This article reports upon the emergence of a novel cognitive, computer-based technology which may lead to significantly improved methods of cardiological diagnosis and a rapid and inexpensive method of cardiological screening.
The technology ‘Virtual Scanning’ illustrates how, in blood, the reaction of proteins and their reactive substrates releases light; that the colour and intensity of this bioluminescence is unique to each reaction and it's rate; and that the development of pathologies influence cognition and visual perception. This illustrates that the function of the autonomic nervous system is linked to that of the physiological systems and that the rate of biochemical reactions, and the progression of disease, can be measured by a cognitive test procedure and used as an indication of the disease(s) affecting heart function.
The article discusses the limitations of the conventional biomarker technique, and the potential value of non-invasive cognitive techniques, such as Virtual Scanning, to the medical practitioner. Finally, it discusses how the ability of Virtual Scanning to diagnose disease from its presymptomatic origins may lead to improved diagnostic accuracy and significantly reduced costs.
Computer diagnosis; autonomic nervous system; visual perception; virtual scanning; mathematical modeling; physiological systems
Breakdown of the blood-brain barrier (BBB) is present in several neurological disorders such as stroke, brain tumors, and multiple sclerosis. Non-invasive evaluation of BBB breakdown is important for monitoring disease progression and evaluating therapeutic efficacy in such disorders. One of the few techniques available for non-invasively and repeatedly localizing and quantifying BBB damage is magnetic resonance imaging (MRI). This usually involves the intravenous administration of a gadolinium-containing MR contrast agent such as Gd-DTPA, followed by dynamic contrast-enhanced MR imaging (DCE-MRI) of brain and blood, and analysis of the resultant data to derive indices of blood-to-brain transfer. There are two advantages to this approach. First, measurements can be made repeatedly in the same animal; for instance, they can be made before drug treatment and then again after treatment to assess efficacy. Secondly, MRI studies can be multiparametric. That is, MRI can be used to assess not only a blood-to-brain transfer or influx rate constant (Ki or K1) by DCE-MRI but also complementary parameters such as: 1) cerebral blood flow (CBF), done in our hands by arterial spin-tagging (AST) methods; 2) magnetization transfer (MT) parameters, most notably T1sat, which appear to reflect brain water-protein interactions plus BBB and tissue dysfunction; 3) the apparent diffusion coefficient of water (ADCw) and/or diffusion tensor, which is a function of the size and tortuosity of the extracellular space; and 4) the transverse relaxation time by T2-weighted imaging, which demarcates areas of tissue abnormality in many cases. The accuracy and reliability of two of these multiparametric MRI measures, CBF by AST and DCE-MRI determined influx of Gd-DTPA, have been established by nearly congruent quantitative autoradiographic (QAR) studies with appropriate radiotracers. In addition, some of their linkages to local pathology have been shown via corresponding light microscopy and fluorescence imaging. This chapter describes: 1) multiparametric MRI techniques with emphasis on DCE-MRI and AST-MRI; 2) the measurement of the blood-to-brain influx constant and CBF; and 3) the role of each in determining BBB permeability.
Apparent diffusion coefficient; Arterial spin tagging; Blood-brain barrier; Cerebral blood flow; Cerebral ischemia; Gd-DTPA; Hemorrhagic transformation; Influx constant; Look-Locker; Magnetic resonance contrast agents; Magnetization transfer; Patlak plot; Quantitative autoradiography; Rat; T1; T1sat; T1WI; T2; TOMROP
Sexual concurrency poses significant HIV/STI transmission risk. The correlates of concurrency have not been examined among homeless men. A representative sample of 305 heterosexually active homeless men utilizing meal programs in the Skid Row area of Los Angeles reported on their mental health, substance use, and social network characteristics. Nearly 40% of men reported concurrency with one of their four most recent sex partners. Results indicated that HIV seropositivity (OR = 4.39, CI: 1.10, 17.46; p = 0.04), PTSD (OR = 2.29, CI: 1.05, 5.01; p = 0.04), hard drug use (OR = 2.45, CI: 1.07, 5.58; p = 0.03), and the perception that network alters engage in risky sex (OR = 3.72, CI: 1.49, 9.30; p = 0.01) were associated with increased odds of concurrency. Programs aimed at reducing HIV/STI transmission in this vulnerable population must take into account the roles that behavioral health and social networks may play in sexual concurrency.
