Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey

After injury, regrowth of axons in mammalian adult central nervous system is highly limited. However, in monkeys subjected to unilateral cervical lesion (C7-C8 level), neutralization of an important neurite outgrowth inhibitor, Nogo-A, stimulated axonal sprouting caudal to the lesion, accompanied by enhanced functional recovery of manual dexterity, compared with lesioned monkeys treated with a control antibody (Freund et al. [2006] Nat. Med. 12:790-792). The present study aimed at comparing the same two groups of monkeys for axonal sprouting rostral to the cervical lesion. The corticospinal tract was labeled by injecting the anterograde tracer biotinylated dextran amine into the contralesional motor cortex. The corticospinal axons were interrupted at the level of the lesion, accompanied by retrograde axonal degeneration (axon dieback), reflected by the presence of terminal retraction bulbs. The number of terminal retraction bulbs was lower in anti-Nogo-A antibody treated monkeys, and, when present, they were found closer to the lesion than in control-antibody treated monkeys. Compared with control antibody treated monkeys, the anti-Nogo-A antibody treated monkeys exhibited an increased cumulated axon arbor length and a higher number of axon arbors going in the medial direction from the white to the gray matter. Higher in the cervical cord (at C5 level), the anti-Nogo-A treatment enhanced the number of corticospinal fibers crossing the midline, suggesting axonal sprouting. Thus, the anti-Nogo-A antibody treatment enhanced axonal sprouting rostral to the cervical lesion; some of these fibers grew around the lesion and into the caudal spinal segments. These processes paralleled the observed improved functional recovery.     

Hippocampus, amygdala, and basal ganglia morphometrics in children after moderate-to-severe traumatic brain injury

While closed head injury frequently results in damage to the frontal and temporal lobes, damage to deep cortical structures, such as the hippocampus, amygdala, and basal ganglia, has also been reported. Five deep central structures (hippocampus, amygdala, globus pallidus, putamen, and caudate) were examined in 16 children (eight males, eight females; aged 9-16y), imaged 1 to 10 years after moderate-to-severe traumatic brain injury (TBI), and in 16 individually-matched uninjured children. Analysis revealed significant volume loss in the hippocampus, amydala, and globus pallidus of the TBI group. Investigation of relative volume loss between these structures and against five cortical areas (ventromedial frontal, superomedial frontal, lateral frontal, temporal, and parieto-occipital) revealed the hippocampus to be the most vulnerable structure following TBI (i.e. greatest relative difference between the groups). In a separate analysis excluding children with focal hippocampal abnormalities (e.g. lesions), group differences in hippocampal volume were still evident, suggesting that hippocampal damage may be diffuse rather than focal.     

Apolipoprotein E epsilon4 allele frequency in elderly depressed patients with and without cerebrovascular disease

Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) epsilon4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE epsilon4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE epsilon4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group (p<0.05 to 0.001). The frequency of the epsilon4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the epsilon4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE epsilon4 allele and the LOD without CVD. These patients could be at risk of developing AD by an epsilon4-dependent pathway. In contrast, the results show no association between the presence of ApoE epsilon4 allele and vascular depression and provide further evidence in support of the concept that ApoE epsilon4 allele is not associated with clinical CVD.     

The effects of selective amygdala, orbital frontal cortex or hippocampal formation lesions on reward assessment in nonhuman primates

