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The purpose of this study was to evaluate the effectiveness of existing psychological interventions on the social adjustment of young refugees. From 51 peer-reviewed articles identified in the literature, 11 studies with 25 therapeutic effect sizes met criteria for inclusion (N = 1,736). Hedges’ g was used to measure effect sizes and a random-effects model was conducted. The number of sessions and participant age were considered as potential moderator variables in moderator analyses through meta-regression. The effect sizes of the included studies were compared based on the type of intervention. The results showed that the aggregated effect size for all included interventions was significant, computed as g = 0.14, p < 0.01, 95% confidence interval [0.06, 0.21]. The effect size is considered small, based on Cohen's (1992) guidelines. The results of the meta-regression showed that the effectiveness of the included psychological interventions on social adjustment was not moderated by either the number of sessions (b = 0.006 p = 0.35) or age (b = –0.008, p = 0.59). Furthermore, there were no significant differences between different therapeutic approaches (Q = 7.37, df (Q) = 6; p = 0.28). This meta-analysis demonstrates that mental-health interventions in young refugees mildly improve their social adjustment. Due to the importance of social adjustment in refugees, we suggest that existing interventions place greater specific focus on improving social adjustment. The details of implications for future studies are discussed.

Putative risk factors (DNA damage) and risk modifying factors (DNA repair and cell proliferation) were examined in an experimental mouse model in which treatment with dimethylhydrazine (6.8 mg/kg DMH i.p. once weekly) for up to 20 weeks induces colon tumours in a site specific manner with 0, 43 and 87% of animals having proximal, mid and distal colon tumours respectively at the highest cumulative dose. Levels of the pro-carcinogenic DNA adduct, O(6)-methylguanine (O(6)-MeG), in colonic DNA were found to vary with time after final treatment and with location within the colon but not with total DMH dose. O(6)-MeG levels were generally lowest in proximal colon DNA and highest in distal colon DNA. Steady state O(6)-MeG levels were obtained at the highest cumulative DMH dose with O(6)-MeG levels in mid and distal colon DNA being 5 and 10 times higher those in proximal colon DNA. O(6)-alkylguanine-DNA alkyltransferase (MGMT) activity, and cell proliferation indices in the colon were also found to vary with time after final treatment but not with either location within the colon or total DMH dose. O(6)-MeG levels, MGMT activity and cell proliferation indices at specific time points as well as basal MGMT activity were not associated with differences in tumour yield within the colon. However tumour yield was associated with the cumulative amount of O(6)-MeG present in DNA over the treatment period and with the treatment induced cumulative increase in cell proliferation, particularly within regions of the colon crypt where stem cells reside but not with cumulative changes in MGMT activity. Results are consistent with an increased cancer risk arising from an increased mutation load in the target stem cell population due to increased adduct formation/persistence and cell proliferation but also suggest that other cell specific factors may help to determine tumourigenic response.

O6-alkylguanine DNA-alkyltransferase (ATase) provides protection against the toxic, mutagenic and carcinogenic effects of alkylating agents, principally by removing the promutagenic lesion O6-alkylguanine from DNA. Differences in ATase activity in human tissue may thus determine mutational susceptibility. As GC--AT transitions, which can be induced by O6-alkylguanine in DNA, are commonly observed in the K-ras oncogene of alkylating agent induced animal tumours and in human colorectal tumours, we have examined whether differences in ATase activity may affect the risk of K-ras mutations in humans with colorectal tumours. NTase activity in normal tissue from individuals with a K-ras mutation in colorectal tissue and more specifically a GC--AT transition (but not a transversion mutation) was significantly lower than that in individuals without a mutation (P0.01). Thus, individuals with low ATase activity in normal tissue (i.e. below the median) were at increased risk of having a transition (OR 10.1; 95% CI 1.9-99.0), but not a transversion mutation (OR 1.7; 95% CI 0.3-12.2). There were no significant differences in tumour ATase activity in individuals with or without a mutation. These results suggest that ATase can protect colorectal tissue against the mutagenic effects of alkylating agents and furthermore, that alkylating agent exposure plays a role in the aetiology of colorectal tumours containing a GC--AT transition in the K-ras oncogene.

Male Wistar rats were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) either as a single dose of 50, 125 or 250 mg/kg given by gavage or via drinking water for 28 weeks at a concentration of 40, 80 or 160 micrograms/ml, in the case of the higher concentration reverting to 80 micrograms/ml after the first 8 weeks. The single dose regimen had no effect on water intake or body weight, but the chronic exposure led to a dose-dependent reduction in water intake that was paralleled by a slower weight gain, with the final body weights at approximately 90, 84 and 79% of the control weight values. The combined yield of benign and malignant tumours (79-100% of the animals treated) occurred in the forestomach in the case of the single doses, whereas the chronic exposure resulted in a maximum yield of tumours located in the pyloric region of the glandular stomach (64-100% of animals treated). The principal histological types of tumours induced were squamous cell papilloma and carcinoma in the forestomach and adenocarcinoma in the pylorus. There was a persistent, but low yield (25-30% of animals treated) of tumours in the jejunum, mainly adenocarcinoma, after administration via drinking water, whereas after single doses, multiple solitary cysts and cholangioma (30% and 25-70% respectively of the animals treated) were found in the liver. This report differs from earlier reports in that marked effects were noted on water consumption and body weight gain and that tumour induction can be achieved after much shorter periods of exposure than previously reported in the literature. These data confirm the tissue specificity of MNNG when given either as a single or chronic dose regimen and provide a suitable model for the investigation of the target cell specificity of tumour induction.

