Search

In May/June 2011, the new Shiga-like toxin-producing Escherichia coli (STEC) strain O104:H4 caused the severest outbreak ever recorded of hemorrhagic enterocolitis in 3842 patients in Germany.As bacterial enterocolitis is an established risk factor of subsequent irritable bowel syndrome (IBS), we aimed to estimate prevalence and incidence of post-infectious (PI)-IBS after six and 12 months in a cohort of STEC O104:H4 patients and to prospectively identify associated somatic and psychometric risk factors.A total of 389 patients were studied prospectively at baseline and at six and 12 months after STEC infection using STEC disease-related questionnaires and validated instruments for IBS (Rome III) and psychological factors. Frequencies and logistic regression models using multiple imputations were applied to assess predictor variables.Prevalence of IBS increased from 9.8% prior to STEC infection to 23.6% at six and 25.3% at 12 months after STEC infection. In patients without IBS symptoms prior to STEC infection, incidence of new IBS was 16.9%. Logistic regression models indicated higher somatization and anxiety scores as risk factors for, and mesalazine treatment during, STEC infection as the only significant protective factor against IBS. No other factor analyzed, including disease severity, showed an association.PI-IBS rates following this unusually severe STEC outbreak were similar to what has been observed after other infectious gastroenteritis outbreaks. Our findings suggest that mesalazine may have reduced the risk of subsequent PI-IBS. As altered mucosal immune activity is a pivotal pathogenic factor in PI-IBS, our observation of a potential protective effect of mesalazine might be explained by its known modulatory action on mucosal immunity, and may warrant further investigation.

The nuclear factor of kappa light polypeptide gene enhancer B-cells inhibitor-alpha (NFKBIA) gene encodes a member of the nuclear factor-kappa-B inhibitor family. Polymorphisms in this gene might be associated with a susceptibility to acute rejection episodes following liver transplantation, as they may cause an increased activation level of the proinflammatory transcription factor nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB). The aim of this study was to evaluate whether the NFKBIA polymorphisms -297 C/T (rs2233409), -826 C/T (rs2233406) and 126 G/A (rs696) affect the incidence of acute liver graft rejection. A total of 199 liver transplant recipients was analyzed, 100 without (NAR) and 99 with early acute rejection (AR). Thirty-two individuals with multiple acute rejections (MAR) were analyzed as a subgroup of AR. Polymerase chain reaction-allele specific restriction enzyme analysis (PCR-ASRA) and allele-specific hybridization with fluorescence resonance energy transfer (FRET) were used for genotyping. We identified the genotype NFKBIA 126 AA (P = 0.002) as well as the haplotype NFKBIA-126A-297T-826T (P = 0.002) as a potential risk factor for the occurrence of recurrent acute rejections. Furthermore, we assessed an association between the 126 A allele and susceptibility to recurrent acute rejections (P = 0.027). Our data suggest that the NFKBIA 126 G/A polymorphism might be potentially helpful to identify liver transplant recipients with an increased susceptibility to develop recurrent acute rejections.

Summary This study was carried out to evaluate the association between 77C>G transversion (rs17612648) in exon A of the PTPRC gene and liver transplant rejection. No significant differences in genotype and allele frequencies of the 77C>G transversion were detected between recipients without rejection (n = 106) and recipients with rejection (n = 104). In conclusion, there was no evidence for the contribution of the 77C>G transversion in susceptibility to liver transplant rejection in a Caucasian population.

Bronchopulmonary dysplasia (BPD) is a common perinatal complication of very low birth weight preterm infants with a significant risk of long-term disability and morbidity. While clinical conditions such as prematurity and mechanical ventilation are its major risk factors, studies suggest that there is an individual susceptibility to BPD. This comprehensive review summarizes data collected about the implication of genetic polymorphisms in BPD and in its risk factors. Some studies have directly related the risk of BPD to genotype. Indeed, carrier states of genetic variants of cytokines (IFNgamma T+874A), adhesion molecules (L-selectin-Pro213Ser), elements of renin-angiotensin system (ACE-I/D), antioxidant enzymes (GST-P1 Val105Ile), and surfactant proteins (SPA1, SPB intron 4) has been identified as risk factors to BPD. Other studies investigated the role of genotype in BPD risk factors. Premature birth has been linked to carrier states of genetic variants with an impact on immune status (such as IL-6 G(-174)C, MBL2 54G/A, VEGF G+405C, HSP72 A+1267G genes) and matrix metalloproteases. Fetal inflammatory response syndrome, a major determinant of BPD is also affected by genotype (including LTalpha A+250G). Disturbed intrauterine lung development and vascularization may also contribute to BPD; these processes may be impaired in the presence of some rare genetic mutations. Furthermore, there is also a genetic component in the susceptibility to other perinatal adaptational disturbances such as respiratory distress syndrome that are associated with an increased need for mechanical ventilation, and, hence, with lung damage. The genetic variants presented in this article may help to identify infants at risk for BPD.

