Hereditary hemochromatosis: genetic complexity and new diagnostic approaches

Since the discovery of the hemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron-overload diseases. At least 4 main types of hereditary hemochromatosis (HH) have been identified. Surprisingly, genes involved in HH encode for proteins that all affect pathways centered around liver hepcidin synthesis and its interaction with ferroportin, an iron exporter in enterocytes and macrophages. Hepcidin concentrations in urine negatively correlate with the severity of HH. Cytokine-mediated increases in hepcidin appear to be an important causative factor in anemia of inflammation, which is characterized by sequestration of iron in the macrophage system. For clinicians, the challenge is now to diagnose HH before irreversible damage develops and, at the same time, to distinguish progressive iron overload from increasingly common diseases with only moderately increased body iron stores, such as the metabolic syndrome. Understanding the molecular regulation of iron homeostasis may be helpful in designing innovative and reliable DNA and protein tests for diagnosis. Subsequently, evidence-based diagnostic strategies must be developed, using both conventional and innovative laboratory tests, to differentiate between the various causes of distortions of iron metabolism. This review describes new insights in mechanisms of iron overload, which are needed to understand new developments in diagnostic medicine.     

Dendritic cell recruitment following xenografting of pig fetal mesencephalic cells into the rat brain

Following transplantation into the rat brain, porcine neuroblasts differentiate and integrate host tissue, but due to their xenogeneic nature, these cells are generally rejected within several weeks. This rejection is accompanied by infiltration of the graft by macrophages and alphabetaT lymphocytes, but so far nothing is known about the potential role of dendritic cells (DCs) in this process. DCs are professional antigen presenting cells that have the unique ability to prime naive T cells, thereby initiating an antigen-directed immune response. Here, we provide evidence for DC recruitment following the transplantation of pig mesencephalic neural cells into the striatum of LEW.1A rats, as indicated by the high number of OX62+ cells in the rejecting graft and the absence of V65 staining. DCs were found as early as 3 and 8 days postimplantation together with ED1+ and OX42+ cells. This early recruitment, which is probably due to the surgical procedure, might be a critical step in the rejection process, enabling DCs to be loaded with xenoantigens. The number of intracerebral DCs subsequently decreased, being barely detectable in older non-infiltrated xenografts. However, DCs re-appeared as they were observed in grafts infiltrated by macrophages and T cells, a phenomenon that usually precedes graft rejection. Interestingly, we observed a tight correlation between the number of DCs and that of R7.3+ T cells infiltrating the graft. In addition, DCs were often found in close proximity to alphabetaT cells and most expressed MHCII. Taken together, these findings give credence to a role for infiltrating DCs in the mediation of T cell responses to intracerebral xenografting.     

Children with mixed language disorder do not discriminate accurately facial identity when expressions change

We investigated the recognition of pairs of faces (same or different facial identities and expressions) in two groups of 14 children aged 6–10 years, with either an expressive language disorder (ELD), or a mixed language disorder (MLD), and two groups of 14 matched healthy controls. When looking at their global performances, children with either expressive (ELD) or MLD have few differences from controls in either face or emotional recognition. At contrary, we found that children with MLD, but not those with ELD, take identical faces to be different if their expressions change. Since children with mixed language disorders are socially more impaired than children with ELD, we think that these features may partly underpin the social difficulties of these children. We thank S. Hugues and E. Shapiro for providing us with the MNTAP. We thank the children and their parents, for their participation to the study. This work was supported by the “Fondation de France”.     

Process evaluation of a school based physical activity related injury prevention programme using the RE-AIM framework

Background  

In general, only information regarding the effectiveness of an intervention programme is ever published. However, in recent years evaluating the translatability and feasibility of an intervention programme has become more important. Therefore, this paper presents the results of the evaluation of the iPlay programme aimed at preventing physical activity related injuries in primary school children.     

