Fragile X‐associated tremor/ataxia syndrome (FXTAS) in grey zone carriers

The grey zone (GZ; 45–54 CGG repeats in the FMR1 gene) is considered a normal allele; however, several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of fragile X‐associated tremor/ataxia syndrome (FXTAS) in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55–200 CGG repeats). Both patients had family members who had premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated fragile X mental retardation 1 mRNA (FMR1‐mRNA) combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may require revision.     

Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.      

Retroviral-mediated transfer and amplification of a functional human factor VIII gene

Hemophilia A results from a deficiency in factor VII (FVIII), a cofactor in the intrinsic pathway of blood coagulation. As an approach toward genetic therapy of this disease, we constructed a retroviral vector encoding human FVIII and a selectable and amplifiable genetic marker, human adenosine deaminase (Ada). A retrovirus packaging line was transfected with this vector and stable transformants were selected for Ada expression. Isolated transformants produced both FVIII activity in the conditioned medium and retrovirus capable of transferring the Ada selectable marker and FVIII expression to the mouse 3T3 fibroblasts. Selection of virus-producer cell lines for increasing levels of Ada expression yielded a 20-fold increase in both FVIII expression and viral titer. Similarly, selection of infected 3T3 fibroblasts for Ada gene amplification yielded a 20-fold increase in FVIII expression. The results demonstrate the feasibility of retrovirus- mediated transfer of human FVIII, and also the utility of selection for gene amplification to increase retrovirus titers in producer cell lines as well as expression levels in infected cells.     

Cerebrovascular burden and depressive symptomatology interrelate over 18 years: support for the vascular depression hypothesis

Objective

Potentially incongruent research literatures suggest three divergent hypotheses about depressive symptomatology: (1) symptoms are recurrent; (2) later‐life depression results from high cerebrovascular burden (CVB); and (3) depressive symptoms contribute to comorbidities causing vascular burden. Past vascular depression research assumes that later‐life depressive symptoms relate uniquely to high CVB and not to prior, recurrent depression. This study examines these divergent hypotheses.

Methods

Data include 5175 participants across 18 years from the Wisconsin Longitudinal Study (mean age at 1993 baseline was 53 years; follow‐ups in 2004 and 2011). Depressive symptomatology was measured using the Center for Epidemiological Studies Depression. CVB was operationalized as hypertension, high blood sugar, diabetes, and other heart problems. Hypotheses were examined via a cross‐lagged structural equation model and logistic regression.

Results

Model fit was acceptable (root mean square error of approximation (RMSEA) = 0.047; comparative fit index = 0.963). Hypotheses 1 and 2 were supported. Depressive symptomatology at 2004 and 2011 follow‐ups was predicted by earlier depressive symptomatology and prior CVB. Hypothesis 3 was partially supported; depressive symptomatology in 2004 predicted subsequent CVB. Logistic regression results were that CVB predicted clinically significant depressive symptoms based on the Center for Epidemiological Studies Depression clinical cutoff.

Conclusions

Cerebrovascular burden in midlife predicts depressive symptomatology in later‐life, even after accounting for prior depressive symptomatology, supporting a fundamental assumption of the vascular depression hypothesis. Midlife depressive symptomatology also predicted escalation of CVB in later‐life. Results suggest a process model of later‐life depressive symptom development that interrelates CVB and depressive symptoms throughout the life span and have clinical implications for the interruption of this process through the integration of primary care and behavioral health specialists. Copyright © 2017 John Wiley & Sons, Ltd.     

The role of unstirred layers for water exchange across the blood-brain barrier

Theoretical considerations of the influence of unstirred layers around cerebral capillaries and of the effect of cerebral capillary endothelial cells on filtration and diffusion of water across the blood-brain barrier are presented. The theoretical analyses are applied to a previously published clinical investigation in which the filtration and diffusion permeability coefficient (P_f and P_d) were measured. In that study the $\text{P}{}_{\mathrm{<mtext>f</mtext>}}\text{P}{}_{\mathrm{<mtext>d</mtext>}}$ ratio was found to be slightly above unity, have a value of 4.3. The analyses in the present study demonstrate that the unstirred layer, in the classic sense, in the extracellular fluid around the capillaries will not have any significant influence on either the measured P_f or the P_d value. The unstirred layer inside the cerebral endothelial cells will also be without significance on the measured P_d values. However, for reasonable values of the parameters of the system, this unstirred layer may have a significant influence on the measured P_f value and may cause it to appear to be larger than the true steady-state value. This is especially true for the case where the luminal endothelial cell membrane is more permeable to water than the abluminal. Thus, the fact that the measured P_f might be too high can explain the observation of the $\text{P}{}_{\mathrm{<mtext>f</mtext>}}\text{P}{}_{\mathrm{<mtext>d</mtext>}}$ ratio of 4.3 although a minimal amount of water might still be filtered through pores in the blood-brain barrier. Quantitatively these amounts are, however, negligible compared to the filtration in other organs.