Background: Studies have shown an association between altered expression of selectins and premature birth, early sepsis and bronchopulmonary dysplasia. Aim: To investigate the possible link between functional polymorphisms of the E-, P- and L-selectin genes and perinatal morbidity. Methods: We compared the genotype distribution of the E-selectin Ser128Arg, P-selectin Thr715Pro and L-selectin Pro213Ser polymorphisms in 125 low-birthweight singleton infants with those of 156 healthy term neonates. We also analysed the association of genotype with risk of sepsis and bronchopulmonary dysplasia. Results: We found no association between E-selectin or P-selectin polymorphisms and premature birth, nor did we find any association between E-selectin or P-selectin and early postnatal sepsis or bronchopulmonary dysplasia. Carriers of the 213Ser L-selectin allele were found to be more prevalent in low-birthweight infants, particularly in those with bronchopulmonary dysplasia. We found no association between the L-selectin polymorphism and early postnatal sepsis. Conclusion: Our results underline the importance of L-selectin in perinatal pathology, but further studies are needed to evaluate the alteration of L-selectin levels in carriers of the 213Ser allele and their possible contribution to premature birth and bronchopulmonary dysplasia.

Background Amplification of c-myc is a common genetic alteration and associated with a poor prognosis in a variety of cancers. Extra copies of the gene have been found in large numbers of melanoma metastases, but only few primary tumours have been studied. We investigated the c-myc copy number alterations in two different subtypes of primary melanomas with different biological behaviours. Methods Fluorescence in situ hybridisation was performed using c-myc and centromeric 8 (C8) probes on 68 lesions (28 nodular melanomas [NMs], 26 superficial spreading melanomas [SSMs], and 14 metastases). To assess the ploidy pattern, copy number distribution of seven different chromosomes was also investigated. Results All tumours showed aneuploid populations for at least three chromosomes. Whereas 61% of the NMs exhibited extra c-myc copies, only 27% of SSMs showed increased gene dosage. The c-myc/C8 ratio exceeding 1.5 was significantly higher in NMs (P = 0.01). High level amplification was seen only in NMs. An elevated c-myc/C8 ratio was higher than 1.5 in only four metastases. Conclusion Our data show that c-myc copy number alterations differ in the two melanoma subtypes and are associated with the advanced stage of the disease. The less frequent amplification of the c-myc gene in metastatic lesions indicates that it may play an important role in the development of an invasive potential rather than in the metastatic process. © 2004 Wiley-Liss, Inc.

Summary objective Several data indicate that endogenous sex steroids might influence left ventricular mass. Our aim was to examine the association between dehyroepiandrosterone-sulphate (DHEAS) levels and left ventricular mass index (LVMI) and ventricular septal thickness (VST) in pre- and in postmenopausal women with treated essential hypertension. patients and methods LVMI and VST were related to serum DHEAS in 26 pre- and in 34 postmenopausal women. The associations between DHEAS and LVMI, VST were adjusted for body mass index, duration of hypertension, systolic blood pressure, serum cholesterol and testosterone levels using a multiple regression model. results In premenopausal women there was a significant linear correlation between DHEAS and LVMI (P < 0·02) after adjustment for confounding variables. In contrast, DHEAS was inversely correlated with LVMI and VST in postmenopausal women (r = −0·49, P

Characteristic genetic changes underlying the metastatic progression of malignant melanoma is incompletely understood. The goal of our study was to explore specific chromosomal alterations associated with the aggressive behavior of this neoplasm. Comparative genomic hybridization was performed to screen and compare genomic imbalances present in primary and metastatic melanomas. Sixteen primary and 12 metastatic specimens were analyzed. We found that the pattern of chromosomal aberrations is similar in the two subgroups; however, alterations present only in primary and/or metastatic tumors were also discovered. The mean number of genetic changes was 6.3 (range 1-14) in primary and 7.8 (range 1-16) in metastatic lesions. Frequent losses involved 9p and 10q, whereas gains most often occurred at 1q, 6p, 7q, and 8q. Distinct, high-level amplifications were mapped to 1p12-p21 and 1p22-p31 in both tumor types. Amplification of 4q12-q13.1, 7q21.3-qter and 8q23-qter were detected only in primary tumors. The 20q13-qter amplicon was present in a metastatic tumor. The number of genetic alterations were significantly higher in primary tumors which developed metastases within one year after the surgery compared to tumors without metastasis during this time period. Fluorescence in situ hybridization with centromeric and locus-specific probes was applied to validate CGH results on a subset of tumors. Comparison of FISH and CGH data gave good correlation. The aggressive behavior of melanoma is associated with accumulation of multiple genetic alterations. Chromosome regions, which differ in the primary and metastatic lesions, may represent potential targets to identify metastases-related chromosomal alterations.

