dose group, serum DHEA-S concentrations decreased from the baseline by a mean of 8 % (95 % confidence interval (CI), 3-13 %, P<0.01) after 2 weeks of therapy, and by 2 % (95 % CI, 9 % decrease to 5 % increase, NS) after 12 weeks. In the high dose group, the respective decreases were 16 % (95 % CI, 10-21 %, P<0.001) and 18 % (95 % CI, 12-24 %, P<0.001). The difference between the treatment groups was significant at both 2 and 12 weeks. During the 12 week treatment period the baseline concentrations of serum cortisol did not decrease in the low dose group, while in the high dose group the decrease was significant at 12 weeks (P<0.01), but not at 2 weeks. The forced expiratory volume in 1 s improved equally well in both groups. CONCLUSIONS: Inhaled budesonide decreased serum DHEA-S concentrations, which may indicate adrenocortical suppression. Reduced adrenal production of androgen and estrogen precursors may increase the risk of osteoporosis especially in postmenopausal women.     

The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high micromolar serum concentrations following ingestion of doses of ≥100 mg of the drug. The serum transport protein— 1-acid glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the ≥200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2–5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.