Young offspring at genetic risk of adult psychoses: the form of the trajectory of IQ or memory may orient to the right dysfunction at the right time

Objective

Neurocognitive dysfunctions analogous to those of adult patients have been detected in children at risk of schizophrenia and bipolar disorder. This led to the following developmental question: Do IQ and memory impairments exhibit different developmental courses from childhood to young adulthood in terms of stability or fluctuations?

Methods

In a high risk sample, we used a step by step sampling approach to narrow-down the early disease mechanisms. Upstream, we started with a 20-year follow-up of 48 densely affected multigenerational kindreds, including 1500 clinically characterized adult members. We then identified 400 adult members affected by a DSM-IV schizophrenia or bipolar disorder. Downstream, we finally focused on 65 offspring (of an affected parent) aged 7 to 22, who were administered a neuropsychological battery. We then constructed cross-sectional trajectories that were compared to those of controls.

Results

The childhood IQ deficit displayed a stability until young adulthood. The delay in visual memory exhibited a non-linear two-stage trajectory: a lagging period during childhood followed by a recuperation period from adolescence until adulthood, as supported by a significant Group x Age Periods interaction. No data suggested deterioration between 7 and 22.

Conclusion

In these offspring at genetic risk, the developmental trajectory of global IQ impairment may not apply to specific domains of cognition such as episodic memory. Different cognitive dysfunctions would mark different developmental courses. The shape of the trajectories might itself have a meaning and provide empirical leads for targeting the right dysfunction at the right time in future prevention research.     

Diopatra cuprea worm burrow parchment: a cautionary tale of infaunal surface reactivity

Many infaunal marine invertebrates produce mucus excretions that play an important role in metal binding, authigenic mineralization and burrow stabilization. To date, only a handful of studies have characterized the functional groups that control the surface reactivity of burrow linings and backfills. This makes it difficult to place estimates on the overall impact that bioturbation has on metal cycling in tidal flats, the inner shelf, estuaries and other shallow marine environments. Here, we examined the parchment linings of Diopatra cuprea burrows from the Ogeechee River estuary near Savannah, Georgia, USA. Acid–base titrations coupled with Fourier transform infrared spectroscopy demonstrate that the parchment is essentially composed of hydroxyl (R-OH) groups, yielding total ligand densities of only 0.017 mmol/g. To place this value into context, it is orders of magnitude less than previously reported mucopolysaccharides for other marine worms, indicating that D. cuprea is essentially unreactive in the estuarine waters from which it was collected. This was corroborated by minimal Cd²⁺ adsorption to, and limited silicification of, pre-rinsed parchment. The lack of silica adsorption was surprising given that the parchment was generally coated with an abundance of quartz grains when extracted from the sediment. This suggests that perhaps the physical, rather than chemical, characteristics of the parchment material were responsible for this association. Indeed, scanning electron microscope images show that the parchment is fibrous and envelopes quartz grains, implying that detritus may get trapped by the parchment mesh. It appears that unlike many other infaunal mucopolysaccharide-rich linings that might be produced to provide reactive surfaces to which dissolved metal cations can adsorb for the organism's nutritional benefit, the parchment of D. cuprea may instead function to protect the animal from stresses such as predation or high-energy disturbances.     

Seawater temperature, Gambierdiscus spp. variability and incidence of ciguatera poisoning in French Polynesia

In the context of global warming and climate change, ciguatera disease is put forward as an indicator of environmental disturbance. However, to validate this indicator, some unknown parameters such as the delay between environmental perturbation and outbreaks of ciguatera need to be investigated. The main goal of this study was to investigate the temporal link between the growth of Gambierdiscus spp., and one of its influencing factors and the declared cases of ciguatera disease in humans. Algal cell density and seawater temperature (SWT) were recorded monthly from February 1993 to December 2001 on the Atimaono barrier reef of Tahiti Island. Reports of ciguatera cases were obtained from three community health clinics near the study sites. The autoregressive integrated moving average model (ARIMA) shows: (1) SWT were positively associated with Gambierdiscus spp. growth at a lagtime of 13 and 17 months (p < 0.001); (2) Gambierdiscus spp. growth measured at a given time is related to a peak number of cases of ciguatera recorded 3 months after peak densities of this dinoflagellate (p < 0.001). These results allow the construction of a predictive model of the temporal link between ciguatera disease in humans and its etiologic agent: Gambierdiscus spp. This model constructed by using 1993–1999 data, then validated by 2000–2001 data, demonstrates an appreciable ability to predict changes in the incidence of ciguatera disease following algae blooms.     

Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation.

The immunosuppressant drug rapamycin blocks progression of the cell cycle at the G1 phase in mammalian cells and yeast. Here we show that rapamycin inhibits cap-dependent, but not cap-independent, translation in NIH 3T3 cells. Cap-dependent translation is also specifically reduced in extracts from rapamycin-treated cells, as determined by in vitro translation experiments. This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function. These effects of rapamycin are specific as FK506, a structural analogue of rapamycin, had no effect on either cap-dependent translation or 4E-BP1 phosphorylation. The rapamycin-FK506 binding protein complex is the effector of the inhibition of 4E-BP1 phosphorylation as excess of FK506 over rapamycin reversed the rapamycin-mediated inhibition of 4E-BP1 phosphorylation. Thus, inactivation of eIF-4E is, at least in part, responsible for inhibition of cap-dependent translation in rapamycin-treated cells. Furthermore, these results suggest that 4E-BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.     

The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients

Introduction

B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.

Methods

In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina^® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).

Results

Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria.

Conclusions

This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.