Educational trajectories after childhood cancer: When illness experience matters.

With the increase in survival from childhood cancer, research has increasingly focused on the educational and professional achievements of childhood cancer survivors. Yet, if large-scale studies provide an acute description of the current situation of childhood cancer survivors, little is known about their trajectories and the social processes shaping these trajectories. Using a qualitative methodology, drawing from a life course perspective, this study sought to describe the role of childhood cancer and its side effects in educational trajectories, as perceived by the participants. We investigated related processes of social adjustment to cancer, that is to say, choices or decisions that survivors related to the illness in the making of their career plans. Eighty long-term French childhood cancer survivors participating in the Euro2K longitudinal study were interviewed through in-depth, face-to-face interviews undertaken in 2011-2012. There were various types of impact described by respondents of the diagnosis of cancer on their trajectories. These varied according to gender. In women, childhood cancer tended to result in poor educational achievement, or in steering the individual towards a health care or child care occupation. This was justified by a desire to return the support that had been offered to them as patients. In men, however, childhood cancer led to a shift in career plans, because of physical sequelae, or because of concerns about their future health. Paradoxically, this limitation had a positive impact in their occupational achievement, as most of these men disregarded blue-collar jobs and chose more qualified white-collar occupations. Overall, findings suggest that childhood cancer influenced educational trajectories and, thus, socioeconomic status in adulthood, through mechanisms embedded in gender norms. These mechanisms could explain gender inequalities in educational achievement after childhood cancer reported in large-scale cohort studies.

Ultrasonic microscanning.

A detailed review is given of the application of high-frequency ultrasound (HFUS) at frequencies of 20 MHz and above for high-resolution, cross-sectional imaging of biological soft tissue. The state of the art of HFUS imaging systems is discussed with respect to the underlying engineering concepts, system designs, and available transducer technology. Furthermore, the dependency of the spatial resolution on the system's parameters is analysed. Skin imaging, eye imaging, small animal imaging for preclinical research, and intravascular ultrasound in coronary arteries for arteriosclerotic disease diagnostics are presented as examples for the application of HFUS imaging in medical diagnostics. It is shown that, in the frame of the indicated applications, ultrasound in the frequency range 20-100MHz gives a good compromise between the contrary demands for a good spatial resolution and a sufficiently large penetration depth of ultrasound waves into the tissue. Scanning schemes for the imaging of tissue morphology are considered, including spatial compounding as a multidirectional imaging technique.

Pharmacological and electrophysiological characterization of nine, single nucleotide polymorphisms of the hERG-encoded potassium channel.

BACKGROUND AND PURPOSE: Potencies of compounds blocking K(V)11.1 [human ether-ago-go-related gene (hERG)] are commonly assessed using cell lines expressing the Caucasian wild-type (WT) variant. Here we tested whether such potencies would be different for hERG single nucleotide polymorphisms (SNPs). EXPERIMENTAL APPROACH: SNPs (R176W, R181Q, Del187-189, P347S, K897T, A915V, P917L, R1047L, A1116V) and a binding-site mutant (Y652A) were expressed in Tet-On CHO-K1 cells. Potencies [mean IC(50); lower/upper 95% confidence limit (CL)] of 48 hERG blockers was estimated by automated electrophysiology [IonWorks HT (IW)]. In phase one, rapid potency comparison of each WT-SNP combination was made for each compound. In phase two, any compound-SNP combinations from phase one where the WT upper/lower CL did not overlap with those of the SNPs were re-examined. Electrophysiological WT and SNP parameters were determined using conventional electrophysiology. KEY RESULTS: IW detected the expected sixfold potency decrease for propafenone in Y652A. In phase one, the WT lower/upper CL did not overlap with those of the SNPs for 77 compound-SNP combinations. In phase two, 62/77 cases no longer yielded IC(50) values with non-overlapping CLs. For seven of the remaining 15 cases, there were non-overlapping CLs but in the opposite direction. For the eight compound-SNP combinations with non-overlapping CLs in the same direction as for phase 1, potencies were never more than twofold apart. The only statistically significant electrophysiological difference was the voltage dependence of activation of R1047L. CONCLUSION AND IMPLICATIONS: Potencies of hERG channel blockers defined using the Caucasian WT sequence, in this in vitro assay, were representative of potencies for common SNPs.