Male and female BK-TO mice were infected with different numbers of Schistosoma mansoni cercariae under standard environmental conditions. Promutagenic methylation damage (O 6 -methyldeoxyguanosine; O 6 -MedG) was detected in liver DNA, but not in kidney, spleen or bladder DNA of infected animals. It was shown that levels of hepatic O 6 -MedG increased with increasing intensities of schistosomal infection. Possible mechanisms of action are discussed. These include the activating effects of schistosomes and their products on murine macrophages and subsequent endogenous formation of N-nitroso compounds by the activated macrophages

Radioimmunoassays (RIAs) have been used to detect the promutagenic lesion O6-methyldeoxyguanosine (O6-MedG) in DNA isolated from the bladder tissues of Egyptian patients presenting with bladder carcinoma and concomitant schistosomiasis (bilharziasis), a parasitic disease known to be associated with the presence of N-nitrosamines in the urine. Alkylation damage was present in the DNA of the majority of the samples (44/46, 96%); 38 samples were of tumour tissue and 8 from uninvolved bladder mucosa. Levels of O6-MedG ranged from undetectable (ND; i.e. less than 0.01 mumol O6-MedG/mol dG) to 0.485 mumol/mol dG with an overall mean of 0.134 +/- 0.10 mumol/mol dG, including the two samples that were below the limit of detection. In contrast, methylation damage was detected in only 4/12 (33%) of the DNA samples from normal bladder tissue of European origin. In these samples levels of O6-MedG ranged from ND to 0.225 mumol/mol dG with an overall mean of 0.046 +/- 0.082 mumol O6-MedG/mol dG. These results confirm that alkylation events can be detected in the DNA of schistosome-infected human bladder tissue. The methylation of uninvolved and tumour tissue DNA to similar extents suggests that the alkylating intermediate may have been present in the urine. These results indicate the need for further investigation to determine whether relationships exist between levels of DNA damage and the prevalence of schistosome infection and/or the extent and type of bacterial infection that frequently accompanies this disease.

Two direct-acting mutagens, N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU), and two agents requiring metabolic activation, 1-2-dimethylhydrazine (DMH) and N-nitrosodimethylamine (NDMA), were administered i.p. to mice. Sections of crypts of the small intestine were assayed for acute histological cell death at various times up to 12 h after treatment. Dead or dying cells exhibited the typical light microscopic morphological features of apoptosis. The incidence of apoptosis at each cell position along the side of longitudinal crypt sections was recorded and frequency plots of the incidence against cell position were determined. NEU (50 mg/kg) produced the highest incidence of cell death but this was closely followed by NDMA (50 mg/kg) and NMU (200 mg/kg). DMH (40 or 80 mg/kg) was the least cytotoxic but even here significantly elevated levels of cell death were observed. The highest incidence of cell death occurred 4-5 h after treatment with NEU, NMU and DMH and at 6 h after NDMA. The data obtained at 4 h after NEU suggest that approximately 22 cells out of a total crypt population of 250 cells are killed, but that for some cell positions near the crypt base (stem cell regions) up to 24% of the cells may be killed. Analysis of the changing shape of the frequency plots with time after treatment enabled the target cell position in the crypts for cytotoxicity to be estimated. This was at cell position 4 for NEU, NMU and DMH and at cell position 5 for NDMA. The stem cells in the crypts are believed to be located at the fourth cell position and hence at least NEU, NMU and DMH are targeting the stem cells with some specificity.

A rat O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA has been isolated from a rat liver cDNA library by hybridization with the human homologue. The candidate 806 bp cDNA was sequenced and shown to contain a 630 bp open reading frame that could encode a protein of 22.2 kd. Fluorography of labelled ATase indicates a 24 kd protein which is consistent with several previous reports. The derived amino acid sequence demonstrated 81% similarity with the human ATase and 94% identity over a 67 residue region encompassing the putative alkyl acceptor site. Peptide sequences derived from cleaved homogeneous rat ATase have been located in the predicted protein providing additional confirmation of the identity of the cDNA. A 1.05 kb mRNA has been detected in rat liver by Northern analysis; treatment of adult rats with 2-acetylaminofluorene causes an approximately 10-fold induction of this message in liver. Following site directed mutagenesis of the 806 bp cDNA, the 630 bp protein coding sequence has been ligated into an Escherichia coli expression vector to achieve ATase levels of greater than 3% of total protein in bacterial extracts.

