pylori-associated conditions. Aim:  The aim of this study was to investigate whether the birth cohort effect of H. pylori observed between 1978 and 1993 continued in subsequent years. Methods:  Anti-H. pylori IgG antibodies and anti-CagA IgG antibodies were determined in serum samples obtained in 2005/2006 from 545 Dutch children Silmitasertib price aged 7–9 years who participated in the Prevention and Incidence of Asthma and Mite Allergy birth cohort. The H. pylori and CagA antibodies were determined by enzyme-linked immunosorbent assays that have been extensively validated in children, with a 94% sensitivity for H. pylori colonization and

a 92.5% sensitivity for colonization with a cagA-positive strain. Results:  Of the 545 children (M/F 300/245), most (91.5%) were of Dutch descent. The H. pylori positivity rate was 9% (95% CI 6.6–11.4%). The prevalence of CagA antibodies was 0.9% (95% CI 0.1–1.6%). No significant differences were demonstrated in H. pylori and cagA prevalence in relation to gender or ethnicity. Conclusion:  The prevalence of H. pylori in childhood has remained stable in the Netherlands from 1993 to 2005, suggesting a stabilization of the previously decreasing trend in subsequent birth cohorts. This finding

may reflect stabilization in determinants such as family size, housing, and hygienic conditions (or offset by day care). If confirmed in other populations in developed countries, it implies that colonization with H. pylori will remain common in the coming decades. Remarkably however, the rate of colonization with cagA+H. pylori strains has become very low, consistent with prior Volasertib clinical trial observations that cagA+ strains are disappearing in Western countries. “
“The current therapy for Helicobacter pylori infection includes antimicrobial agents and 上海皓元 proton pump inhibitors. We have examined the ability of Lactobacillus spp. to inhibit H. pylori infection. Probiotic strains isolated from samples of adult feces, infant feces, breast milk, and vaginal swab collected from healthy volunteers in Taiwan and commercially

available strains were screened for antagonism toward H. pylori. Inhibition liquid culture assay was used to screen potential anti-H. pylori activity. Then, we performed agar plate inhibition assay, and assays to determine the capacity of probiotics for adhesion, and inhibition and killing of H. pylori, and measured the levels of IL-8 and IL-10. Using animal models, we studied regulation of gastric acid and histopathological changes accompanying anti-H. pylori activity. We found that six of the tested strains suppressed urease activity of H. pylori: Lactobacillus acidophilus TYCA08, L. acidophilus TYCA15, L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32 were more effective than the others. In vivo, L. johnsonii MH-68 and L. salivarius subsp. salicinius AP-32 alone or in combination, reduced the H.

pylori-associated conditions. Aim:  The aim of this study was to investigate whether the birth cohort effect of H. pylori observed between 1978 and 1993 continued in subsequent years. Methods:  Anti-H. pylori IgG antibodies and anti-CagA IgG antibodies were determined in serum samples obtained in 2005/2006 from 545 Dutch children selleckchem aged 7–9 years who participated in the Prevention and Incidence of Asthma and Mite Allergy birth cohort. The H. pylori and CagA antibodies were determined by enzyme-linked immunosorbent assays that have been extensively validated in children, with a 94% sensitivity for H. pylori colonization and

a 92.5% sensitivity for colonization with a cagA-positive strain. Results:  Of the 545 children (M/F 300/245), most (91.5%) were of Dutch descent. The H. pylori positivity rate was 9% (95% CI 6.6–11.4%). The prevalence of CagA antibodies was 0.9% (95% CI 0.1–1.6%). No significant differences were demonstrated in H. pylori and cagA prevalence in relation to gender or ethnicity. Conclusion:  The prevalence of H. pylori in childhood has remained stable in the Netherlands from 1993 to 2005, suggesting a stabilization of the previously decreasing trend in subsequent birth cohorts. This finding

may reflect stabilization in determinants such as family size, housing, and hygienic conditions (or offset by day care). If confirmed in other populations in developed countries, it implies that colonization with H. pylori will remain common in the coming decades. Remarkably however, the rate of colonization with cagA+H. pylori strains has become very low, consistent with prior selleck screening library observations that cagA+ strains are disappearing in Western countries. “
“The current therapy for Helicobacter pylori infection includes antimicrobial agents and MCE公司 proton pump inhibitors. We have examined the ability of Lactobacillus spp. to inhibit H. pylori infection. Probiotic strains isolated from samples of adult feces, infant feces, breast milk, and vaginal swab collected from healthy volunteers in Taiwan and commercially