Low BMD increases fracture risk; how changes in BMD influence fracture risk in older men is uncertain.
BMD was assessed at 2–3 time points over 4.5 years using DXA for 4,470 men aged ≥65 years in the MrOS study. Change in femoral neck BMD was estimated using mixed effects linear regression models. BMD change was categorized as “accelerated” (≤−0.034 g/cm2), “expected” (between 0 and −0.034 g/cm2), or “maintained” (≥0 g/cm2). Fractures were adjudicated by central medical record review. Multivariate proportional hazards models estimated the risk of hip; non-spine non-hip; and non-spine fracture over 4.5 years after the final BMD measure, during which time 371 (8.3%) men experienced at least one non-spine fracture, including 78 (1.7%) hip fractures. Men with accelerated femoral neck BMD loss had an increased risk of non-spine (HR: 2.0, 95% CI: 1.4, 2.8); non-spine non-hip (HR: 1.6, 95% CI: 1.1, 2.3); and hip fracture (HR: 6.3, 95% CI: 2.7, 14.8) compared to men who maintained BMD over time. No difference in risk was seen for men with expected loss. Adjustment for the initial BMD measure did not alter the results. Adjustment for the final BMD measure attenuated the change in BMD/non-spine fracture and the change in BMD/non-spine non-hip relationships such that they were no longer significant, while the change in BMD-hip fracture relationship was attenuated (HR: 2.6, 95% CI: 1.1, 6.4). Total hip BMD change produced similar results.
Accelerated decrease in BMD is a strong, independent risk factor for hip and other non-spine fractures in men.
Few articles have examined specific counseling tools used to increase antiretroviral therapy (ART) adherence. We present communication tools used in the context of Project MOTIV8, a randomized clinical trial.
We developed, piloted, and evaluated pictorial images to communicate the importance of consistent dose timing and the concept of drug resistance. Electronic drug monitoring (EDM) review was also used to provide visual feedback and facilitate problem solving discussions. Adherence knowledge of all participants (n=204) was assessed at baseline and 48 weeks. Participant satisfaction with counseling was also assessed.
Adherence knowledge did not differ at baseline, however, at 48 weeks, intervention participants demonstrated significantly increased knowledge compared to controls F(1,172) = 10.76, p=0.001, (12.4% increase among intervention participants and 1.8% decrease among controls). Counselors reported that the tools were well-received, and 80% of participants felt the counseling helped them adhere to their medications.
Counseling tools were both positively received and effective in increasing ART adherence knowledge among a diverse population.
While developed for research, these counseling tools can be implemented into clinical practice to help patients; particularly those with lower levels of education or limited abstract thinking skills to understand medical concepts related to ART adherence.
ART adherence; counseling tools; patient communication tools; concrete; education tools; high and low resource; electronic drug monitoring (EDM) review; Motivational Interviewing
The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent.
Materials & methods
A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly4 and a fluorescent agent, DyLight® 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent.
The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging.
This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales.
brain tumor; contrast agent; dendrimer; MRI; pharmacokinetic
Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene.
We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.
Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10−7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10−6).
The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)
CCAAT/enhancer-binding protein-β (C/EBPβ) is a mediator of cell survival and tumorigenesis. When C/EBPβ−/− mice are treated with carcinogens that produce oncogenic Ras mutations in keratinocytes, they respond with abnormally elevated keratinocyte apoptosis and a block in skin tumorigenesis. Although this aberrant carcinogen-induced apoptosis results from abnormal upregulation of p53, it is not known whether upregulated p53 results from oncogenic Ras and its ability to induce p19Arf and/or activate DNA-damage response pathways or from direct carcinogen-induced DNA damage. We report that p19Arf is dramatically elevated in C/EBPβ−/− epidermis and that C/EBPβ represses a p19Arf promoter reporter. To determine whether p19Arf is responsible for the proapoptotic phenotype in C/EBPβ−/− mice, C/EBPβ−/−;p19Arf−/− mice were generated. C/EBPβ−/−;p19Arf−/− mice responded to carcinogen treatment with increased p53 and apoptosis, indicating p19Arf is not essential. To ascertain whether oncogenic Ras activation induces aberrant p53 and apoptosis in C/EBPβ−/− epidermis, we generated K14-ER:Ras; C/EBPβ−/− mice. Oncogenic Ras activation induced by 4-hydroxytamoxifen did not produce increased p53 or apoptosis. Finally, when C/EBPβ−/− mice were treated with differing types of DNA-damaging agents, including alkylating chemotherapeutic agents, they displayed aberrant levels of p53 and apoptosis. These results indicate that C/EBPβ represses p53 to promote cell survival downstream of DNA damage and suggest that inhibition of C/EBPβ may be a target for cancer cotherapy to increase the efficacy of alkylating chemotherapeutic agents.