Using the FIB to characterize nanoparticle materials.

In the 1-100-nm size regime, the properties of materials can differ significantly from those of their bulk counterparts. The present study applies the focused ion beam (FIB) tool to the characterization of nanoscale structures for scanning and transmission electron microscopy. The strength of this method is its ability to manufacture samples that cannot be produced using traditional means. The films of nanoparticles examined here are examples of such systems; the films are found to be not fully dense, composed of chemically heterogeneous areas and mechanically different from the substrate. Distinct advantages of the application of the FIB for characterization of nanoscale structures are highlighted for several nanoparticle structures. This successful application of FIB techniques provides a pathway to integrate the study of nanoscale production techniques and their resulting structure-property relationships.

Strain imaging with intravascular ultrasound array scanners: validation with phantom experiments.

Intravascular Ultrasound (IVUS) is routinely used in interventional cardiology for imaging coronary plaque morphology. However, the use of B-mode images for tissue characterization and detection of vulnerable coronary plaques is limited. Strain imaging with ultrasound is a new modality that provides additional information for tissue characterization by imaging differences in tissue stiffness. The aim is to differentiate between vulnerable (soft) plaques and less dangerous calcified (hard) plaques. In this work, the applicability of a time efficient strain imaging algorithm in conjunction with data from IVUS array transducers is evaluated. Unfocused radiofrequency (rf) data from the transducer array is acquired using custom made hardware. Rf line reconstruction is performed offline by synthetic aperture focusing techniques. Vessel mimicking phantoms of different geometries and material stiffness are made from agar and Polyvinyl Alcohol Cryogel (PVA). Experiments are conducted in a water tank and a water column is used for applying intraluminal pressure differences required for strain imaging. The results show that strain images can be calculated with A-lines reconstructed from unfocused rf raw data. Regions of different stiffness can be identified qualitatively by local strain variations. With the used algorithm strains of up to 2% can be imaged without significant decor-relation.

Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component?

BACKGROUND AND AIMS: Inflammation may play a role in the pathogenesis of irritable bowel syndrome in some individuals, such as in those who develop symptoms following a dysenteric illness. Persisting inflammation, resulting from an imbalance of cytokines regulating the inflammatory response, is one possible mechanism. As the elaboration of cytokines is under genetic control, this study was designed to establish whether there might be a genetic predisposition to an altered pattern of anti-inflammatory cytokine production in patients with irritable bowel syndrome. SUBJECTS: A total of 230 unselected patients with irritable bowel syndrome and 450 healthy, ethnically matched controls were studied. METHODS: DNA was extracted from peripheral blood leucocytes of subjects. Allele and genotype frequencies were determined for the anti-inflammatory cytokine interleukin 10 at the site (-1082) concerned with production in lymphocytes. Transforming growth factor beta(1) (codons 10 and 25) genotypes were also examined in a smaller group of subjects. RESULTS: Patients with irritable bowel syndrome had significantly reduced frequencies of the high producer genotype for interleukin 10 than controls (21% v 32%; p=0.003). There was no apparent relationship with any particular bowel habit subtype. Genotypes for transforming growth factor beta(1) were not altered. CONCLUSIONS: These preliminary results suggest that at least some patients with irritable bowel syndrome may be genetically predisposed to produce lower amounts of the anti-inflammatory cytokine interleukin 10. This lends some support to the hypothesis that there may be an inflammatory or genetic component in some cases of this condition and that further studies in specific irritable bowel syndrome subgroups are justified.

Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients.

African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-beta). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p < 0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p < 0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL-10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes.

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production.

The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age- and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at -1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p = 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.

Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss.

Approximately one in 300 women experience recurrent pregnancy loss (RPL), the aetiology of which is unknown in at least 40% of cases. Previously, some studies have shown increased production of pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma) and reduced production of anti-inflammatory cytokines (interleukin-10) by circulating blood lymphocytes isolated from these patients when compared with controls. The reasons for this are unclear. The production of these cytokines are partly under genetic control. This study investigated whether polymorphisms in these three cytokine genes known to be associated with either high or low production, are associated with idiopathic RPL. No association was found. It may be that genetic factors are not a major determinant of cytokine production during pregnancy, or alternatively it may be that the observed differences in cytokine production by peripheral lymphocytes do not accurately indicate what is occurring at the local maternofoetal interface during successful and abortive pregnancies.