available strains were screened for antagonism toward H. pylori. Inhibition liquid culture assay was used to screen potential anti-H. pylori activity. Then, we performed agar plate inhibition assay, and assays to determine the capacity of probiotics for adhesion, and inhibition and killing of H. pylori, and measured the levels of IL-8 and IL-10. Using animal models, we studied regulation of gastric acid and histopathological changes accompanying anti-H. pylori activity. We found that six of the tested strains suppressed urease activity of H. pylori: Lactobacillus acidophilus TYCA08, L. acidophilus TYCA15, L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32 were more effective than the others. In vivo, L. johnsonii MH-68 and L. salivarius subsp. salicinius AP-32 alone or in combination, reduced the H.

In the first set of experiments

we confirmed that an increased number of vessels within the liver is a characteristic Autophagy Compound Library feature of experimental liver fibrosis. In the CCl4 model, vessel formation was associated with strong expression of the pivotal proangiogenic growth factor VEGF and its receptor VEGFR2, which have been earlier considered a prerequisite for fibrogenesis in vivo. 25 Notably, all of these features were strongly augmented in Cxcr3−/− mice compared with their WT littermates, providing the first evidence that this chemokine pathway displays a nonredundant functional role in liver neoangiogenesis. As angiogenic as well as angiostatic chemokines were induced by CCl4, we speculate that the increased expression of the Cxcr3 ligands Cxcl9 and Cxcl10 are part of a feedback loop in response to liver damage. However, as angiogenesis and fibrosis

are considered to develop in parallel in chronically damaged liver, 26 the question of a primary effect of Cxcr3 ligands SRT1720 nmr on angiogenesis or fibrogenesis remains obscure at this point. We therefore used a bitransgenic mouse model with a strong systemic overexpression of VEGF to further assess the direct impact of this angiogenic growth factor on liver fibrogenesis and intrahepatic chemokine expression. VEGF overexpression indeed led to a fibrogenic tissue response within the liver as determined by significantly increased Col1a1 mRNA and hydroxyproline concentrations, although frank scar formation was not evident after 4 weeks by Sirius red staining. Notably, VEGF overexpression also strongly increased intrahepatic concentrations of Cxcl9, suggesting a functional feedback loop between the molecules. As CXCR3 agonists in humans have been shown to directly

interfere with VEGF signaling, 17, 27 we next assessed whether there is a direct biological interaction between VEGF and Cxcl9 on target cells. Indeed, Cxcl9 repressed proliferatory and migratory effects as well as tube formation of VEGF-stimulated endothelial cells. As Cxcl9 does not directly inhibit VEGF secretion from liver cells (data not shown), these effects appear to be mediated by direct interference of Cxcl9 with the VEGF signaling pathway, as 上海皓元 described for Cxcl4. 27 As endothelial and stellate cells are considered strong contributors to angiogenesis and fibrogenesis, 22, 28 we also evaluated the inhibitory potential of Cxcl9 on the interaction between these cell types. Indeed, Cxcl9-treated endothelial cells were less potent in inducing stellate cell migration and proliferation. Because these in vitro results suggested a possible direct effect of Cxcl9 on multiple aspects of chronic liver damage, we next assessed the feasibility of amelioration of liver damage in vivo by therapeutic application of Cxcl9.

5 g/kg) or insulin (1.0 U/kg). Blood glucose levels were determined with a diabetes monitoring kit (Roche Diagnostics, IN). Insulin XAV-939 resistance was assessed with the homeostasis model assessment of insulin resistance (HOMA-IR) as follows10: The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and plasma homocysteine measurements, the liver lipid extraction and analysis, the primary hepatocyte isolation, the extractions and analysis of RNA and whole cell

or nuclear proteins, and the liver histology by hematoxylin and eosin (H&E), Sirius red, and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining were described previously.11, selleck products 12 The primers are listed in Supporting Table 1. Histological changes were confirmed by a pathologist blinded to the genotypes. The quantitation of Sirius red staining was performed with ImageJ software from the National Institutes of Health. Values are expressed as means and standard errors of the mean unless otherwise indicated. Statistical analyses were performed with the Student t test for paired data when each group of animals were from one litter and for unpaired data when each group of animals were from two or more litters or with an analysis of variance for the comparison of multiple