Dual Diagnosis: Prevalence, Risk Factors, and Relationship With Suicide Risk in a Nationwide Sample of French Prisoners

Background:  Axis I psychiatric disorders (PD) and substance use disorders (SUD) are common in prison, but only few studies have focused on their association in this setting. Dual diagnosis (DD) (the co-occurrence of a SUD and any axis I disorder) is known to have a poorer prognosis and to require more intense supportive care.
Objectives:  The objectives of this study were (1) to describe prisoners with DD (prevalence and characteristics); (2) to compare DD prisoners with 3 other groups of prisoners: no diagnosis (ND), SUD alone, or other isolated PD; and (3) to evaluate the impact of DD on suicide risk in prison.
Method:  A random stratified strategy was used to select 23 various types of prisons and 998 prisoners. Diagnoses were assessed using a unique procedure, each prisoner being evaluated by 2 psychiatrists, 1 junior, using a structured interview (MINI 5 plus), and 1 senior, using an open clinical interview. Following interviews, clinicians met to establish a list of diagnoses. Cloninger's temperament and character inventory was also used.
Results:  Of the prisoners, 26.3% had a DD. DD prevalence was almost 80% in prisoners with SUD, while only one-third of the prisoners with an axis I PD had co-morbid SUD. No significant differences were observed in drug use patterns between DD and SUD without co-morbid PDs. DD showed the strongest association with suicide risk [OR = 5.7 (1.7–4.6)].
Conclusion:  DD is very frequent in prison and is a major risk factor for suicide. Systematic psychiatric/SUD screening of prisoners with either a SUD or an axis I PD should be encouraged.     

Muscle Strength Rather Than Muscle Mass Is Associated With Standing Balance in Elderly Outpatients

ObjectivesAssessment of the association of muscle characteristics with standing balance is of special interest, as muscles are a target for potential intervention (ie, by strength training).DesignCross-sectional study.SettingGeriatric outpatient clinic.ParticipantsThe study included 197 community-dwelling elderly outpatients (78 men, 119 women; mean age 82 years).MeasurementsMuscle characteristics included handgrip and knee extension strength, appendicular lean mass divided by height squared (ALM/height²), and lean mass as percentage of body mass. Two aspects of standing balance were assessed: the ability to maintain balance, and the quality of balance measured by Center of Pressure (CoP) movement during 10 seconds of side-by-side, semitandem, and tandem stance, with both eyes open and eyes closed. Logistic and linear regression models were adjusted for age, and additionally for height, body mass, cognitive function, and multimorbidity.ResultsHandgrip and knee extension strength, adjusted for age, were positively related to the ability to maintain balance with eyes open in side-by-side (P = .011; P = .043), semitandem (P = .005; P = .021), and tandem stance (P = .012; P = .014), and with eyes closed in side-by-side (P = .004; P = .004) and semitandem stance (not significant; P = .046). Additional adjustments affected the results only slightly. ALM/height² and lean mass percentage were not associated with the ability to maintain standing balance, except for an association between ALM/height² and tandem stance with eyes open (P = .033) that disappeared after additional adjustments. Muscle characteristics were not associated with CoP movement.ConclusionMuscle strength rather than muscle mass was positively associated with the ability to maintain standing balance in elderly outpatients. Assessment of CoP movement was not of additional value.     

Genetics of chemical carcinogenesis: analysis of bidirectional selective breeding inducing maximal resistance or maximal susceptibility to 2-stage skin tumorigenesis in the mouse

We report on bidirectional selective breeding, initiated from a genetically defined foundation population and carried out to selection limit, for producing lines of mice endowed with maximal resistance (Car-R) or maximal susceptibility (Car-S) to 2-stage skin tumorigenesis. The initial population resulted from a balanced intercrossing of 8 inbred strains of mice. The tumors, induced by a single application of DMBA (initiation) and twice weekly applications of TPA (promotion), were benign papillomas; their number at the end of the promotion period was the phenotype chosen for assortative mating. Afterward, the majority of them regressed while others progressed to malignant carcinomas. The Car-R line was selected through a strong challenge, while the Car-S line selection was based on responses to decreasing concentrations of DMBA and TPA. The selection limit was reached after 14 or 15 generations showing progressive interline divergence, which strongly suggests the interaction of several quantitative trait loci (QTL). The phenotypic difference was extremely large: the tumor response was 73 times higher in Car-S than in Car-R mice, though the applied concentrations of DMBA and TPA were 100 and 40 times lower, respectively. The mean heritability realized during the selective breeding was 0.20 in Car-R and 0.49 in Car-S. Our results are compatible with a minimal QTL estimate of 8 in the Car-R line and of 9 or 10 in the Car-S line. The Car-S line is also much more susceptible to carcinoma induction. An association of coat color with tumorigenesis was observed in interline F2 segregants. The Car-R and Car-S lines, obtained through a long-lasting breeding program, are a unique model for identifying the QTL involved in chemical tumorigenesis and will be provided to interested investigators.