apoptosis; p53; C/EBPβ; p19Arf; DNA damage; keratinocytes
Large-scale protein–protein interaction data sets have been generated for several species including yeast and human and have enabled the identification, quantification, and prediction of cellular molecular networks. Affinity purification-mass spectrometry (AP-MS) is the preeminent methodology for large-scale analysis of protein complexes, performed by immunopurifying a specific “bait” protein and its associated “prey” proteins. The analysis and interpretation of AP-MS data sets is, however, not straightforward. In addition, although yeast AP-MS data sets are relatively comprehensive, current human AP-MS data sets only sparsely cover the human interactome. Here we develop a framework for analysis of AP-MS data sets that addresses the issues of noise, missing data, and sparsity of coverage in the context of a current, real world human AP-MS data set. Our goal is to extend and increase the density of the known human interactome by integrating bait–prey and cocomplexed preys (prey–prey associations) into networks. Our framework incorporates a score for each identified protein, as well as elements of signal processing to improve the confidence of identified protein–protein interactions. We identify many protein networks enriched in known biological processes and functions. In addition, we show that integrated bait–prey and prey–prey interactions can be used to refine network topology and extend known protein networks.
protein–protein interaction network; affinity purification-mass spectrometry; interactome
Selected members of the A2B3 (A = Sb, Bi; B = Se, Te) family are topological insulators. The Sb2Se3 compound does not exhibit any topological properties at ambient conditions; a recent high-pressure study, however, indicated that pressure transforms Sb2Se3 from a band insulator into a topological insulator above ~2 GPa; in addition, three structural transitions were proposed to occur up to 25 GPa. Partly motivated by these results, we have performed x-ray diffraction and Raman spectroscopy investigations on Sb2Se3 under pressure up to 65 GPa. We have identified only one reversible structural transition: the initial Pnma structure transforms into a disordered cubic bcc alloy above 51 GPa. On the other hand, our high-pressure Raman study did not reproduce the previous results; we attribute the discrepancies to the effects of the different pressure transmitting media used in the high-pressure experiments. We discuss the structural behavior of Sb2Se3 within the A2B3 (A = Sb, Bi; B = Se, Te) series.
We evaluated the association between the county sprawl index, a measure of residential density and street accessibility, and physical activity and body mass index (BMI).
We conducted a multilevel cross-sectional analysis in a sample of Nurses’ Health Study participants living throughout the United States in 2000 to 2001 (n = 136 592).
In analyses adjusted for age, smoking status, race, and husband’s education, a 1-SD (25.7) increase in the county sprawl index (indicating a denser, more compact county) was associated with a 0.13 kilograms per meters squared (95% confidence interval [CI] = −0.18, −0.07) lower BMI and 0.41 (95% CI = 0.17, 0.65) more metabolic equivalent (MET) hours per week of total physical activity, 0.26 (95% CI = 0.19, 0.33) more MET hours per week of walking, and 0.47 (95% CI = 0.34, 0.59) more MET hours per week of walking, bicycling, jogging, and running. We detected potential effect modification for age, previous disease status, husband’s education level (a proxy for socioeconomic status), and race.
Our results suggest that living in a dense, compact county may be conducive to higher levels of physical activity and lower BMI in women.