groups. P values < 0.05 were considered statistically significant. The supporting information includes information on breeding, insulin detection, antibodies, immunoblotting, MCE Phos-tag gel use, proteasome activity, electron microscopy, DNA microarrays, two-dimensional difference gel electrophoresis, and mass spectrometry. Mice with a liver-specific Grp78 deletion [i.e., Grp78f/f Alb-CreTg/0 or liver-specific glucose-regulated protein 78 knockout (LGKO) mice] were generated (Supporting Fig. 1A,B). The liver-specific deletion was detected in genomic DNA from the livers of LGKO mice but not from their

kidneys (Supporting Fig. 1C). The GRP78 protein level was reduced by 35% to 70% between the ages of 30 and 90 days in the LGKO mouse liver versus the WT mouse liver (Fig. 1A,B). The protein level was reduced by 15% to 25% in the GRP78 heterozygous [i.e., Grp78f/w Alb-CreTg/0 (WK)] mice in comparison with the WT mice between the ages of 30 and 90 days (Supporting Fig. 1D). The immunohistochemistry of liver tissue with anti-GRP78 antibodies confirmed the decrease in the liver GRP78 levels (Supporting Fig. 1E). Some of the remaining brown spots were identified as possible stromal cells in which Alb-Cre was not active. The viability rate for primary hepatocytes from LGKO mice was 68%, whereas the viability rate for primary hepatocytes from WT or WK mice was greater than 90%.

22,51 Hepatocytic differentiation proceeds following

exposure to fibronectin27 in the absence of Notch signaling.22 Allen Cowley Jr, Chairman of Physiology at the University of Wisconsin and editor of Physiological Genomics, has written: “At its core, systems biology represents a renewed recognition that biology is best understood by taking a coordinated, integrative systems view. In practice, systems biology means the application of many currently defined disciplines with the goal of bringing together information from the smallest units of the biological system (genes) to help understand the function of the whole organism.”52 Certainly, studies of individual cell types, specific cell: cell interactions, molecular intracellular signaling pathways, and genomic analyses have elucidated many DR mechanisms and behaviors. However, the point of cell and molecular biology reductivism was selleckchem to make things simple enough to study when our tools were insufficiently Ivacaftor price complex for modeling cell:cell and cell:matrix interactions at the tissue level. We should not lose sight of the actual goal, however, of reintegrating these data

into what might be considered a sub-branch of systems biology as considered by Dr Cowley, namely, tissue biology, the level of scientific analysis most appropriate to considerations by academic pathologists who concern themselves, first and foremost, with considerations of the tissue level of scale.25,53,54 DRs, similar to all stem cell systems in all organs, fully reveal their physiologic behaviors only at the tissue level.47,48,55 Thus, a tissue biology approach is needed for full understanding. Complexity theory suggests that cells and matrix interact as members of complex adaptive systems.54,56,57

Such systems can change their community-level self-organization so that the community as a whole can adapt to a changing environment. This approach opens up the possibility of computerized, agent-based modeling of cell:cell and cell:matrix interactions to test hypotheses generated from molecular and cell biological data.54,58 This class of computational modeling simulates the actions and interactions of autonomous agents (such medchemexpress as cells and matrix elements) with a view to assessing their effects on the system as a whole. This methodology has been fruitfully and extensively applied in studying the participation of hematopoietic stem cells in homeostasis or in pathophysiology, in particular neoplasia (reviewed by Roeder59). A recent application to liver disease has been presented by Hoehme et al. in which they modeled data derived from immunohistochemistry and confocal microscopy of murine hepatic regeneration following CCl4 injury.