Further evidence for the preferential interaction of carcinogens with mitochondrial DNA (mtDNA) has been obtained. In rats treated with high doses of N-nitrosodimethylamine (NDMA) or N-nitroso-N-butylurea (NBU), hepatic mtDNA contains 1.4 times more O6-methyl-2'-deoxyguanosine (O6-MedG) or 2.3 times more O6-butyl-2'-deoxyguanosine (O6-BudG) than does nuclear DNA (nDNA). The kinetics of removal of O6-MeG from mtDNA and nDNA are similar at both high (20 mg/kg) and low (2 mg/kg) doses of NDMA, and the removal of O6-MeG can be increased by pretreating the animals with 2-acetylaminofluorene (AAF), indicating that O6-MeG is repaired in the mitochondrion by a mechanism similar to that which functions in the nucleus. In contrast, O6-BudG is removed very slowly from mtDNA and rapidly from nDNA, an observation which is consistent with the absence of a nucleotide excision mechanism in the mitochondrion and the repair of O6-BudG, predominantly by an excision mechanism, in the nucleus of mammalian cells. A 23-kd methyltransferase (MT) protein, similar to the one found in the nucleus, has been isolated from hepatic mitochondria and is present in mitochondria from which the outer membrane has been removed. It is suggested that O6-MeG, but not O6-BuG can be repaired from mtDNA by a MT protein that is nuclear encoded and transported across the mitochondrial membrane.

A 10-16 fold increase in rat liver cytoplasmic DNA polymerase (DNA polymerase-alpha) was observed by 24 hrs after two thirds partial hepatectomy. Injection of either N,N-dimethylnitrosamine (DMN) or methyl methanesulphonate (MMS) At 6 or 12 hrs after partial hepatectomy completely inhibited this increased production of polymerase, but when given at 20 hours they had less effect. Neither compound altered the molecular size distribution of the enzyme. These data indicate that the lowered levels of DNA polymerase-alpha could play a major role in the reduction in DNA synthesis which occurs after carcinogen treatment.

Methylated purines were determined in the liver and kidney DNA of rats that had been pretreated for several weeks by inclusion of 2-acetylaminofluorene in the diet and then given single injections of N,N-dimethylnitrosamine. In comparison ith relevant controls the capacity to remove O(6)-methylguanine from the livers of the pretreated animals was enhanced but there was no evidence for a similar effect in kidney. No market effects of this pretreatment were observed for the removal of 3-methyladenine or 7-methylguanine. The data indicate that an inducing agent may affect the capacity of an animal to repair DNA which is subsequently damaged by another agent of chemically different identity. The mechanisms involved are not clear but potentially these observations have wide implications when organisms are exposed to a variety of chemicals.

Exposure to phenobarbital (PB) (0.05% in drinking water) markedly increased the rate of repair of O6-methylguanine (O6-MeG) from the hepatic DNA of rats given N-nitrosodimethylamine (2 mg/kg). No effect of comparable magnitude was seen for the repair of O4-methylthymine. During 21 weeks of exposure to PB the increased repair of O6-MeG exhibited a biphasic response and was maximal at approximately 3 weeks of treatment. Although this increased repair was readily observed when direct measurements were made of the loss of O6-MeG from hepatic DNA in vivo, no corresponding increased level of methyltransferase activity was detected in cell-free liver extracts, indicating that the methyltransferase protein was induced in a relatively limited population of cells. Immunohistochemical procedures have been used to demonstrate the formation of O6-MeG in, and its repair from, the DNA of hepatocytes in the centrilobular region of the liver lobule. Comparison with published data, for changes in the level of asialoglycoprotein receptors [Evarts et al. (1985) Carcinogenesis, 6, 1767-1773] and for the induction of cytochrome P450 [Schwartz et al. (1987) Carcinogenesis, 8, 1355-1357] in hepatocytes during PB administration, indicate that PB is acting at membrane sites in a relatively limited population of cells associated with the central vein. These observations show that the methyltransferase activity responsible for the repair of the major promutagenic base O6-MeG can be induced by a membrane active agent, without recourse to the genotoxic action of initiators and toxins, or the induction of restorative hyperplasia, previously employed for this purpose.

The enhanced repair of O6-methylguanine from hepatic DNA in rats is a well established phenomenon that can be induced by pretreatment with a variety of hepatotoxic agents as well as by partial hepatectomy. Attempts to induce a similar hepatic response by treatment with single doses of aflatoxin B1 in C57Bl mice, single doses of dimethylnitrosamine (DMN) in C57Bl or BALB/C mice or by prolonged pretreatment with DMN by addition to the drinking water of C57Bl mice were uniformly unsuccessful. Furthermore, the intense proliferative response induced by two-thirds partial hepatectomy in C57Bl mice was also apparently incapable of increasing the activity of this repair function. These experiments, in which repair of O6-methylguanine has been determined both in vivo after administration of [14C]DMN and in vitro using crude tissue extracts and a methylated DNA substrate, indicate the presence of an intergeneric difference between rats and mice with respect to this repair function.