At this time, compared with mainstream (Caucasian) youth, cultural minority adolescents experience more severe substance-related consequences and are less likely to receive treatment. While several empirically supported interventions (ESIs), such as motivational interviewing (MI), have been evaluated with mainstream adolescents, fewer published studies have investigated the fit and efficacy of these interventions with cultural minority adolescents. Additionally, many empirical evaluations of ESIs have not explicitly attended to issues of culture, race, and socioeconomic background in their analyses. As a result, there is some question about the external validity of ESIs, particularly in disadvantaged cultural minority populations. This review seeks to take a step towards filling this gap, by addressing how to improve the fit and efficacy of ESIs like MI with cultural minority youth. Specifically, this review presents the existing literature on MI with cultural minority groups (adult and adolescent), proposes two approaches for evaluating and adapting this (or other) behavioral interventions, and elucidates the rationale, strengths, and potential liabilities of each tailoring approach.
substance abuse; treatment; cultural minority; adolescents
Campylobacter jejuni is a major cause of bacterial diarrheal disease worldwide. The organism is characterized by a diversity of polysaccharide structures, including a polysaccharide capsule. Most C. jejuni capsules are known to be decorated nonstoichiometrically with methyl phosphoramidate (MeOPN). The capsule of C. jejuni 81-176 has been shown to be required for serum resistance, but here we show that an encapsulated mutant lacking the MeOPN modification, an mpnC mutant, was equally as sensitive to serum killing as the nonencapsulated mutant. A nonencapsulated mutant, a kpsM mutant, exhibited significantly reduced colonization compared to that of wild-type 81-176 in a mouse intestinal colonization model, and the mpnC mutant showed an intermediate level of colonization. Both mutants were associated with higher levels of interleukin 17 (IL-17) expression from lamina propria CD4+ cells than from cells from animals infected with 81-176. In addition, reduced levels of Toll-like receptor 4 (TLR4) and TLR2 activation were observed following in vitro stimulation of human reporter cell lines with the kpsM and mpnC mutants compared to those with wild-type 81-176. The data suggest that the capsule polysaccharide of C. jejuni and the MeOPN modification modulate the host immune response.
A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.
CHD1; homozygous deletion; prostate cancer
Quantitative measurement of blood–brain barrier (BBB) permeability using MRI and its application to cerebral ischemia are reviewed. Measurement of BBB permeability using MRI has been employed to evaluate ischemic damage during acute and subacute phases of stroke and to predict hemorrhagic transformation. There is also an emerging interest on the development and use of MRI to monitor vascular structural changes and angiogenesis during stroke recovery. In this review, we describe MRI BBB permeability and susceptibility-weighted MRI measurements and its applications to evaluate ischemic damage during the acute and subacute phases of stroke and vascular remodeling during stroke recovery.
Blood–brain barrier permeability; Blood-to-brain transfer constant; Hemorrhage; Angiogenesis; Vascular remodeling; Ischemia; Dynamic contrast-enhanced MRI; MRI
In this article, we consider the implications of Murray Last’s (1981)
Knowing About Not Knowing for the study of ethnoveterinary knowledge of mobile pastoralists in the Far North Region of Cameroon. Specifically, we ask two interrelated questions: (1) what is the nature of this knowledge, and (2) what is the best way to study it? We conducted a study of pastoralists’ knowledge of human and animal infectious diseases to evaluate the claim that mobile pastoralists in the Chad Basin do not have a concept for zoonotic diseases. We used a combination of free lists and semi-structured interviews to study pastoralists’ knowledge. The results suggest that pastoralists do not have a concept for zoonotic diseases. Moreover, we found considerable variation in pastoralists’ ethnoveterinary knowledge and examples of not knowing, which contrasts with previous studies that do not describe much variation in ethnoveterinary knowledge. In our discussion, we consider to what extent descriptions of ethnoveterinary knowledge are the product of researchers’ conceptual framework and methodology.
ethnoveterinary knowledge; zoonotic diseases; practical knowledge; pastoral systems; Africa
Several anatomical attributes of the human corpus callosum (CC) including the midsagittal cross-sectional area, thickness, and volume, have been used to assess CC integrity. We extended our previous lifespan quantitative diffusion tensor imaging (DTI) study of the regional CC midsagittal areas to include the CC volumes obtained from DTI fiber tracking. In addition to the entire CC tracked subvolumes we normalized volume with respect to each subject’s intracranial volume (ICV) and the corresponding DTI metrics of the different specialized fiber pathways of the CC on a cohort of 99 right-handed children and adults aged 7–59 years. Results indicated that the CC absolute volume, the normalized volume fraction, and the fractional anisotropy followed inverted U-shaped curves, while the radial diffusivities followed a U-shaped curve reflecting white matter progressive and regressive myelination dynamics that continue into young adulthood. Our study provides for the first time normative baseline macro- and microstructural age trajectories of the human CC subvolumes across the lifespan that can be helpful for normative behavioral and clinical studies.