Cytokine gene polymorphisms in psoriasis.

BACKGROUND: Cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo. Psoriasis is associated with an overexpression in the involved skin of T-helper cell type 1 (Th1) cytokines, e.g. interferon (IFN) -gamma and tumour necrosis factor (TNF) alpha and relative underexpression of Th2 cytokines, e.g. interleukin (IL) -4 and IL-10. Objective We investigated the hypothesis that allelic variants of genes for a high production of Th1 cytokines or TNF-alpha, or conversely low production of Th2 cytokines might represent a risk factor for developing psoriasis. METHODS: Genotyping for IFN-gamma, IL-10, IL-4 and TNF-alpha was undertaken for 84 patients with psoriasis and compared with control data on file. RESULTS: Genotype frequencies showed no differences between patients and controls for IFN-gamma, TNF-alpha or IL-4. For IL-10, patients with late onset psoriasis (over 40 years) were more likely to be heterozygous at position - 1082 (P = 0.02), corresponding to intermediate production of IL-10 in vitro and in vivo. CONCLUSIONS: Psoriasis is not determined by a genotype consistent with high production of Th1 cytokines or low production of Th2 cytokines. Thus, the Th1 cytokine profile found in psoriatic plaques is most likely a consequence of local factors.

Axial strain imaging using a local estimation of the scaling factor from RF ultrasound signals.

The main signal-processing techniques used in elastography compute strains as the displacement derivative. They perform well for very low deformations, but suffer rapidly from decorrelation noise. Aiming to increase the range of accurate strain measurements, we developed an adaptive method based on the estimation of strains as local scaling factors. Its adaptability makes this method appropriate for computing scaling factors resulting from larger strains or a wide spread of strain variations. First, segments corresponding to the same part of tissue are adaptively selected in the rest and stressed state echo signals. Then, local scaling factors are estimated by iteratively varying their values until reaching the zero of the phase of the complex cross-correlation function. Results from simulation and from experimental data are presented. They show how this adaptive method can track various local deformations and its accuracy for strain up to 7%.

A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production.

We have described previously a variable length CA repeat sequence in the first intron of the human IFN-gamma gene and showed that allele #2 is associated with high in vitro IFN-gamma production. In a consecutive study, allele #2 was found to be associated with allograft fibrosis in lung transplant patients, confirming its role as a marker of high IFN-gamma production, both in vivo and in vitro. In this study we have sequenced 50 PCR products that had been typed previously by PAGE for the identification of CA microsatellite alleles. We report on a novel single nucleotide polymorphism, T to A, at the 5' end of the CA repeat region in the first intron of the human IFN-gamma gene (+874*T/A). There is an absolute correlation between the presence of T allele and the presence of the high-producing microsatellite allele #2. This T to A polymorphism coincides with a putative NF-kappa B binding site which might have functional consequences for the transcription of the human IFN-gamma gene. Therefore, the T to A polymorphism could directly influence the level of IFN-gamma production associated with the CA microsatellite marker.

Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation.

BACKGROUND: In vitro production of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin 10 (IL-10), and transforming growth factor-beta (TGF-beta) correlate with their respective genetic polymorphisms. We analyzed the relationship between these genetic polymorphisms and posttransplant outcome. METHODS: Using DNA polymerase chain reaction (PCR) technology, polymorphisms for TNF-alpha, IFN-gamma, IL-10, and TGF-beta were determined for 82 kidney (K) and 19 simultaneous kidney-pancreas (SKP) recipients. These results were analyzed with regard to the incidence of acute rejection (AR), and the timing and severity of the first AR episode. RESULTS: A high TNF-alpha production phenotype correlated with recurrent acute rejection (AR) episodes (P<0.026). Compared with the low TNF-alpha production phenotype, more patients with the high production phenotype had a post-AR serum creatinine >2.0 mg/dl, but this was not statistically significant (64 vs. 35%, P=0.12). There was no relationship between TNF-alpha genotype and the time to first AR episode or incidence of graft loss. IFN-gamma production phenotype showed no correlation with any of these clinical outcome parameters. There was an increase in AR incidence as the IL-10 production phenotype increased (low, intermediate, high), but only in low TNF-alpha producer phenotypes (P=0.023). CONCLUSIONS: Patients with a polymorphic cytokine genotype putatively encoding for high in vivo TNF-alpha production, and to a lesser extent IL-10 cytokine genotypes putatively encoding for higher levels of in vivo IL-10 production, had a worse clinical outcome regarding AR episodes. These data support the hypothesis that the strength of alloimmune responsiveness after transplantation in part is genetically determined.

