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Spinal cord injury (SCI) results in an acute reduction in neuronal and glial cell viability, disruption in axonal tract integrity, and prolonged increases in glial activity and inflammation, all of which can influence regional metabolism and glucose utilization. To date, the understanding of glucose uptake and utilization in the injured spinal cord is limited. Positron emission tomography (PET)-based measurements of glucose uptake may therefore serve as a novel biomarker for SCI. This study aimed to determine the acute and sub-acute glucose uptake pattern after SCI to determine its potential as a novel non-invasive tool for injury assessment and to begin to understand the glucose uptake pattern following acute SCI. Briefly, adult male Sprague-Dawley rats were subjected to moderate contusion SCI, confirmed by locomotor function and histology. PET imaging with [(18)F] Fluorodeoxyglucose (FDG) was performed prior to injury and at 6 and 24h and 15days post-injury (dpi). FDG-PET imaging revealed significantly depressed glucose uptake at 6h post-injury at the lesion epicenter that returned to sham/naïve levels at 24h and 15 dpi after moderate injury. FDG uptake at 15 dpi was likely influenced by a combination of elevated glial presence and reduced neuronal viability. These results show that moderate SCI results in acute depression in glucose uptake followed by an increase in glucose uptake that may be related to neuroinflammation. This acute and sub-acute uptake, which is dependent on cellular responses, may represent a therapeutic target., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

We propose and demonstrate a read-out technique for a superconducting qubit by dispersively coupling it with a Josephson parametric oscillator. We employ a tunable quarter wavelength superconducting resonator and modulate its resonant frequency at twice its value with an amplitude surpassing the threshold for parametric instability. We map the qubit states onto two distinct states of classical parametric oscillation: one oscillating state, with 185±15 photons in the resonator, and one with zero oscillation amplitude. This high contrast obviates a following quantum-limited amplifier. We demonstrate proof-of-principle, single-shot read-out performance, and present an error budget indicating that this method can surpass the fidelity threshold required for quantum computing.

High-resolution tracking of stem cells remains a challenging task. An ultra-bright contrast agent with extended intracellular retention is suitable for in vivo high-resolution tracking of stem cells following the implantation. Here, a plasmonic-active nanoplatform was developed for tracking mesenchymal stromal cells (MSCs) in mice. The nanoplatform consisted of TAT peptide-functionalized gold nanostars (TAT-GNS) that emit ultra-bright two-photon photoluminescence capable of tracking MSCs under high-resolution optical imaging. In vitro experiment showed TAT-GNS-labeled MSCs retained a similar differentiability to that of non-labeled MSCs controls. Due to their star shape, TAT-GNS exhibited greater intracellular retention than that of commercial Q-Tracker. In vivo imaging of TAT-GNS-labeled MSCs five days following intra-arterial injections in mice kidneys showed possible MSCs implantation in juxta-glomerular (JG) regions, but non-specifically in glomeruli and afferent arterioles as well. With future design to optimize GNS labeling specificity and clearance, plasmonic-active nanoplatforms may be a useful intracellular tracking tool for stem cell research. An ultra-bright intracellular contrast agent is developed using TAT peptide-functionalized gold nanostars (TAT-GNS). It poses minimal influence on the stem cell differentiability. It exhibits stronger two-photon photoluminescence and superior labeling efficiency than commercial Q-Tracker. Following renal implantation, some TAT-GNS-labeled MSCs permeate blood vessels and migrate to the juxta-glomerular region., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18-24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 <350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.

In the Canadian forensic mental health system, a person found Not Criminally Responsible on account of Mental Disorder (NCRMD) and given a conditional discharge returns to the community while remaining under the jurisdiction of a provincial/territorial Review Board. However, the individual can be re-hospitalized while on conditional discharge, for reasons such as substance use, violation of conditions, or violence. We investigated whether being re-hospitalized has an impact on the factors associated with the subsequent Review Board disposition. Persons found NCRMD from the three largest Canadian provinces who were conditionally discharged at least once during the observation period were included in the sample (N = 1,367). These individuals were involved in 2,920 disposition hearings; nearly one-third of patients (30%) were re-hospitalized after having been conditionally discharged by the Review Board. The factors examined included the scales of the Historical Clinical Risk Management-20 and salient behavior that occurred since the previous hearing, such as substance use or violence. The greater presence of clinical items resulted in a greater likelihood of a hospital detention decision at the next hearing. The effect was larger for the re-hospitalized group than for the group who successfully remained in the community since the last hearing. The results suggest that dynamic factors, specifically indicators of mental health, are heavily weighted by the Review Boards, consistent with the literature on imminent risk and in line with the NCRMD legislation. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: There is very little published work on the visual needs of homeless people. This paper is the first study to investigate the visual needs of homeless people in the UK. Although similar work has been done in other countries, this study is unique because the United Kingdom is the only country with a National Health Service which provides free healthcare at the point of access. This study analysed the refractive status of the sample used, determined the demographics of homeless people seeking eye care and established if there is a need for community eye health with access to free spectacle correction in East London., Methods: This retrospective case study analysed the clinical records of 1,141 homeless people using the Vision Care for Homeless People services at one of their clinics in East London. All eye examinations were carried out by qualified optometrists and, where appropriate, spectacles were dispensed to patients. Data captured included age, gender, ethnicity and refractive error. Results were analysed using two-sample t-tests with Excel and Minitab., Results: Demographics of age, gender and ethnicity are described. Spherical equivalents (SE) were calculated from prescription data available for 841 clinic users. Emmetropia was defined as SE-0.50DS to +1DS, myopia as SE < -0.50DS, and hyperopia as SE > +1DS. The majority of clinic users were male (79.2 %, n = 923). Approximately 80 % (n = 583) of clinic users were white, 10 % (n = 72) were 'black', 4 % (n = 29) 'Asian' and the remaining 5.6 % (n = 40) were of 'mixed ethnicity' and 'other' groups. The mean age of females attending the clinic was significantly lower than that of males (45.9 years, SD = 13.8 vs' 48.4 years, SD = 11.8) when analysed using a two-sample t-test (t (317) = 2.44, p = 0.02). One third of service users were aged between 50-59 years. Myopia and hyperopia prevalence rates were 37.0 % and 21.0 % respectively. A total of 34.8 % of homeless people were found to have uncorrected refractive error, and required spectacle correction., Conclusions: This study has identified a high proportion of uncorrected refractive error in this sample and therefore a need for regular eye examinations and provision of refractive correction for homeless people.