Diffusion tensor imaging; Fiber tracking; Corpus callosum; Child; Adult; Brain development; Aging; Lifespan; Witelson subdivisions
This study compared mathematical outcomes in children with predominantly moderate to severe traumatic brain injury (TBI; n =50) or orthopedic injury (OI; n=47) at 2 and 24 months post-injury. Working memory and its contribution to math outcomes at 24 months post-injury was also examined. Participants were administered an experimental cognitive addition task and standardized measures of calculation, math fluency, and applied problems; as well as experimental measures of verbal and visual-spatial working memory. Although children with TBI did not have deficits in foundational math fact retrieval, they performed more poorly than OIs on standardized measures of math. In the TBI group, performance on standardized measures was predicted by age at injury, socioeconomic status, and the duration of impaired consciousness. Children with TBI showed impairments on verbal, but not visual working memory relative to children with OI. Verbal working memory mediated group differences on math calculations and applied problems at 24 months post-injury. Children with TBI have difficulties in mathematics, but do not have deficits in math fact retrieval, a signature deficit of math disabilities. Results are discussed with reference to models of mathematical cognition and disability and the role of working memory in math learning and performance for children with TBI.
Head injury; Cognitive addition; Math fluency; Calculation; Math problem solving; Verbal working memory; Visual-spatial working memory
Affinity-purification mass spectrometry (AP-MS) is the preeminent technique for identification of eukaryotic protein complexes in vivo. AP-MS workflows typically express epitope-tagged bait proteins, immunopurify, and then identify associated protein complexes using mass spectrometry. However, challenges of existing strategies include the construction of expression vectors for large open reading frames and the possibility that overexpression of bait proteins may result in expression of nonphysiological levels of the bait protein with concomitant perturbation of endogenous protein complexes. To address these issues, we use human cell lines with epitope-tagged endogenous genes as AP-MS substrates to develop a platform that we call “knock-in AP-MS”, thereby avoiding the challenges of expression vector construction and ensuring that expression of tagged proteins is driven by endogenous regulatory mechanisms. Using three different bait genes (MRE11A, DNMT1 and APC), we show that cell lines expressing epitope-tagged endogenous genes make good substrates for sensitive and reproducible identification of protein interactions using AP-MS. In particular, we identify novel interactors of the important oncoprotein Adenomatous Polyposis Coli (APC), including an interaction with Flightless-1 homologue (FLII) that is enriched in nuclear fractions.
Protein-protein interactions; protein complexes; epitope-tagging; knock-in; AP-MS; colorectal cancer; Adenomatous Polyposis Coli
Preliminary discoveries of the efficacy of cell therapy are currently being translated to clinical trials. Whereas a significant amount of work has been focused on cell therapy applications for a wide array of diseases, including cardiac disease, bone disease, hepatic disease, and cancer, there continues to be extraordinary anticipation that stem cells will advance the current therapeutic regimen for acute neurological disease. Traumatic brain injury is a devastating event for which current therapies are limited. In this report the authors discuss the current status of using adult stem cells to treat traumatic brain injury, including the basic cell types and potential mechanisms of action, preclinical data, and the initiation of clinical trials.
cell therapy; clinical trial; stem cells; traumatic brain injury
Behavioral dysregulation is a common and detrimental consequence of traumatic brain injury (TBI) in children that contributes to poor academic achievement and deficits in social development. Unfortunately, behavioral dysregulation is difficult to predict from either injury severity or early neuropsychological evaluation. The uncinate fasciculus (UF) connects orbitofrontal and anterior temporal lobes, which are commonly implicated in emotional and behavioral regulation. Using probabilistic diffusion tensor tractography (DTT), we examined the relationship between the integrity of the UF 3 months post-injury and ratings of executive functions 12 months post-injury in children with moderate to severe TBI and a comparison group with orthopedic injuries. As expected, fractional anisotropy of the UF was lower in the TBI group relative to the orthopedic injury group. DTT metrics from the UF served as a biomarker and predicted ratings of emotional and behavior regulation, but not metacognition. In contrast, the Glasgow Coma Scale score was not related to either UF integrity or to executive function outcomes. Neuroanatomical biomarkers like the uncinate fasciculus may allow for early identification of behavioral problems and allow for investigation into the relationship of frontotemporal networks to brain-behavior relationships.
