Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis

Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320-400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type.     

Evaluation of Dream Content in Combat-Related PTSD

Nightmares that replicate traumatic events are among the criteria that define posttraumatic stress disorder (PTSD); however, there has been limited systematic assessment of the content of dreams in PTSD. A PTSD dream rating instrument was developed to ope rationalize features attributed to dreams associated with combat-related PTSD that incorporated dimensions from the dream content analysis literature, and its reliability was assessed. Then the instrument was used to characterize dream reports in 18 Vietnam combat veterans diagnosed with PTSD. Approximately half of the group's target dreams contained features characteristic of combat, and all but 3 (17%) were moderately to highly threatening. Fifty-three percent were set at least partially in the present and 79% contained distorted elements. We therefore conclude that target dreams of combat veterans with PTSD vary with regard to replication of trauma and elements normally associated with dreaming, but typically are threatening.     

Protoporphyrin accumulation by mitogen stimulated lymphocytes and protoporphyrinogen oxidase activity in patients with porphyria variegata and erythropoietic protoporphyria: evidence for deficiency of protoporphyrinogen oxidase and ferrochelatase in both diseases

In erythropoietic protoporphyria (EPP) and porphyria variegata (PV) excess protoporphyrin is excreted in the stool, suggesting one or more enzyme defects in the terminal steps of the haem biosynthetic pathway. We measured protoporphyrinogen oxidase (PPO), which catalyses the oxidation of protoporphyrinogen to protoporphyrin, in both EPP and PV patients and in the offspring of PV patients. In the same subjects we measured protoporphyrin formation by mitogen stimulated lymphocytes, with delta aminolaevulinic acid (ALA) as substrate and with the addition of chelators or iron, an indirect measure of ferrochelatase activity. PPO activity was reduced by 41% (P less than 0.001) in PV patients and in 50% of their offspring, and by 36% (P less than 0.001) in EPP patients. Protoporphyrin accumulation in stimulated lymphocytes was increased by 1.3-fold (P less than 0.001) in EPP and 1.5-fold (P less than 0.001) in PV patients compared to normal subjects. There was a significant difference in protoporphyrin accumulation between iron deficient and iron replete cells from PV patients as compared to normals but not as marked as for EPP cells treated similarly. Stimulated lymphocytes from prepubertal PV offspring with reduced PPO activity accumulated normal amounts of protoporphyrin. We have interpreted our findings as follows: PPO is significantly reduced in both diseases. Ferrochelatase becomes defective in PV patients after puberty. This could explain why PV is clinically and biochemically manifest only after puberty. As it has been repeatedly shown that ferrochelatase is markedly reduced in EPP, it would appear that both enzymes are deficient in these two porphyrias.     

A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity

Human     

Effect of nicotine treatment and withdrawal on random-pattern skin flaps in rats

BACKGROUND: Tobacco use is associated with a high incidence of skin necrosis after surgery. The ideal timing for the cessation of tobacco use before plastic surgery has not, however, been precisely determined. The aim of this work was to define the ideal duration of nicotine withdrawal prior to random-pattern skin flap surgery in rats. METHODS: Groups of 11 animals were subcutaneously injected with saline or nicotine (2mg/kg) twice a day and subjected to random-pattern skin flap surgery according to the following protocol: Group I: continuously injected with saline 4 weeks before and 1 week after the surgery; Group II: injected with nicotine for 4 weeks until the day of the surgery; Group III: injected with nicotine for 4 weeks until one day before the surgery; Group IV: injected with nicotine for 4 weeks until 5 days before the surgery; Group V: injected with nicotine for 4 weeks until 10 days before the surgery; Group VI: continuously injected with nicotine for 4 weeks before and 1 week after the surgery. McFARLANE skin flaps were performed on the dorsal skin, and the rats were sacrificed 1 week after the surgery. RESULTS: The necrotic area was smaller in group I (8.85cm(2)) than in group II (12.15cm(2)), III (12.88cm(2)) and VI (14.84cm(2)) (ANOVA p<0.0001). There was no difference between groups I, IV (10.13cm(2)) and V (9.27cm(2)). CONCLUSIONS: In conclusion, 5 days before surgery was considered the ideal time for nicotine withdrawal in this experimental model.     