Importance: Human immunodeficiency virus (HIV) diagnoses continue to increase among young men who have sex with men (YMSM). Many YMSM living with HIV engage in sexual risk behaviors, and those who have a detectable viral load can transmit HIV to sex partners. Understanding factors that are related to sexual risk taking among virologically detectable (VL+) YMSM can inform prevention and treatment efforts., Objectives: To describe differences between virologically suppressed (VL-) and VL+ YMSM living with HIV and to identify correlates of condomless anal intercourse (CAI) and serodiscordant CAI among VL+ YMSM., Design, Setting, and Participants: In this cross-sectional survey conducted from December 1, 2009, through June 30, 2012, we studied 991 HIV-infected YMSM 15 to 26 years of age at 20 adolescent HIV clinics in the United States. Data analysis was conducted December 1, 2013, through July 31, 2015., Main Outcomes and Measures: Demographic, behavioral, and psychosocial assessments obtained using audio computer-assisted self-interviews. Viral load information was obtained via blood draw or medical record abstraction., Results: Of the 991 participants, 688 (69.4%) were VL+ and 458 (46.2%) reported CAI, with 310 (31.3%) reporting serodiscordant CAI in the past 3 months. The VL+ YMSM were more likely than the VL- YMSM to report CAI (detectable, 266 [54.7%]; suppressed, 91 [44.4%]; P = .01) and serodiscordant CAI (detectable, 187 [34.9%]; suppressed, 57 [25.0%]; P < .01). Multivariable analyses indicated that among VL+ YMSM, those reporting problematic substance use were more likely to report CAI (adjusted odds ratio [AOR], 1.46; 95% CI, 1.02-2.10) and serodiscordant CAI (AOR, 1.45; 95% CI, 1.06-1.99). Black VL+ YMSM were less likely to report CAI (AOR, 0.63; 95% CI, 0.44-0.90) or serodiscordant CAI (AOR, 0.66; 95% CI, 0.46-0.94) compared with other VL+ YMSM. In addition, VL+ YMSM who disclosed their HIV status to sex partners were more likely to report CAI compared with nondisclosing YMSM (AOR, 1.35; 95% CI, 1.01-1.81). Transgender participants were less likely to report CAI than cisgender participants (AOR, 0.35; 95% CI, 0.14-0.85). Last, VL+ YMSM who reported currently being employed were less likely to report serodiscordant CAI than those who were unemployed (AOR, 0.74; 95% CI, 0.55-0.99)., Conclusions and Relevance: Targeted multilevel interventions are needed to reduce HIV transmission risk behaviors among YMSM living with HIV, particularly among those who are VL+.

We report here the full mitochondrial genome sequence of Limonius californicus, a species of click beetle that is an agricultural pest in its larval form. The circular genome is 16.5 kb and contains 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes., (Copyright © 2016 Gerritsen et al.)

The neurotensin receptor-3 also known as sortilin was the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) discovered two decades ago in the human brain. The expression of sortilin is not confined to the nervous system but sortilin is ubiquitously expressed in many tissues. Sortilin has multiple roles in the cell as a receptor or a co-receptor, in protein transport of many interacting partners to the plasma membrane, to the endocytic pathway and to the lysosomes for protein degradation. Sortilin could be considered as the cells own shuttle system. In many human diseases including neurological diseases and cancer, sortilin expression has been shown to be deregulated. In addition, some studies have highlighted that the extracellular domain of sortilin is shedded into the culture media by an unknown mechanism. Sortilin can be released in exosomes and appears to control some mechanisms of exosome biogenesis. In lung cancer cells, sortilin can associate with two receptor tyrosine kinase receptors called the TES complex found in exosomes. Exosomes carrying the TES complex can convey a microenvironment control through the activation of ErbB signaling pathways and the release of angiogenic factors. Deregulation of sortilin function is now emerging to be implicated in four major human diseases- cardiovascular disease, Type 2 diabetes mellitus, Alzheimer disease and cancer.