Diffusion tensor imaging; Executive function; Neuropsychology; Child; Anisotropy; Behavior
The purpose of this study was to investigate the effects of pediatric traumatic brain injury (TBI) on verbal and visual-spatial working memory (WM). WM tasks examined memory span through recall of the last item of a series of stimuli. Additionally, both verbal and visual-spatial tests had a dual-task condition assessing the effect of increasing demands on the central executive (CE). Inhibitory control processes in verbal WM were examined through intrusion errors. The TBI group (n = 73) performed more poorly on verbal and visual-spatial WM tasks than orthopedic-injured children (n = 30) and non-injured children (n = 40). All groups performed more poorly on the dual-task conditions, reflecting an effect of increasing CE load. This effect was not greater for the TBI group. There were no group differences in intrusion errors on the verbal WM task, suggesting that problems in WM experienced by children with TBI were not primarily due to difficulties in inhibitory control. Finally, injury-related characteristics, namely days to follow commands, accounted for significant variance in WM performance, after controlling for relevant demographic variables. Findings suggest that WM impairments in TBI are general rather than modality-specific and that severity indices measured over time are better predictors of WM performance than those taken at a single time point.
Traumatic brain injury; Pediatric; Working memory; Inhibitory control; Dual-task; Outcome
Traumatic brain injury (TBI) and orthopedic injury (OI) patients are prone to anxiety and mood disorders. In the present study, we integrated anatomical and diffusion tensor neuroimaging to investigate structural properties of the amygdala and hippocampus, gray matter regions implicated in anxiety and mood disorders. Children and adolescents were evaluated during the late sub-acute phase of recovery following trauma resulting from either moderate to severe TBI or OI. Mean diffusivity (MD) of the amygdala and hippocampus was elevated following TBI. An interaction of hemisphere, structure, and group revealed that MD of the right amygdala was elevated in females with TBI. Self-reported anxiety scores were not related to either volume or microstructure of the hippocampus, or to volume or fractional anisotropy of the amygdala. Left amygdala MD in the TBI group accounted for 17.5% of variance in anxiety scores. Anxiety symptoms may be mediated by different mechanisms in patients with TBI or OI.
Anxiety; Amygdala; DTI; TBI; Children
RP105 (CD180) is TLR4 homologue lacking the intracellular TLR4 signaling domain and acts a TLR accessory molecule and physiological inhibitor of TLR4-signaling. The role of RP105 in vascular remodeling, in particular post-interventional remodeling is unknown.
Methods and Results
TLR4 and RP105 are expressed on vascular smooth muscle cells (VSMC) as well as in the media of murine femoral artery segments as detected by qPCR and immunohistochemistry. Furthermore, the response to the TLR4 ligand LPS was stronger in VSMC from RP105−/− mice resulting in a higher proliferation rate. In RP105−/− mice femoral artery cuff placement resulted in an increase in neointima formation as compared to WT mice (4982±974 µm2 vs.1947±278 µm2,p = 0.0014). Local LPS application augmented neointima formation in both groups, but in RP105−/− mice this effect was more pronounced (10316±1243 µm2 vs.4208±555 µm2,p = 0.0002), suggesting a functional role for RP105. For additional functional studies, the extracellular domain of murine RP105 was expressed with or without its adaptor protein MD1 and purified. SEC-MALSanalysis showed a functional 2∶2 homodimer formation of the RP105-MD1 complex. This protein complex was able to block the TLR4 response in whole blood ex-vivo. In vivo gene transfer of plasmid vectors encoding the extracellular part of RP105 and its adaptor protein MD1 were performed to initiate a stable endogenous soluble protein production. Expression of soluble RP105-MD1 resulted in a significant reduction in neointima formation in hypercholesterolemic mice (2500±573 vs.6581±1894 µm2,p<0.05), whereas expression of the single factors RP105 or MD1 had no effect.
RP105 is a potent inhibitor of post-interventional neointima formation.