Purpose Uveal melanoma is a rare but very aggressive malignancy. Independently of the currently available therapies, 50 % of uveal melanoma patients will develop metastasis and the average survival time of these patients is only 2-8 months. Genetic and epigenetic background of uveal melanoma is not fully understood and useful prognostic markers for metastasis development are not well characterized. It was suggested that in various tumors cancer stem cells are responsible for the development of primary tumors and their metastases. In uveal melanoma, the role of cancer stem cells is not clear that’s why our aim with the present study was to investigate the expression of mRNA of stem cell markers. Methods Human uveal melanoma specimens were obtained from 31 enucleated patients at the University of Debrecen, Department of Ophthalmology. The expression of stem cell markers was studied by RT-PCR, using gene specific primers for FZD6, NES, NGFR, PROM1 and SOX10. Results mRNA for FZD6 and SOX10 could be detected in 100% of the investigated samples. NES, NGFR and PROM1 were present in 94%, 94% and 82%, respectively. Conclusion Results of our study demonstrate that certain stem cell markers are present in nearly all uveal melanoma specimens. Therefore, they are not suitable as prognostic markers. However, our findings that a high percentage of uveal melanomas express stem cell markers support the view that stem cell genes may play an important role in the development and progression of this aggressive cancer. Further studies are needed to evaluate the exact role of these markers and to explore potential therapeutic approaches to target cancer stem cells in human uveal melanoma. Grant support: TAMOP 4.2.2.A-11/1/KONV-2012-0025 (G.H.)

Purpose The expression of luteinizing hormone-releasing hormone (LH-RH) receptors has been demonstrated in various human cancers. Over the past decade, a direct receptor-mediated antiproliferative effect of analogs of LH-RH on tumor cells was proposed. The receptors for LH-RH on human tumors can also serve as targets for LH-RH analogs that can be linked to various cytotoxic agents. Methods In our study we investigated the expression of LH-RH and transcript forms of LH-RH receptor in human uveal melanoma specimens with RT-PCR using gene specific primers. LH-RH receptor protein were also evaluated by Western blot. Tumor specimens from 9 patients were collected at the University of Debrecen. Results Expression of mRNA for LH-RH receptor transcript forms were detected in 6 samples. No PCR products for pituitary type of LH-RH receptors were found. In our study 8 specimens expressed mRNA for the LH-RH ligand. The presence of specific LH-RH receptor protein was detected in tumor specimens by Western blotting. Conclusion We were able to detect the expression of LH-RH and transcript forms of LH-RH receptors in human uveal melanomas. Our results support the merit of further investigation of the expression of LH-RH receptors and its transcript forms in human ophthalmological tumors as well as the application of LH-RH analogs for receptor-based treatment of such malignancies. These observations signify the importance of the development of new LH-RH analogs with potential therapeutical applications.

During the perinatal period, preterm neonates face severe complications. These include disorders of the lung such as respiratory distress syndrome and chronic lung disease. The risk of complications depends on maturity, but data also suggest the existence of an inherited susceptibility. This may be due to genetic polymorphisms and inherited mutations. Reported associations between lung disease and polymorphisms of genes encoding proteins that regulate inflammation, vasoregulation and lung development helped the identification of specific genetic elements in perinatal respiratory disorders. In a minority of newborns inherited mutations such as those of surfactant protein encoding gene may be responsible for the development of perinatal lung disorders. Further studies are required to assess those genetic patterns that can be used for the identification of patients at risk. Key concepts: Perinatal respiratory disorders affect primarily preterm infants. These include idiopathic respiratory disorder, bronchopulmonary dysplasia. Inherited genetic polymorphisms may be a risk factor of these complications. Genetic polymorphisms with an impact on immune response, vasoregulation and lung development are extensively tested. Several associations between polymorphisms and disease were reported. Other data support the contribution of genetics to other perinatal complications that are risk factors for respiratory disorders. Rare mutations may also cause perinatal lung disorders in some infants. One day the results of these studies may serve as a basis for individualized therapy and risk assessment; currently we are far from this goal. Keywords: preterm neonate; genetic polymorphism; complication; idiopathic respiratory disorder; bronchopulmonary dysplasia