Endoproteolysis is a normal post-translational process in the eukaryotic cell that plays a role in protein evolution allowing protein catabolism and the generation of amino acids. Endoproteolytic cleavage regulates many crucial cellular processes including the activity of many proteins, their protein-protein interactions and the amplification of cell signals. Not surprisingly, disruption or alternation of endoproteolytic cleavage may be the root cause of many human diseases such as Alzheimer's disease, Huntington's disease and prion diseases. Most neurodegenerative diseases (ND) are caused by the build-up of misfolded proteins and the promotion of aggregation events. A common event that occurs in these ND is the alteration of endoproteolytic cleavage due to genetic mutations of the associated-proteases or target substrate. Endoproteolytic cleavage resulting in protein truncation has significant effects on the structure and function of a protein representing a common feature of ND. In this review, we will discuss the endoproteolytic cleavage events that lead to ND, namely Alzheimer's disease, Huntington's disease and prion diseases.

Lung cancer is the most common cause of cancer- related death worldwide, causing over 1.2 million deaths each year. Non-small-cell lung cancer (NSCLC) consists of a group of malignancies that are pathologically and molecularly diverse but that are all characterised by a poor prognosis. Survival rates for lung cancer patients have improved very slowly and only to a modest degree owing partly to poor funding for research into this malignancy and stigma associated with smoking, as well as relative chemo-resistance. However, in recent years, NSCLC has become an exemplar for precision medicine, mainly following development of drugs targeting the receptors of epidermal growth factor and anaplastic lymphoma kinase. While epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors are only applicable to a minority of patients and benefits are almost invariably short-lived, current studies indicate that at least 50% of patients with NSCLC have a targetable mutation. With a growing armamentarium of inhibitors against these targets in development, there is a hope that a greater proportion of patients will benefit from precision medicine and that such benefits will be sustained. However, there remain significant challenges in the development of precision medicine in NSCLC. These include: identification and validation of new targets; ensuring biopsies are fit for purpose; tumour heterogeneity; requirements for serial tumour assessments; and not least cost. In this review, we will discuss the current status of precision medicine in NSCLC as well as how basic and translational research are paving the way towards overcoming the above challenges. In addition, we will pay attention to clinical strategies in respect to liquid biopsies and the potential use of extracellular vesicles such as exosomes in cancer therapeutics.

Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues.

Background: Clostridium thermocellum is a promising consolidated bioprocessing candidate organism capable of directly converting lignocellulosic biomass to ethanol. Current ethanol yields, productivities, and growth inhibitions are industrial deployment impediments for commodity fuel production by this bacterium. Redox imbalance under certain conditions and in engineered strains may contribute to incomplete substrate utilization and may direct fermentation products to undesirable overflow metabolites. Towards a better understanding of redox metabolism in C. thermocellum, we established continuous growth conditions and analyzed global gene expression during addition of two stress chemicals (methyl viologen and hydrogen peroxide) which changed the fermentation redox potential., Results: The addition of methyl viologen to C. thermocellum DSM 1313 chemostat cultures caused an increase in ethanol and lactate yields. A lower fermenter redox potential was observed in response to methyl viologen exposure, which correlated with a decrease in cell yield and significant differential expression of 123 genes (log2 > 1.5 or log2 < -1.5, with a 5 % false discovery rate). Expression levels decreased in four main redox-active systems during methyl viologen exposure; the [NiFe] hydrogenase, sulfate transport and metabolism, ammonia assimilation (GS-GOGAT), and porphyrin/siroheme biosynthesis. Genes encoding sulfate transport and reduction and porphyrin/siroheme biosynthesis are co-located immediately downstream of a putative iscR regulatory gene, which may be a cis-regulatory element controlling expression of these genes. Other genes showing differential expression during methyl viologen exposure included transporters and transposases., Conclusions: The differential expression results from this study support a role for C. thermocellum genes for sulfate transport/reduction, glutamate synthase-glutamine synthetase (the GS-GOGAT system), and porphyrin biosynthesis being involved in redox metabolism and homeostasis. This global profiling study provides gene targets for future studies to elucidate the relative contributions of prospective pathways for co-factor pool re-oxidation and C. thermocellum redox homeostasis.

Periodic quantum-chemistry methods as implemented in the CRYSTAL14 code were considered to analyse the interaction of acid clinoptilolite with water. Initially adsorbed molecules hydrolyse the Al-O bonds, giving rise to defective dealuminated materials. A suitable and representative periodic model of the partially disordered hydrated H-zeolite is the primitive cell (18 T sites) of a decahydrated trialuminated structure of HEU topology. The water distribution inside the material cavities was initially investigated. The model considered for further dealumination was the most stable one from those generated through a combined force field Monte Carlo and ab initio optimization strategy. Optimizations and energy estimations were made at the hybrid DFT level of theory (PBE0 functional) with an atomic basis set of VDZP quality. The energetics of the different pathways involved in the dealumination process was addressed by considering the Gibbs free energy with thermal and zero-point corrections through phonon analysis. It arises that hydrated models exhibit protonated water clusters stabilized by different kinds of H-bonds. The first Al extraction is slightly more energetically favourable from T3 than T2 sites, but at the same time the latter is more probable owing to its larger Al population. However, concerning the second dealumination step, it is more favourable removing the Al atom from both remaining sites after a starting abstraction from T2 rather than T3. These facts determine that the most probable overall pathways go through a first Al removal from T2. The agreement with experimental results is discussed.