We examined the effects of bilateral amygdaloid, hippocampal or orbital frontal cortex lesions on reward assessment in rhesus monkeys (Macaca mulatta). In Experiment 1, basic preferences for foods and inedible nonfoods were measured pre- and postsurgery. None of the lesions produced changes in animals' preferences for palatable foods or raw meat relative to presurgery, although amygdaloid or hippocampal lesions yielded increased preference for inedible nonfoods postsurgery. When the reinforcement value of each animal's highest-preferred food was decreased by selective satiation, only animals with neurotoxic orbital frontal cortex lesions continued to select the sated food. Experiment 2 measured the impact of each lesion on learning 60 concurrent discrimination problems and, then, on flexibly avoiding objects associated with sated foods in favour of objects associated with nonsated foods. None of the lesions affected concurrent discrimination learning, but animals with neurotoxic amygdala or aspiration orbital frontal lesions could not refrain from displacing items covering devalued foods. Only animals with orbital lesions also selected the devalued food beneath the object. The results indicate a functional dissociation for the amygdala and orbital frontal cortex in reward assessment, depending on the type of the reinforcer available (objects vs. food). Finally, this is the first study indicating that the hippocampal formation is involved in the assessment of familiar nonfoods, but not in judging the current value of unconditioned and conditioned reinforcers.     

A plasminogen-like protease in thyroid rough microsomes degrades thyroperoxidase and thyroglobulin

Proteasome activity takes place in the cytosolic compartment and acts to degrade several proteins translated and unfolded. In transfected CHO cells expressing thyroid peroxidase (TPO), just-translated TPO undergoes proteasome activity, and then a second proteolytic system degrades more mature forms of TPO. A plasminogen-like (Pl-like) protease is found in microsomal liver membranes and in the thyroid. In the thyroid, this Pl-like protease is localized in the follicular lumen and efficiently degrades thyroglobulin (Tg) in vitro. Here we checked for the presence, in purified endoplasmic reticulum (ER) membranes of transfected CHO and in rough microsomes purified from thyroid tissue, of a second proteolytic system, different from the proteasome, and active against the two major proteins of the thyroid gland, TPO and Tg. We first confirmed that this proteolytic system was able to degrade folded endogenous TPO. We showed also that externally added TPO (folded form) was degraded by opened vesicles of ER in the same system. For thyroid tissue, we showed that added TPO, as well as purified Tg, was degraded by some unknown membrane-associated protease(s) in human and porcine thyroid rough microsomes, whereas BSA and IgG were not. These results indicated that major thyroid glycoproteins are preferential substrates of such protease(s). Immunoblot and zymography experiments identified the unknown membrane-associated protease in rough microsomes from thyroid tissues as being a Pl-like protease. These results highly suggest that this system acts as a nonproteasomal degradation enzyme at the ER level, and we hypothesize that it contributes in regulating the level of major thyroid glycoproteins.     

Spatiotemporal electrocardiographic characterization of ventricular depolarization and repolarization abnormalities in long QT syndrome

Background and Purpose

If only a standard electrocardiogram (ECG) is available, at least 25% of patients with long QT syndrome (LQTS) may be missed. Our goal is to quantify abnormal electrical activity and to develop an ECG decision rule for the patients with LQTS.

Methods

One hundred forty-one subjects were included in this study (71 patients with LQTS and 70 healthy subjects). A 12-lead digital ECG was recorded for each subject and analyzed using the CAVIAR (comparative analysis of ECG-VCG and their interpretation with auto-reference to the patient) method.

Results

A decision tree involving criteria based on 3 spatiotemporal ECG measurements—the QT interval and the maximum amplitude of the T wave, both corrected from heart rate, and the loss of planarity of the end of QRS—identified patients with LQTS from healthy subjects with a sensitivity of 89%, a specificity of 96%, and a total accuracy of 92%.

Conclusions

This study suggests that 3-dimensional ECG analysis may improve the detection of patients with LQTS.     

.VO2 kinetics during supramaximal exercise: relationship with oxygen deficit and 800-m running performance