Patients’ demographic characteristics, base-line liver biochemistry and HBV serological

markers were recorded. Liver biopsy was performed simultaneously with LSM. All patients started on treatment had high ALT, serum HBV DNA>2,000 IU/ml and compensated liver disease. ALT was monitored every 3 months and HBV DNA every 6 months. LSM was repeated annually. Results; Two hundred and forty of the 587 patients were started on antiviral treatment, 347 were observed without treatment. Male to female ratios in treated and untreated patients were 97/143 and 140/207, respectively. Mean ages were 35.8±13.0 and 38.1±11.9 (p=0.029). Eighty (33.3%) patients in the treatment group and 55 (15.9%) in the non-treatment GSK1120212 manufacturer group were HBe Ag positive. Mean baseline HBV DNA in the treatment group was 5.5±2.3 log 1 0IU, and ALT was 117±189. Baseline liver histology in the 123 patients (51.3%) undergoing LB revealed F4 fibrosis in 27 (22.0%) patients, F3 in 28 (22.8%), F2 in 33 (26.8%) and F0-1 in 35 (28.5%). Initial LSM results in patients receiving treatment and those observed without treatment were 8.3±4.6 and 6.6±3.2, respectively (p<0.001). Comparison of LB and LSM results revealed a positive correlation between fibrosis scores (r=0.291; p<0.001). A total of 48.3% (n=1 16) of patients received teno-fovir, 26.7% entecavir (n=64), 12.5% telbivudin

(n=30) and 12.5% lamivudin (n=30). There was no significant difference between pre-treatment LB and LSM results among antiviral drugs (p>0.05). Mean Ku-0059436 datasheet duration of monitoring was 2.8±1.3 in patients receiving antiviral treatment and 2.3±1.2 in patients not receiving treatment. 上海皓元医药股份有限公司 At the end of monitoring, improvement was seen at LSM in patients receiving antiviral treatment (7.4±3.9) (p<0.001), but no difference was observed in the untreated group (7.0±4.3) (p=0.561). There was no difference among the antiviral drugs in terms of fibrosis improvement (p>0.05). Conclusion; Since LSM is correlated with liver biopsy and is non-invasive

and reproducible, it can be used in the diagnosis and long-term monitoring of CHB patients. It is a non-invasive test that also contributes to patients’ compliance with treatment. Disclosures: Iftihar Koksal – Advisory Committees or Review Panels: MSD, Johnson; Speaking and Teaching: Gilead Sciences, Roche, BMS, MSD, Johnson The following people have nothing to disclose: Gurdal Yilmaz, Selcuk Kaya Background Chronic hepatitis B (CHB) patients on nucleos(t)ide analog therapy can achieve maintained hepatitis B virus (HBV) DNA suppression, but over 75% do not achieve sustained immune control (hepatitis B e antigen [HBeAg] seroconversion post-treatment) and potentially require lifelong therapy. In the OSST study, HBeAg-positive patients who switched from long-term entecavir (ETV) therapy (0.

Patients’ demographic characteristics, base-line liver biochemistry and HBV serological

markers were recorded. Liver biopsy was performed simultaneously with LSM. All patients started on treatment had high ALT, serum HBV DNA>2,000 IU/ml and compensated liver disease. ALT was monitored every 3 months and HBV DNA every 6 months. LSM was repeated annually. Results; Two hundred and forty of the 587 patients were started on antiviral treatment, 347 were observed without treatment. Male to female ratios in treated and untreated patients were 97/143 and 140/207, respectively. Mean ages were 35.8±13.0 and 38.1±11.9 (p=0.029). Eighty (33.3%) patients in the treatment group and 55 (15.9%) in the non-treatment see more group were HBe Ag positive. Mean baseline HBV DNA in the treatment group was 5.5±2.3 log 1 0IU, and ALT was 117±189. Baseline liver histology in the 123 patients (51.3%) undergoing LB revealed F4 fibrosis in 27 (22.0%) patients, F3 in 28 (22.8%), F2 in 33 (26.8%) and F0-1 in 35 (28.5%). Initial LSM results in patients receiving treatment and those observed without treatment were 8.3±4.6 and 6.6±3.2, respectively (p<0.001). Comparison of LB and LSM results revealed a positive correlation between fibrosis scores (r=0.291; p<0.001). A total of 48.3% (n=1 16) of patients received teno-fovir, 26.7% entecavir (n=64), 12.5% telbivudin