The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection.

BACKGROUND: The occurrence of acute rejection in orthotopic liver transplantation is unpredictable. The role of cytokines in the process of rejection is not entirely clear. We investigated polymorphisms in the genes encoding tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and transforming growth factor (TGF)-beta1, which affect the amount of cytokine produced in vitro, in a liver transplant population to determine any association with acute rejection. METHOD: DNA was extracted from whole blood of liver transplant patients. After amplification with polymerase chain reactions, the polymorphisms at TNF-alpha -308, IL-10 -1082, and TGF-beta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Acute cellular rejection was a clinical and histological diagnosis. RESULTS: Acute cellular rejection requiring treatment occurred in 68 (48%) of 144 patients. Acute cellular rejection was significantly associated with the TNF-alpha -308 A/A genotype (P<0.02). There was no significant association with either IL-10 or TGF-beta1 polymorphisms in acute rejection. CONCLUSION: Patients with a homozygous TNF-alpha -308 genotype A/A are more likely to suffer from acute cellular rejection after liver transplantation.

Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease.

OBJECTIVE: To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNFalpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1) and end-stage liver disease. METHODS: Whole-blood samples were taken from patients attending the Scottish Liver Transplant Unit with end-stage liver disease (primary biliary cirrhosis, n = 61; alcoholic liver disease, n = 25; primary sclerosing cholangitis, n = 17; viral disease, n = 8; type 1 auto-immune hepatitis, n = 8; acute liver failure, n = 20). DNA was extracted and the polymorphisms at positions TNF -308, IL-10 -1082 and TGFbeta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Samples were also analysed from normal healthy controls. RESULTS: There was a significant difference between patients with primary sclerosing cholangitis and healthy controls, with 65% of patients (11/17) possessing at least one TNF2 allele (A at position -308) compared with 38% of controls (P = 0.02). Four of the eight patients with auto-immune hepatitis were homozygous for TNF2 while the other four were heterozygous (P = 0.001). No significant difference between controls and patients was seen in polymorphisms for IL-10 or TGFbeta1. No association between genotype and Child's class was found in primary biliary cirrhosis. CONCLUSION: Patients with primary sclerosing cholangitis and auto-immune hepatitis are more likely to possess TNF2 than normal controls. This allele has been associated with an increased production of TNFalpha in vitro and may indicate a predisposition to these inflammatory conditions.

CA repeat allele polymorphism in the first intron of the human interferon-gamma gene is associated with lung allograft fibrosis.

Interferon-gamma (IFN-gamma) is an inflammatory cytokine that has been implicated in the development of fibrosis in inflamed tissues. In this study we have analysed the association between genetically-determined high IFN-gamma production and development of fibrosis in lung transplants. The human IFN-gamma gene has a variable length CA repeat in the first intron. Our previous study showed that polymorphism of this microsatellite is associated with individual variation in the levels of IFN-gamma production. In vitro production of IFN-gamma showed significant correlation with presence of allele #2 (p < 0.01). In this study allele #2 was found to be associated with allograft fibrosis defined by transbronchial biopsy. An analysis of two groups of lung transplant recipients showed a significant increase in the frequency of allele #2 in the group which developed fibrosis after transplantation compared to the group that did not (p < 0.005). We postulate that the production of IFN-gamma, which is under genetic control, can influence the development of fibrosis in lung allografts.

In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene.

The DNA sequence of the human IFN-gamma gene shows the presence of a variable-length CA repeat in the first intron of the gene. We investigated the allele distribution of this microsatellite region in 164 unrelated healthy individuals, and the association with interferon-gamma (IFN-gamma) production. In vitro production of IFN-gamma showed a significant correlation with the presence of allele #2.