The aim of this study was to compare .VO2 kinetics of highly- versus recreationally-trained subjects during a constant velocity test of supramaximal intensity. Eighteen trained male subjects were recruited to one of two groups: highly trained (HT, n = 8, .VO(2max) = 70.1 +/- 6.5 ml . min (-1) . kg (-1)) and recreationally trained (RT, n = 10, .VO(2max) = 63.2 +/- 6.4 ml . min (-1) . kg (-1)). All subjects performed an incremental test to exhaustion for the determination of .VO(2max) and peak treadmill velocity (PTV), two constant velocity tests at 110 % of PTV to determine .VO2 kinetics and oxygen deficit (O(2)def), and a 800-m time trial to determine running performance (mean velocity over the distance, V (800 m)). We found significant differences between HT and RT for the on-transient of the .VO2 response (tau, 24.7 +/- 3.3 and 30.9 +/- 7.0 s, respectively), the amplitude of the .VO2 response (60.0 +/- 5.0 and 53.5 +/- 5.7 ml . min (-1) . kg (-1), respectively) and V (800 m) (6.27 +/- 2.1 and 5.45 +/- 0.38 m . s (-1), respectively). O(2)def (24.6 +/- 2.7 and 27.7 +/- 7.8 ml . kg (-1), respectively) and the gain of the .VO2 response (193 +/- 14 and 194 +/- 13 ml . kg (-1) . m (-1), respectively) were similar between groups. tau was associated with O(2)def (r = 0.90, p < 0.05), but not with V (800 m) (r = 0.30, p > 0.05). It was concluded that HT subjects exhibited faster on-kinetics and higher amplitude than their RT counterparts. The higher amplitude was not thought to reflect any difference in underlying physiological mechanisms. The faster tau, whose exact mechanisms remain to be elucidated, may have practical implications for coaches.     

Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions

Induction of Forkhead‐box p3 (Foxp3) expression in developing T cells upon peptide‐MHC encountering has been proposed to define a lineage of committed Treg cells. However, sustained expression of Foxp3 is required for Treg function and what maintains Foxp3 expression in peripheral Treg remains obscure. To address this issue, we monitored natural Treg phenotype and function upon adoptive transfer into lymphocyte‐deficient mice. We first show that about 50% of Foxp3‐GFP⁺ Treg isolated from Foxp3^gfp KI animals loose Foxp3 expression in severe lymphopenic conditions. We next evidence that the cytokine IL‐2, either produced by co‐transferred conventional T cells or administrated i.v. prevents Foxp3 downregulation. Moreover, we document that Treg that lost Foxp3 expression upon adoptive transfer produce IL‐2 are not suppressive and promote tissue infiltration and damage upon secondary transfer into alymphoid mice. Our findings that Treg convert into pathogenic Th cells in absence of IL‐2 provide new clues to the success of Treg‐based immune therapies.     

Prevalence and characteristics of significant social anxiety in children aged 8–13 years

Background  Social anxiety has been frequently studied in both population- and clinical-based adult and adolescent samples. Corresponding research in children is scarce and is dominated by clinical studies. The aim of the present population-based study was to examine the prevalence of significant social anxiety (SSA) in preadolescent children and compare their characteristics with those of children without SSA. The spectrum of social anxiety is explored by comparing children with different levels of social anxiety, as defined by 1–2 versus 3–5 social situations feared. Method  The sample consisted of 14,497 parents and their 3rd–7th grade children (8–13 years old) who participated in a health profile study, including questions covering DSM-IV criteria A–D for social anxiety disorder (SAD). Socio-demographic data, social and school functioning, somatic complaints, parent–child relationships, and use of health services were added to a logistic regression model to explore characteristics associated with children with, and without SSA. Associated emotional and behavioural problems were measured by the Strengths and Difficulties Questionnaire (SDQ) using parent and self-report. Results  Parents described 2.3% of all children as significantly socially anxious and 0.9% feared at least three social situations. The majority of children with SSA managed their everyday life well. However, compared with children without SSA, children with SSA struggled more often in different areas of life and showed a significantly higher prevalence of associated emotional and behavioural symptoms. Our findings also support the notion of social anxiety as a spectrum concept. Conclusions  Social anxiety problems start in childhood and can be impairing, even in non-clinical populations and in reasonably young age groups. Increased awareness of different aspects of social anxiety is needed to identify children who are at risk and to devise appropriate interventions to improve the immediate and long-term outcome.