Purpose: The present study examines religiousness and its connection to suicidal thoughts, plans, and attempts among Trinidad and Tobago adolescents and young adults., Method: Data are from Trend Research Empowering National Development on adolescents and young adults in Trinidad and Tobago (N = 4448). Religious affiliation, self-perceived religiousness, attendance at religious services, prayer frequency, socio-demographic variables, and suicidal thoughts, plans, and attempts were assessed., Results: Compared to nonreligious, Catholics (OR 0.63, p < 0.05) and Seventh-day Adventists (OR 0.47, p < 0.01) were less likely to think about suicide, and hindus (OR 5.81, p < 0.05) and other affiliates (OR 7.28, p < 0.01) were more likely to be treated for suicide. Higher self-rated religiosity was related to lower likelihood of thinking about suicide (OR 0.86, p < 0.01) and lower likelihood of planning suicide (OR 0.78, p < 0.001). Attendance at religious services was related to lower likelihood of thinking about suicide (OR 0.94, p < 05) and fewer suicide attempts (β = -0.11, p < 0.01). More frequent prayer was related to lower likelihood of thinking about suicide (OR 0.92, p < 0.01) and lower likelihood of planning suicide (OR 0.90, p < 0.001)., Conclusions: Religiousness may offer benefits for adolescents and young adults in Trinidad and Tobago by reducing the likelihood that they engage in suicide thoughts and behaviors. Results may hold implications for counselors, clergy, teachers, and others working with adolescents and young adults in Trinidad and Tobago.

In order for an animal to survive, the heart beat must go on in all environmental conditions, or at least restart its beat. This review is about maintaining a rhythmic heartbeat under the extreme conditions of anoxia (or very severe hypoxia) and high temperatures. It starts by considering the primitive versions of the protein channels that are responsible for initiating the heartbeat, HCN channels, divulging recent findings from the ancestral craniate, the Pacific hagfish (Eptatretus stoutii). It then explores how a heartbeat can maintain a rhythm, albeit slower, for hours without any oxygen, and sometimes without autonomic innervation. It closes with a discussion of recent work on fishes, where the cardiac rhythm can become arrhythmic when a fish experiences extreme heat., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Considerable resources are spent on habitat restoration across the globe to counter the impacts of habitat loss and degradation on wildlife populations. But, because of time and resourcing constraints on many conservation programs, the effectiveness of these habitat restoration programs in achieving their long-term goals of improving the population viability of particular wildlife species is rarely assessed and many restoration programs cannot demonstrate their effectiveness. Without such demonstration, and in particular demonstrating the causal relationships between habitat restoration actions and demographic responses of the target species, investments in restoration to achieve population outcomes are of uncertain value., Approach: Here, we describe an approach that builds on population data collected for a threatened Australian bird - the Grey-crowned Babbler Pomatostomus temporalis - to evaluate how effectively targeted habitat restoration work improves its viability. We built upon an extensive historical survey by conducting surveys 13 years later at 117 sites stratified by presence/absence of restoration works and by detection or not of birds in the first survey. Our performance metric was the number of individuals in a social group, which is both a measure of local abundance and directly related to breeding success. We employed an occupancy model to estimate the response of Grey-crowned Babbler social group size to the effects of time, restoration works, local habitat as measured by the density of large trees, and distance to the nearest other known group of babblers., Results and Implications: Babbler group size decreased over the survey period at sites without restoration works, but restoration works were effective in stemming declines where they were done. Restoration was responsible for a difference of about one bird per group of 3-5 individuals; this is an important effect on the reproductive success of the social group. Effectiveness of restoration works targeted at the Grey-crowned Babbler was only demonstrable by sampling through time and including control sites without restoration works. This work demonstrates that while calls for better monitoring of restoration are valid, scope exists to recover a signal of effectiveness from opportunistic retrospective analyses.

Background: Research outputs in sub-Saharan Africa may be limited by a scarcity of clinical research expertise. In Zambia, clinical and biomedical postgraduate students are often delayed in graduation due to challenges in completing their research dissertations. We sought to strengthen institutional research capacity by supporting student and faculty researchers through weekly epidemiology and biostatistics clinics., Methods: We instituted a weekly Analytical Support Clinic at the University of Zambia, School of Medicine. A combination of biostatisticians, clinical researchers and epidemiologists meet weekly with clients to address questions of proposal development, data management and analysis. Clinic sign-in sheets were reviewed., Results: 109 students and faculty members accounted for 197 visits to the Clinic. Nearly all clients (107/109, 98.2%) were undergraduate or postgraduate students. Reasons for attending the Clinic were primarily for proposal development (46.7%) and data management/analysis (42.1%). The most common specific reasons for seeking help were data analysis and interpretation (36.5%), development of study design and research questions (26.9%) and sample size calculation (21.8%)., Conclusions: The Analytical Support Clinic is an important vehicle for strengthening postgraduate research through one-on-one and small group demand-driven interactions. The clinic approach supplements mentorship from departmental supervisors, providing specific expertise and contextual teaching.

