Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity

Model cell lines developed from MCF7 breast carcinoma cells were used to examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4- nitroquinoline 1-oxide (4NQO) toxicities. Increased expression of GSTP1- 1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO- SG) conjugate formation and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO. Moreover, this MRP- dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.      

Bioactivation of the cooked food mutagen N-hydroxy-2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine by estrogen sulfotransferase in cultured human mammary epithelial cells

Cooked food mutagens from fried meat and fish have recently been suggested to contribute to the etiology of breast cancer. Thus, the most prevalent of these compounds, i.e. 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine, or rather its more mutagenic N- hydroxylated metabolite (N-OH-PhIP), forms DNA adducts in mammary cells, including human mammary epithelial (HME) cells. The objective of this study was to determine the involvement of estrogen sulfotransferase (EST), the only sulfotransferase identified in HME cells, in the further bioactivation of N-OH-PhIP. These studies were done in vitro using human recombinant EST and in intact HME cells. Human recombinant EST increased the covalent binding of [3H]N-OH-PhIP to calf thymus DNA approximately 3.5-fold in the presence of the sulfotransferase co-substrate 3'-phosphoadenosine-5'-phosphosulfate at each N-OH-PhIP concentration (1, 10 and 100 microM) (n = 6, P < 0.001). In contrast, EST did not catalyze the DNA binding of two other cooked food mutagens, N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline and N- hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, which are mainly hepatocarcinogens. Cultured HME cells displayed high EST activity, which could be completely inhibited by 1 microM estrone. When the cells were incubated with [3H]N-OH-PhIP, binding to native DNA occurred at 60- 240 pmol/mg DNA. This binding was inhibited to 55% of control by 1 microM estrone (P < 0.01, n = 8), suggesting that EST plays a significant role in carcinogen bioactivation in human breast tissue.      

Prise en charge du mélanome cutané

Cutaneous melanoma represents the main cause of death among skin cancers. Early diagnosis gives, for the time being, the only possibility for high rate of curative treatment. Diagnosis is based on pathological findings, and at primary tumor stage, Breslow thickness of the lesion is the best prognostic index. At local stage of the disease, treatment is precisely codified by international recommendations and consensus conferences. Follow-up after surgical treatment is also well codified. Treatment of lymph node invasion or metastatic disease is, on the other hand, less codified. Despite recent advances, especially in immunotherapy, treatment of advanced stages of melanoma remains difficult.     

Sleeping position for infants and cot death in The Netherlands 1985-91

Until the early 1970s the traditional sleeping position for Dutch infants was not prone. After a much publicised lecture in October 1987 on the possible relation between sleeping prone and cot death, the fairly new habit of placing infants prone is being replaced by more traditional positions. The decrease in the prevalence of the prone sleeping position has been documented in six studies. Since 1987 the incidence of registered cot deaths has decreased from 1.04/1000 live births in 1986 to 0.44 in 1991; the real decrease of sudden unexpected death in infancy, however, is greater.     

How much wrapping do babies need at night?

In a longitudinal, population based study, overnight temperature recordings were made in the bedrooms of 152 babies aged 3-18 weeks and the insulation provided by their bedclothing was assessed. Outdoor temperatures for the study nights were also available. Parents applied more insulation on colder nights with lower bedroom temperatures than on warmer nights (mean 8.5 tog at 15 degrees C minimum bedroom temperature falling to 4.0 tog at 25 degrees C). For a particular temperature they also applied 2 tog more insulation in winter than in summer. The amounts of bedclothing used in the home were compared with insulation levels predicted to achieve thermo-neutrality over a similar range of environmental temperature from heat balance studies in young infants. They corresponded closely. The average amount of bedclothing chosen for babies in Avon allows them to remain in thermoneutral conditions throughout the night. These values are proposed as broad guidelines for the thermal care of young babies at night.     

Rebreathing expired gases from bedding: a cause of cot death?