Camptocormia induced by atypical antipsychotics and resolved by electroconvulsive therapy.

We present a depressive patient who developed mild parkinsonian signs and camptocormia after the introduction of olanzapine. She had been treated before with other antipsychotic drugs. When camptocormia was diagnosed, olanzapine was withdrawn and levodopa was introduced. Depressive symptoms got worse and electroconvulsive therapy was tried. When the treatment was completed, her depression substantially improved and her posture became completely upright.     

Insulin treatment normalizes reduced free insulin-like growth factor-I concentrations in diabetic children

OBJECTIVE We have recently demonstrated multiple aberrations in the GH–IGF axis in the sera of children with untreated insulin-dependent diabetes mellitus (IDDM) which were restored after insulin replacement. However, the net result of these alterations in the IGF system on the concentrations of free/biologically available IGF-I in the serum have not been examined directly in diabetic children. In the present study, the effect of diabetes and subsequent insulin replacement on the circulating free IGF-I concentrations are assessed. DESIGN Fasting venous serum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subjects. SUBJECTS Ten prepubertal, aged (mean ± SEM) 6.3±1.0 years, and six adolescent, aged 12.7±1.1 years, subjects with newly diagnosed and untreated IDDM, and age and pubertal status-matched control children and adolescents were recruited. METHODS The serum samples were collected before initiating insulin treatment and 12–24h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0.5 to 1.2 U/kg/day. MEASUREMENTS Free IGF-I concentration was assayed by a recently developed two-site immunoradiometric assay. Total IGF-I was measured by radioimmunoassay after acid–ethanol extraction of binding proteins. Differences in free and total IGF-I concentrations in IDDM subjects before and during insulin treatment were analysed by repeated measures analysis of variance followed by pairwise multiple comparisons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP-3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and circulating free IGF-I concentrations were examined by linear regression analysis. RESULTS Free IGF-I concentrations in prepubertal subjects with IDDM were 0.9±0.2, 1.5±0.3, 1.6±0.3 and 2.5±0.4μg/l before, 1 day, 1 week and 1 month after insulin treatment, respectively. Free IGF-I concentrations of control prepubertal children were 2.6±0.5μg/l. Pubertal subjects had higher free IGF-I concentrations than prepubertal subjects but demonstrated a similar type of pattern; before insulin 2.3±1.1, 1 day 3.8±1.3, 1 week 3.7±0.6, 1 month 6.5±1.5 vs pubertal controls 7.7±2.0μg/l. Total IGF-I concentrations were also reduced in untreated diabetic subjects and showed a slower pattern of normalization than free IGF-I concentrations. Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations. There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity. CONCLUSION Alterations in the IGF system during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatment. An increase in free IGF-I precedes that of total IGF-I suggesting that the former is a more sensitive indicator of the metabolic status. An inverse correlation between free IGF-I and IGFBP-1 supports the hypothesis that IGFBP-1 plays an important role in the acute modulation of free IGF-I levels.     

Farber lipogranulomatosis: An unusual presentation in a black child

Farber disease, a rare, inherited condition of lipid metabolism usually appears within the first two months of life. The patients may die in the first few years of life or may live into the second decade. We believe this patient to be the first black American reported with Farber disease. Additionally, the characteristics of the disease in this patient were at variance with previously reported cases.     

Sources of influence on infant feeding practices in Hong Kong

The breastfeeding rate in Hong Kong is low compared to the rates in Western countries. To understand the relative importance of different sources of influence on infant feeding practices, 714 Chinese mothers with infants aged 4 weeks to 6 months were studied. It was found that the bottlefeeding mothers were influenced more by the medical professionals who did not support breastfeeding. This influence was further reinforced by the mass media and particularly television advertisements on infant formulae. The successful breastfeeding mothers, on the other hand, were influenced more by their social networks through which they were told of the dangers of bottlefeeding. The failed breastfeeding mothers differed from the other groups in the lack of support they experienced from friends and relatives. Although they received professional encouragement to breastfeed, they were more sheltered from the influence of mass media and social networks. From these findings, it is suggested that different sources of influence are related to different feeding practices. However, to be able to continue with the practice that one has chosen, the availability of social support is essential. Implications of these findings are discussed and several recommendations to promote breastfeeding are made.