Implantable cardioverter defibrillator (ICD) lead insulation failure and conductor externalization have been increasingly reported. The 7.8F silicon-insulated Linox SD and Linox S ICD leads (Biotronik, Berlin, Germany) were released in 2006 and 2007, respectively, with an estimated 85,000 implantations worldwide. A 39-year-old female suffered an out-of-hospital ventricular fibrillation (VF) arrest with successful resuscitation. An ICD was implanted utilizing a single coil active fixation Linox(Smart) S lead (Biotronik, Berlin, Germany). A device-triggered alert approximately 3 years after implantation confirmed nonphysiological high rate sensing leading to VF detection. A chest X-ray showed an abnormality of the ICD lead and fluoroscopic screening confirmed conductor externalization proximal to the defibrillator coil. In view of the combined electrical and fluoroscopic abnormalities, urgent lead extraction and replacement were performed. A review of Linox (Biotronik) and Vigila (Sorin Group, Milan, Italy) lead implantations within our center (n = 98) identified 3 additional patients presenting with premature lead failure, 2 associated with nonphysiological sensed events and one associated with a significant decrease in lead impedance. All leads were subsequently removed and replaced. This case provides a striking example of insulation failure affecting the Linox ICD lead and, we believe, is the first to demonstrate conductor externalization manifesting both electrical and fluoroscopic abnormalities., (© 2015 Wiley Periodicals, Inc.)

A 33-year-old, male professional scallop diver diving on the Outer Hebrides in Scotland rapidly developed symptoms of cerebral arterial gas embolism following a provocative dive with possibly a fast ascent. During transfer by helicopter to the mainland for treatment, his symptoms improved on surface oxygen. He was recompressed on a Royal Navy Treatment Table 62 (RN TT62) with complete resolution. Just over six weeks later, again diving on the Outer Hebrides and after adopting more conservative diving practices, he developed symptoms and signs of vestibular decompression sickness after a problem-free dive, with dizziness, poor co-ordination and gait, nausea and vomiting, and rotational vertigo. He was again transported to the mainland for recompression treatment. He received an extended RN TT62 and required five further Comex 12 (223 kPa) hyperbaric oxygen treatments over the following three days before he was symptom free. A 4 mm persistent foramen ovale (PFO) was subsequently diagnosed and he underwent successful closure of the defect with Amplatzer device and returned to commercial diving a year later.

Genetic polymorphism along mitochondrial DNA (mtDNA) defines population-specific signatures called mtDNA haplogroups. Estimation of mtDNA haplogroup distribution may be prone to errors, notably if the study sample is not drawn from a multicenter cohort. Here, we report on mtDNA diversity in a sample of African American individuals (n = 343) enrolled in a multicenter cohort. Sequencing of the hypervariable regions I and II of the D-loop control region showed that the most common mitochondrial variants are 73G, 146C, 150T, 152C, 189G, 16278T, and 16311C. In agreement with the published data, we observed 17 common mtDNA haplogroups: L0, L1, L1b, L1c, L2, L2a, L2b, L2c, L2e, L3, L3b, L3d, L3e, L3f, L3h, L3x, and L4. The most commonly observed haplogroup is L2a (19.8%), followed by L1b (10.2%). Overall, the observed mtDNA haplogroup distribution in our study is similar to those published for the African American and the African populations.

Background: Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited., Design: Adolescent Trials Network 061 examined changes over 48 weeks of cART in T-cell subsets and markers of T-cell and macrophage activation in subjects with pre-therapy CD4 > 350 cells/mm. All subjects had optimal viral suppression from weeks 24 through 48., Methods: Subjects (n = 48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls., Results: Significant increases over 48 weeks were noted in all CD4 populations, including total, naive, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA), whereas numbers of CM and EM RO CD8 cells declined significantly. By week 48, CD4 naive cells were similar to controls, whereas CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls., Conclusions: In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However, CD8 T-cell and macrophage activation persists at higher levels than uninfected controls.

The experimentally characterized ε and ζ phases of solid oxygen are studied by periodic Hartree-Fock (HF) and Density Functional Theory calculations at pressures from 10 to 160 GPa using different types of exchange-correlation functionals with Gaussian atomic basis sets. Full geometry optimizations of the monoclinic C2/m (O2)4 unit cell were done to study the evolution of the structural and electronic properties with pressure. Vibrational calculations were performed at each pressure. While periodic HF does not predict the ε-ζ phase transition in the considered range, Local Density approximation and Generalized Gradient approximation methods predict too low transition pressures. The performance of hybrid functional methods is dependent on the amount of non-local HF exchange. PBE0, M06, B3PW91, and B3LYP approaches correctly predict the structural and electronic changes associated with the phase transition. GGA and hybrid functionals predict a pressure range where both phases coexist, but only the latter type of methods yield results in agreement with experiment. Using the optimized (O2)4 unit cell at each pressure we show, through CASSCF(8,8) calculations, that the greater accuracy of the optimized geometrical parameters with increasing pressure is due to a decreasing multireference character of the unit cell wave function. The mechanism of the transition from the non-conducting to the conducting ζ phase is explained through the Electron Pair Localization Function, which clearly reveals chemical bonding between O2 molecules in the ab crystal planes belonging to different unit cells due to much shorter intercell O2-O2 distances.

Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

Objective: To state the sociodemographic characteristics, mental health histories, index offence characteristics, and criminal histories of male and female forensic psychiatric patients. Clinicians and researchers advocate that mental health and criminal justice organizations implement gender-specific services; however, few studies have sampled forensic patients to evaluate the extent to which men's and women's treatment and management needs are different., Method: Data were collected from Review Board files from May 2000 to April 2005 in the 3 largest Canadian provinces. Using official criminal records, participants were followed for 3 to 8 years, until December 2008. The final sample comprised 1800 individuals: 15.6% were women and 84.4% were men., Results: There were few demographic differences, but women had higher psychosocial functioning than men. Both men and women had extensive mental health histories; women were more likely diagnosed with mood disorders and PDs and men were more likely diagnosed with schizophrenia spectrum disorders and SUDs. The nature of the index offence did not differ by gender, except women were more likely to have perpetrated murders and attempted murders. For offences against a person, women were more likely to offend against offspring and partners and less likely to offend against strangers, compared with men. Women had significantly less extensive criminal histories than men., Conclusions: Not criminally responsible on account of mental disorder-accused women have a distinct psychosocial, clinical, and criminological profile from their male counterparts, which may suggest gender-specific assessment, risk management, and treatment in forensic services could benefit patients. The findings are also consistent with traditional models (Risk-Need-Responsivity) and ultimately demonstrate the importance of individual assessment and client-centred services.

Canadian legislation makes Review Boards (RBs) responsible for rendering dispositions for individuals found Not Criminally Responsible on account of Mental Disorder (NCRMD) after considering public safety, the mental condition of the accused, and his/her potential for community reintegration. We reviewed 6,743 RB hearings for 1,794 individuals found NCRMD in the three largest Canadian provinces to investigate whether items from two empirically supported risk assessment measures, the Historical Clinical Risk Management-20 and the Violence Risk Appraisal Guide, were considered. Less than half the items were included in expert reports or in RBs' reasons for dispositions, and consideration of these items differed according to gender and index offense severity of the accused. These items included evidence-based risk factors and/or legally specified criteria: mental health, treatment, and criminal history. These results illustrate the gap between research on risk factors and the integration of this evidence into practice. In particular, we recommend the implementation of structured measures to reduce the potential for clinicians to be unduly influenced by gender and offense severity., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: To measure rates of antiretroviral therapy (ART) use and virologic suppression among perinatally HIV-infected youth (PIY) and behaviorally HIV-infected youth (BIY) linked to care in the United States and examine the effects of demographic, biomedical, and psychosocial factors on those rates., Methods: Between 2009 and 2012, 649 PIY and 1547 BIY in 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions sites completed cross-sectional surveys through audio computer-assisted self-interviews. Viral load data were collected from chart abstraction or blood draw., Results: Overall 82.4% of PIY and 49.1% of BIY reported current ART use. Only 37.0% of PIY and 27.1% of BIY were virologically suppressed. Virologic suppression rates did not vary as a function of time since HIV diagnosis in either group. Consistent HIV care and no current substance abuse were significant correlates of ART use among PIY. These variables and non-African American race were some factors associated with virologic suppression for PIY [odds ratios (ORs) P < 0.05]. Among BIY, older age, heterosexuals, employment, and education were significantly related to ART use (ORs: P < 0.05); suppression was related to ART use ≥6 months, ≥90% ART adherence, and consistent HIV care (ORs: P < 0.05). Nearly 75% (n = 498) of nonsuppressed youth reported unprotected sex in the past 3 months., Conclusions: There are continued challenges with successfully treating youth even once diagnosed and linked to HIV care. Strategies targeting barriers to ART access, use, and virologic suppression are needed to optimize the impact of the "Treatment as Prevention" paradigm among PIY and BIY.

The evolution under pressures up to 65 GPa of structural, elastic and vibrational properties of the katoite hydrogarnet, Ca3Al2(OH)12, is investigated with an ab initio simulation performed at the B3LYP level of theory, by using all-electron basis sets with the Crystal periodic program. The high-symmetry Ia3d phase of katoite, stable under ambient conditions, is shown to be destabilized, as pressure increases, by interactions involving hydrogen atoms and their neighbors which weaken the hydrogen bonding network of the structure. The corresponding thermodynamical instability is revealed by anomalous deviations from regularity of its elastic constants and by numerous imaginary phonon frequencies, up to 50 GPa. Interestingly, as pressure is further increased above 50 GPa, the Ia3d structure is shown to become stable again (all positive phonon frequencies and regular elastic constants). However, present calculations suggest that, above about 15 GPa and up to at least 65 GPa, a phase of I4[combining macron]3d symmetry (a non-centrosymmetric subgroup of Ia3d) becomes more stable than the Ia3d one, being characterized by strengthened hydrogen bonds. At low-pressures (between about 5 GPa and 15 GPa), both phases show some instabilities (more so for I4[combining macron]3d than for Ia3d), thus suggesting either the existence of a third phase or a possible phase transition of second order.

As we enter the twenty-first century, several therapies based on using nanoparticles (NPs) ranging in size 1 - 1000 nm have been successfully brought to the clinic to treat cancer, pain and infectious diseases. These therapies bring together the ability of NPs to target the delivery of drugs more precisely, to improve solubility, to prevent degradation, to improve their therapeutic index and to reduce the immune response. NPs come in all shapes and sizes, designed specifically for biomedical applications such as solid lipid polymers, liposomes, dendrimers, nanogels, and quantum dots. These NPs offer many attractive characteristics such as biological stability and biocompatibility, thus incorporating different biological or drug molecules. Among the major therapeutic challenges from neurological diseases through to cancer is the development of nanomaterials that are able to be effective against the disease. In the case of neurodegeneration, one of the most difficult areas to penetrate for drug discovery in the body is the central nervous system, protected by the blood-brain-barrier. Whilst in the case of cancer, the biggest problem is how to specifically target a tumor with sufficient drug without causing side effects or inducing resistance. A new generation of intelligent NPs are emerging for the treatment of human disease such as neurological disorders and cancer. The use of natural alternative therapy is an encouraging idea in drug discovery. To this end as we gain more knowledge into the biological function of exosomes, this will allow us to harness their potential as natural NPs in future therapeutics.