The reported association of cot death and sleeping prone could be due to rebreathing of expired gases. A mechanical model simulating the respiratory system of an infant, exhaling warm humidified air with an end tidal carbon dioxide of 5%, has been used to investigate this. Some commonly used bedding materials caused an accumulation of carbon dioxide of 7% to over 10% with the model lying face down. This phenomenon persisted even with the head inclined at 45 degrees, but only on very soft materials, and could be a cause of cot death in a baby unresponsive to asphyxial blood gas changes. A coir fibre mattress allowed complete dispersal of exhalate as did a rubber sheet between any mattress and the covering sheet.     

Resolution of hepatic abscess after interferon gamma in chronic granulomatous disease

Recombinant interferon gamma has been used prophylactically in children with chronic granulomatous disease, but its role in the treatment of acute infective episodes has not been defined. A 3 year old boy presented with multiple candidal liver abscesses and was given intravenous antifungal treatment and he showed initial improvement. After six weeks his erythrocyte sedimentation rate and C reactive protein remained raised, and a computed tomogram showed a single abscess in the left lobe of the liver from which pus was drained and Staphylococcus aureus isolated. During the next eight months the abscess persisted despite appropriate intravenous antibiotics and percutaneous drainage. Subphrenic extension precluded definitive surgery. Nine months after initial presentation recombinant interferon gamma 0.05 mg/m2 intravenously was commenced three times a week. Complete resolution occurred within two months. It is concluded that interferon gamma is useful in treating infective episodes, and further study of the use of prophylactic antimicrobial treatment and intermittent interferon gamma during acute episodes is now required.     

Individual variation in sleeping metabolic rates in infants

AIM: To measure the variation in sleeping metabolic rate (SMR) of healthy infants in the first year of life. METHODS: Attempts were made to measure SMR in the home of one group of infants at monthly intervals over the first year of life and of another group in the 1 to 12 age range, over three consecutive days. Sixty one infants were recruited and 181 measurements made. In 11 infants six or more satisfactory measurements were made a monthly intervals and in another 11 infants, three consecutive daily measurements were obtained. Parents chose the clothing and bedding that they judged their infant needed to fall asleep. The room air and radiative temperatures, humidity, and amount of insulation were recorded. RESULTS: The mean (SD) SMR was 2.4 (0.4) watts (W)/kg or 45 (10) W/m2. The rate was the same for infants in the age groups 0.25, 0.5, 0.75, and 1 years; individual infants did not show a systematic change with age. There was wide variation. Ninety eight per cent of infants had a SMR between 1.8 and 3.1 W/kg. The mean SMR for the infants measured on three consecutive days varied from 1.7 to 3.1 W/kg, and SMR varied within infants, from 0.06 to 0.86 W/kg. The variation within six to 11 measurements on infants over the first year of life ranged from 0.38 to 1.05 W/kg. CONCLUSION: Infants in the first year of life exhibit wide variations in SMR from day to day and from month to month. As the range is wide, guidance on clothing and bedding for thermal comfort can be given only in broad terms.     

Recurrence of unexpected infant death

Families which had experienced two or more unexpected infant deaths were the subject of detailed confidential enquiries, including necropsy examination. Cases were derived from two main sources: first, deaths occurring during a nationwide programme of support for families with a subsequent baby (8 families) plus 2 families from a scries of confidential enquiries in Sheffield, and second, direct referrals from paediatricians (17 families). Fifty-seven deaths were studied. Twenty-four families had experienced 2 and three had experienced 3 deaths: 11 deaths (19%) were found to be adequately explained by history or post-mortem findings; 7 (12%) were probably accidental; 31 (55%) were most probably due to an action by one of the parents (filicide); only 5 (9%) were considered to be true or idiopathic sudden infant death syndrome; in 3 (5%) cases there was insufficient information to draw a conclusion. Five (18%) of the families lived in circumstances of serious social deprivation. A history of psychiatric illness was present in one or both parents in 18 (67%) of the families.