N255 is a key residue for recognition by a monoclonal antibody which protects against Yersinia pestis infection

Mab7.3 to Yersinia pestis LcrV antigen (LcrV_Ype) protected J774A.1 macrophages in vitro from killing by a Yersinia pseudotuberculosis strain expressing LcrV_Ype. Of 4 site-directed mutations in the coiled-coil region (148–169) and 7 mutations in the 225–255 sequence of LcrV_Ype, only the mutation of N255 to D255, abrogated the binding of Mab7.3 and reduced its protective capacity against plague. Since the Mab7.3 epitope in LcrV_Ype (135–275) encompasses a region (136–180) thought to be exposed on the injectisome, we suggest that Mab7.3 protects by binding to LcrV_Ype and interfering with protein–protein interactions necessary for type three secretion.     

Socioeconomic correlates of generalized anxiety disorder and major depression in primary care: the GADIS II study (Generalized Anxiety and Depression Impact Survey II)

A previous Generalized Anxiety Disorder Impact Survey (GADIS I) performed on 15,399 Belgian patients consulting their primary care physicians, revealed high prevalences of generalized anxiety disorder (GAD) and major depression (MD) with important regional differences. The objective of this study (GADIS II) was to replicate previous findings and to evaluate the role of socioeconomic factors in the diagnoses of GAD and MD. A large-scale cross-sectional survey was conducted in a random sample of 377 general practitioners distributed geographically over Belgium and Luxemburg. Each physician was asked to screen 40 consecutive patients at predefined time periods for the presence of GAD and MD using sections of the Mini International Neuropsychiatric Interview (MINI). Socioeconomic parameters were collected. The level of impairment was assessed using the Sheehan Disability Scale. In a sample of 13,699 patients, point prevalences of GAD and of MD were found to be 13.4 and 11.0%, respectively. Overall, 17.8% of the population was positive for GAD and/or MD. Both disorders were significantly more frequent in women than in men. Marked regional differences were observed with prevalences for GAD and/or MD of 24.2% in Brussels, 22.7% in Wallonia, 13.6% in Luxemburg and 12.9% in Flanders. Several socioeconomic factors were significantly associated with positive diagnoses: living alone, a low level of education and unemployment. However, regional differences remained significant even after controlling for socioeconomic factors. The study confirms the high prevalence of GAD and MD in primary care and the role of several socioeconomic and regional factors in the illnesses.     

Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids

Reduced fetal growth has been closely associated with an increased risk for the development of chronic disease in later life. Accumulating evidence indicates that fetal exposure to excess glucocorticoids represents a critical mechanism underlying this association. Approximately 7% of pregnant women are at risk of preterm delivery and these women are routinely treated with synthetic glucocorticoids (sGC) between 24 and 34 of weeks gestation to improve neonatal outcome. Animal studies have demonstrated that maternally administered sGC crosses the placenta, affecting fetal hypothalamic–pituitary–adrenal (HPA) development, resulting in changes in HPA axis function that persist throughout life. These changes appear to be modulated at the level of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the brain and pituitary. As the HPA axis interacts with many other physiological pathways, the changes in endocrine function are also sex-specific and age-dependent. Alterations in behavior, particularly locomotion, in animals exposed to sGC in utero have also been demonstrated. Consistent with the finding in animal models, emerging human data are indicating attention deficit-hyperactivity disorder (ADHD)-like symptoms in children exposed to repeated courses of sGC in utero. This behavioral phenotype is likely linked to alterations in dopamine (DA) signaling, suggesting that sGC are able to permanently modify or ‘program’ this system. Finally, it is emerging that changes in HPA axis function and behavior following antenatal exposure to sGC are transgenerational and likely involve epigenetic mechanisms. A comprehensive understanding of the acute and long-term impact of sGC exposure in utero is necessary to begin to develop recommendations and treatment options for pregnant women at risk of preterm delivery.     

Pure alexia as a disconnection syndrome: new diffusion imaging evidence for an old concept

Functional neuroimaging and studies of brain-damaged patients made it possible to delineate the main components of the cerebral system for word reading. However, the anatomical connections subtending the flow of information within this network are still poorly defined. Here we study the connectivity of the Visual Word Form Area (VWFA), a pivotal component of the reading network achieving the invariant identification of letter strings, and reproducibly located in the left lateral occipitotemporal sulcus. Diffusion images and functional imaging data were gathered in a patient who developed pure alexia following a small surgical lesion in the vicinity of his VWFA. We had a unique opportunity to compare images obtained before, early after, and late after surgery. Analysis of diffusion images with white matter tractography and voxel-based morphometry showed that the VWFA was mainly linked to the occipital cortex through the inferior longitudinal fasciculus (ILF), and to perisylvian language areas (supramarginal gyrus) through the arcuate fasciculus. After surgery, we observed the progressive and selective degeneration of the ILF, while the VWFA was anatomically intact. This allowed us to establish the critical causal role of this fiber tract in normal reading, and to show that its disruption is one pathophysiological mechanism of pure alexia, thus clarifying a long-standing debate on the role of disconnection in neurocognitive disorders.     

Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice

The accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau protein are pathological features of Alzheimer’s disease (AD) commonly modeled in mice using known human familial mutations; however, the loss of neurons also found to occur in AD is rarely observed in such models. The mechanism of neuron degeneration remains unclear but is of great interest as it is very likely an important factor for the onset of adverse memory deficits occurring in individuals with AD. The role of Aβ in the neuronal degeneration is a matter of controversial debates. In the present study we investigated the impact of extracellular plaque Aβ versus intraneuronal Aβ on neuronal cell death. The thalamus and the frontal cortex of the APP/PS1KI mouse model were chosen for stereological quantification representing regions with plaques only (thalamus) or plaques as well as intraneuronal Aβ (frontal cortex). A loss of neurons was found in the frontal cortex at the age of 6 months coinciding with the decrease of intraneuronal immunoreactivity, suggesting that the neurons with early intraneuronal Aβ accumulation were lost. Strikingly, no neuron loss was observed in the thalamus despite the development of abundant plaque pathology with levels comparable to the frontal cortex. This study suggests that plaques have no effect on neuron death whereas accumulation of intraneuronal Aβ may be an early transient pathological event leading to neuron loss in AD. O. Wirths and T. A. Bayer have equally contributed to this work.     

Mucosal intraepithelial T-lymphocytes in refractory celiac disease: a neoplastic population with a variable CD8 phenotype

Celiac disease (CD) is characterized by villous atrophy and an increase in intraepithelial lymphocytes (IEL). The IEL usually exhibit a suppressor/cytotoxic phenotype (CD3 and CD8) and display a polyclonal profile for T-cell receptor (TCR) rearrangement as opposed to the monoclonality of refractory CD (RCD) with CD8 IEL. A complication of CD is the loss of response to a gluten-free diet called RCD that may progress to an enteropathy-associated T-cell lymphoma. We reviewed 20 uncomplicated CD and 23 complicated CD (19 RCD and 4 diagnosed at the same time as enteropathy-associated T-cell lymphoma). In complicated CD, the IEL phenotype was CD8 in 9 cases and CD8 in 14 cases. In 100% of cases, IEL showed a monoclonal TCR rearrangement. All the 9 CD8 complicated CD exhibited a monoclonal TCR rearrangement and 3 of them were associated with a T-cell lymphoma (2 at the same time as CD and 1 after 43-mo follow-up) and bore the same monoclonal rearrangement in IEL and in lymphoma. Interestingly, the 13 cases (100%) of CD with a CD8 phenotype were also found monoclonal and 2 of them were associated with a T-cell lymphoma diagnosed at the same time as CD and exhibiting the same rearrangement in IEL and in lymphoma. An aberrant CD3 CD8 IEL phenotype is a good criterion for RCD diagnosis. However, cases with a normal CD3 CD8 IEL phenotype may correspond to RCD. In such cases, we suggest that molecular analysis of TCR-gamma genes is a useful method for identifying cases with RCD.     

Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases

Several case reports suggest that rituximab (RTX) could be effective in steroid-dependent nephrotic syndrome, but RTX efficacy has not yet been studied in a series of patients. Safety and efficacy of RTX were assessed in a multicenter series of 22 patients aged 6.3-22 years with severe steroid-dependent nephrotic syndrome or steroid-resistant but cyclosporin-sensitive idiopathic nephrotic syndrome. Patients were treated with two to four infusions of RTX. Seven patients were nephrotic at the time of RTX treatment. Peripheral B cells were depleted in all subjects. Remission was induced in three of the seven proteinuric patients. One or more immunosuppressive (IS) treatments could be withdrawn in 19 patients (85%), with no relapse of proteinuria and without increasing other IS drugs. RTX was effective in all patients when administered during a proteinuria-free period in association with other IS agents. When relapses occurred, they were always associated with an increase in CD19 cell count. Adverse effects were observed in 45% of cases, but most of them were mild and transient. This study suggests that RTX could be an effective treatment for severe steroid-dependent nephrotic syndrome.