Background: Insulation defects resulting in conductor externalization (CE) have been reported in the Riata family of implantable cardioverter defibrillator (ICD) leads (St. Jude Medical, Sylmar, CA, USA). The aim of this study was to identify, prospectively, the rate of CE and outcomes following this, within a group of patients with a Riata ICD lead., Methods: Patients with a Riata ICD lead attended for fluoroscopic screening and electrical assessment of the lead at yearly intervals between 2010 and 2012., Results: One hundred and forty patients had no or borderline evidence of CE on initial assessment in 2010. These patients were prospectively followed for 3 years (304.6 patient-years). During this time, 11 patients developed definite CE, equating to an event rate of 3.6 (95% confidence intervals: 1.8-6.5) per 100 patient-years of follow-up. Of those patients developing definite CE, one patient had the ICD lead explanted (for reasons unrelated to CE) and no patients died. CE was not associated with any electrical abnormalities of the ICD lead., Conclusions: CE was observed at a rate of 3.6 per 100 patient-years of follow-up, in 140 individuals with a Riata ICD lead and no definite evidence of CE at baseline., (©2014 Wiley Periodicals, Inc.)

Comparisons of in vivo (mouse stomach) and in vitro (laboratory culture) transcriptomes of Lactobacillus reuteri strain 100-23 were made by microarray analysis. These comparisons revealed the upregulation of genes associated with acid tolerance, including urease production, in the mouse stomach. Inactivation of the ureC gene reduced the acid tolerance of strain 100-23 in vitro, and the mutant was outcompeted by the wild type in the gut of ex-Lactobacillus-free mice. Urine analysis showed that stable isotope-labeled urea, administered by gavage, was metabolized to a greater extent in Lactobacillus-free mice than animals colonized by strain 100-23. This surprising observation was associated with higher levels of urease activity and fecal-type bacteria in the stomach digesta of Lactobacillus-free mice. Despite the modulation of urea hydrolysis in the stomach, recycling of urea nitrogen in the murine host was not affected since the essential amino acid isoleucine, labeled with a stable isotope, was detected in the livers of both Lactobacillus-free and 100-23-colonized animals. Therefore, our experiments reveal a new and unexpected impact of Lactobacillus colonization on urea hydrolysis in the murine gut., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The transfer of exosomes containing both genetic and protein materials is necessary for the control of the cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, and the mechanism of their action in membrane transport and related signaling events are not clearly understood. In this study, we demonstrate, in human lung cancer A549 cells, that the exosome release mechanism is closely linked to the multifaceted receptor sortilin (also called neurotensin receptor 3). Sortilin is already known to be important for cancer cell function. Here, we report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This new complex (termed the TES complex) is found in exosomes and results in the linkage of the two tyrosine kinase receptors TrkB (also known as NTRK2) and EGFR with sortilin. Using in vitro models, we demonstrate that this sortilin-containing complex exhibits a control on endothelial cells and angiogenesis activation through exosome transfer., (© 2014. Published by The Company of Biologists Ltd.)

Use of symmetry can dramatically reduce the computational cost (running time and memory allocation) of self-consistent-field ab initio calculations for molecular and crystalline systems. Crucial for running time is symmetry exploitation in the evaluation of one- and two-electron integrals, diagonalization of the Fock matrix at selected points in reciprocal space, reconstruction of the density matrix. As regards memory allocation, full square matrices (overlap, Fock, and density) in the Atomic Orbital (AO) basis are avoided and a direct transformation from the packed AO to the symmetry adapted crystalline orbital basis is performed, so that the largest matrix to be handled has the size of the largest sub-block in the latter basis. Quantitative examples, referring to the implementation in the CRYSTAL code, are given for high symmetry families of compounds such as carbon fullerenes and nanotubes.

Concurrent bilateral keratoconus and granular dystrophy is reported in a 32-year-old patient with decreased vision. Initially contact lenses were attempted unsuccessfully to treat the conditions. There are a handful of other reports of these combined pathologies in the literature, and the likelihood of a chance cause or possible genetic linkage between the conditions is discussed., (2014 BMJ Publishing Group Ltd.)

Objective: To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection., Design: HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study., Methods: The mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates., Results: We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta  = -0.08; Bonferroni-adjusted P = 0.004) with decline of CD4 T cells (median loss of 8 ± 1 cells per month) in HAART-naive HIV-infected individuals of African American descent (n = 133). No significant association (P < 0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4 T-cell recovery after antiretroviral therapy in African Americans., Conclusions: Whereas the L2 lineage showed an association with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection is an important step to be taken toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics.