(n=30) and 12.5% lamivudin (n=30). There was no significant difference between pre-treatment LB and LSM results among antiviral drugs (p>0.05). Mean SCH727965 clinical trial duration of monitoring was 2.8±1.3 in patients receiving antiviral treatment and 2.3±1.2 in patients not receiving treatment. 上海皓元医药股份有限公司 At the end of monitoring, improvement was seen at LSM in patients receiving antiviral treatment (7.4±3.9) (p<0.001), but no difference was observed in the untreated group (7.0±4.3) (p=0.561). There was no difference among the antiviral drugs in terms of fibrosis improvement (p>0.05). Conclusion; Since LSM is correlated with liver biopsy and is non-invasive

and reproducible, it can be used in the diagnosis and long-term monitoring of CHB patients. It is a non-invasive test that also contributes to patients’ compliance with treatment. Disclosures: Iftihar Koksal – Advisory Committees or Review Panels: MSD, Johnson; Speaking and Teaching: Gilead Sciences, Roche, BMS, MSD, Johnson The following people have nothing to disclose: Gurdal Yilmaz, Selcuk Kaya Background Chronic hepatitis B (CHB) patients on nucleos(t)ide analog therapy can achieve maintained hepatitis B virus (HBV) DNA suppression, but over 75% do not achieve sustained immune control (hepatitis B e antigen [HBeAg] seroconversion post-treatment) and potentially require lifelong therapy. In the OSST study, HBeAg-positive patients who switched from long-term entecavir (ETV) therapy (0.

Second, acceptable results will be dependent on high quality diagnostic colonoscopy to detect and characterize early lesions, a sound selection process and an exceptional level of therapeutic endoscopy. Even a small rate of unrecognized failure to achieve a complete en bloc excision or perforation

(possibly even when recognized and managed) will yield poor results. Tumors with adverse histological features may result in patients being exposed to the risks of complex therapeutic endoscopy as well as those of surgical resection. At least in the West, few centers will be able to train to the required standard or have a case buy PLX4032 load to maintain the essential skills. It remains to be seen if these problems can be overcome by new technologies.7 Third, surgery cannot be dismissed by blithely quoting overall mortality and complication rates. Laparoscopic resection for cecal cancer in a younger patient without comorbidities cannot be compared with an operation (laparoscopic or open) for

low rectal carcinoma in an elderly obese patient with multiple comorbidities. In the former, the mortality rate and functional impact are negligible. Few patients, properly informed, would be prepared to trade a small (and possibly even uncertain) survival benefit to avoid such treatment. The latter operation is a high risk, life-changing event; alternatives with inferior oncological effectiveness might be acceptable. Apart from endoscopic treatment, other modalities such as Transanal Endoscopic Microsurgery (TEMS)8 and chemoradiation9 medchemexpress Torin 1 therapy could also be considered. Histopathology of the endoscopically resected lesion is key to the successful selection of patients,

who might be safely managed without surgical resection. The highest standard and consistency must be applied throughout the process, beginning with proper harvesting and presentation of the specimen by the endoscopist, as well as the processing and interpretation. For years, surgeons have recognized the essential contribution of the pathologist to achieving good results. A diligent and highly skilled pathologist is more likely to upstage, and the less adept to understage colorectal cancer, leading to the phenomenon of “stage migration”. The proportion of cancers reported as “Stage A” is thereby decreased and that of “Stage C” correspondingly increased, leading to improved outcome of both groups. This is popularly known as the “Will Rogers effect”. (Will Rogers, an American Comedian, reputedly claimed that the migration of poor farmers from Oklahoma to California improved the IQ of both states!)10 A similar effect might apply to the reporting of lymphovascular invasion, budding and maximum depth of invasion. Budding, is an indicator of poor prognosis in node-negative T3 colorectal cancer11 but is not yet a standard feature of colorectal cancer pathology reports. It is not certain if it is a sufficiently reproducible characteristic to justify inclusion in pathology reporting guidelines.

Second, acceptable results will be dependent on high quality diagnostic colonoscopy to detect and characterize early lesions, a sound selection process and an exceptional level of therapeutic endoscopy. Even a small rate of unrecognized failure to achieve a complete en bloc excision or perforation

(possibly even when recognized and managed) will yield poor results. Tumors with adverse histological features may result in patients being exposed to the risks of complex therapeutic endoscopy as well as those of surgical resection. At least in the West, few centers will be able to train to the required standard or have a case Selleckchem FDA-approved Drug Library load to maintain the essential skills. It remains to be seen if these problems can be overcome by new technologies.7 Third, surgery cannot be dismissed by blithely quoting overall mortality and complication rates. Laparoscopic resection for cecal cancer in a younger patient without comorbidities cannot be compared with an operation (laparoscopic or open) for

low rectal carcinoma in an elderly obese patient with multiple comorbidities. In the former, the mortality rate and functional impact are negligible. Few patients, properly informed, would be prepared to trade a small (and possibly even uncertain) survival benefit to avoid such treatment. The latter operation is a high risk, life-changing event; alternatives with inferior oncological effectiveness might be acceptable. Apart from endoscopic treatment, other modalities such as Transanal Endoscopic Microsurgery (TEMS)8 and chemoradiation9 MCE ICG-001 mw therapy could also be considered. Histopathology of the endoscopically resected lesion is key to the successful selection of patients,

who might be safely managed without surgical resection. The highest standard and consistency must be applied throughout the process, beginning with proper harvesting and presentation of the specimen by the endoscopist, as well as the processing and interpretation. For years, surgeons have recognized the essential contribution of the pathologist to achieving good results. A diligent and highly skilled pathologist is more likely to upstage, and the less adept to understage colorectal cancer, leading to the phenomenon of “stage migration”. The proportion of cancers reported as “Stage A” is thereby decreased and that of “Stage C” correspondingly increased, leading to improved outcome of both groups. This is popularly known as the “Will Rogers effect”. (Will Rogers, an American Comedian, reputedly claimed that the migration of poor farmers from Oklahoma to California improved the IQ of both states!)10 A similar effect might apply to the reporting of lymphovascular invasion, budding and maximum depth of invasion. Budding, is an indicator of poor prognosis in node-negative T3 colorectal cancer11 but is not yet a standard feature of colorectal cancer pathology reports. It is not certain if it is a sufficiently reproducible characteristic to justify inclusion in pathology reporting guidelines.

It is interesting to note that the association of iron deficiency with obesity was also described in women only (and in children)32, 33 and attributed to increased hepcidin synthesis secondary to an overweight-related chronic inflammatory state,30 possibly from extrahepatic sites.16 On the other hand, the dysmetabolic iron overload syndrome (DIOS), with associated

features of insulin resistance and moderate iron overload, is mainly described in men.34 Altogether, these data strongly suggests that there is crosstalk between iron metabolism, insulin-resistance, and hormonal environment. In women, after the cessation of menstruation, the incidence of metabolic syndrome progressively increases up to that of men.35 This is commonly attributed to loss of the estrogen-related DAPT ic50 protective effect against insulin resistance.36 Thus, we speculate that the decrease in estrogen production could lead, through an increase of fat mass, to an overweight-related chronic inflammatory state resulting in increased hepcidin expression. Estrogen exposure of fish was found to result

in a decrease in hepatic hepcidin expression, strengthening this hypothesis.37 However, such a link is likely more complex, since visceral adipose tissue is also a site of estrogen synthesis by aromatization of androgens from suprarenal glands,38 proportionally to fat mass.39 Furthermore, the aromatase expression is enhanced by proinflammatory cytokines whose expression is increased in metabolic http://www.selleckchem.com/B-Raf.html syndrome.40 In premenopausal women, even in overweight cases, extraovarian estrogen synthesis would have not enough influence because it is overtaken by ovarian synthesis. In postmenopausal women, fat mass represents the only site of estrogen synthesis, which could influence iron metabolism. Moreover, a possible link between estrogen and the BMP6 pathway, the main pathway of hepcidin regulation,

could also exist since estrogen decrease is associated with a decrease of BMP6 expression in bones, and partly explains osteoporosis in postmenopausal women.41 In conclusion, in C282Y homozygous women, BMI values greater than 28 kg/m2 are associated MCE with a decrease of the amount of iron removed and of both serum iron and transferrin saturation levels, which supports an increased production of hepcidin. Thus, being overweight is likely a modulating factor of iron burden in women with HFE hemochromatosis. The fact that this effect was exclusively demonstrated in women suggests a link between metabolic syndrome, hepcidin metabolism, and sex hormones. The authors thank colleagues from the Liver Unit of Rennes for allowing the use of patient charts, the nursing staff for performing phlebotomy programs and for follow-up of patients, and Béatrice Leclerc for oversight of the administrative and family screening procedures. We thank the Centre de Ressources Biologiques of Rennes for managing patient samples.