Periodic quantum chemistry methods as implemented in the crystal09 code were considered to study acid clinoptilolite (HEU framework type), both anhydrous and hydrated. The most probable location of acid sites and water molecules together with other structural details has been the object of particular attention. Calculations were performed at hybrid and pristine DFT levels of theory with a VDZP quality basis set in order to compare performances. It arises that PBE0 provides the best agreement with experimental data as concerns structural features and the most stable Al distribution in the framework. The role of the water molecule distribution in the stability of the systems, the most probable structure that they induce in the material, and their eventual influence on further chemical modification processes, such as dealumination, are discussed in detail. Results show that, apart from the usually considered interactions of water molecules with the zeolite framework, that is, a H-bond with Brönsted acid sites and coordination with framework Al as Lewis ones, it is necessary to consider cooperation of other weaker effects so as to fully understand the hydration effect in this kind of materials.

The properties of the (n,n) icosahedral family of carbon fullerenes up to n = 10 (6000 atoms) have been investigated through ab initio quantum-mechanical simulation by using a Gaussian type basis set of double zeta quality with polarization functions (84,000 atomic orbitals for the largest case), the hybrid B3LYP functional and the CRYSTAL14 code featuring generalization of symmetry treatment. The geometry of giant fullerenes shows hybrid features, between a polyhedron and a sphere; as n increases, it approaches the former. Hexagon rings at face centres take a planar, graphene-like configuration; the 12 pentagon rings at vertices impose, however, a severe structural constraint to which hexagon rings at the edges must adapt smoothly, adopting a bent (rather than sharp) transversal profile and an inward longitudinal curvature. The HOMO and LUMO electronic levels, as well as the band gap, are well described using power laws. The gap is predicted to become zero for n ≥ 34 (69,360 atoms). The atomic excess energy with respect to the ideal graphene sheet goes to zero following the log(Nat)/Nat law, which is well described through the continuum elastic theory applied to graphene; the limits for the adopted model are briefly outlined. Compared to larger fullerenes of the series, C60 shows unique features with respect to all the considered properties; C240 presents minor structural and energetic peculiarities, too.

Background: KIR2DS4 gene variants encode full-length and truncated protein products, with only the former serving as membrane-bound receptors to activate natural killer (NK) cells. We have previously shown that full-length KIR2DS4 was associated with relatively high viral load and accelerated heterosexual HIV-1 transmission. Our objective here was to provide confirmatory data and to offer new insights about the potential mechanisms., Methodology/principal Findings: Mixed models for repeated (longitudinal) outcome measurements on 207 HIV-1 seropositive American youth revealed an association of full-length KIR2DS4 with relatively high viral load and low CD4+ T-cell count (p<0.01 for both). Depending on KIR2DS4 expression (presence or absence) on cell surface, NK cells from 43 individuals with untreated, chronic HIV-1 infection often differed in functional properties, including degranulation and secretion of IFN-γ and MIP-1β. In particular, polyfunctional NK cells were enriched in the KIR2DS4-positive subset., Conclusions/significance: Full-length KIR2DS4 promotes HIV-1 pathogenesis during chronic infection, probably through the maintenance of an excessively pro-inflammatory state.

Plasmonics-active gold nanostars exhibiting strong imaging contrast and efficient photothermal transduction were synthesized for a novel pulsed laser-modulated plasmonics-enhanced brain tumor microvascular permeabilization. We demonstrate a selective, optically modulated delivery of nanoprobes into the tumor parenchyma with minimal off-target distribution.

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a "golden rush" in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a "happy marriage" between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.

The ability to nondestructively detect the presence of a single, traveling photon has been a long-standing goal in optics, with applications in quantum information and measurement. Realizing such a detector is complicated by the fact that photon-photon interactions are typically very weak. At microwave frequencies, very strong effective photon-photon interactions in a waveguide have recently been demonstrated. Here we show how this type of interaction can be used to realize a quantum nondemolition measurement of a single propagating microwave photon. The scheme we propose uses a chain of solid-state three-level systems (transmons) cascaded through circulators which suppress photon backscattering. Our theoretical analysis shows that microwave-photon detection with fidelity around 90% can be realized with existing technologies.

Epidemiological data testifies the increasing incidence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Some associations were made between occidental lifestyle and development of these pathologies, moreover AD and T2DM are linked since each pathology is a causative risk factor for the other. Interestingly, autophagy, a catabolic pathway whose efficiency declines with age is importantly impaired in the affected tissues. Autophagy regulation is dependent of cell metabolic status and consequently on the 5'AMP-activated protein kinase (AMPK) and mammalian target of rapamycin signaling pathways. These pathways are altered with aging and molecular, pharmacological and physiological interventions increase lifespan in various organismal models and favours healthy aging diminishing the occurrence of age-related diseases such as diabetes, cancer, cardiovascular and neurodegenerative pathologies. Decreasing calorie intake has been known for a long time to have a beneficial effect on longevity and health. Some drug agonists of AMPK are known to mimic these effects such as metformin or resveratrol, a polyphenol extracted from plants and present in red wine, a component of the French paradox related diet. In this review, we present the epidemiological and pathogenesis links existing between AD and T2DM with an insight into the perturbations of the autophagic process highlighting the crucial role of the AMPK in development of age and metabolic related diseases. Hence, in a last part we will discuss the possible interventions susceptible to combat both T2DM and AD.

Acute radiation syndrome is induced when a significant portion of the body receives high-dose, as well as high-dose rate, radiation. We have previously identified a quinic acid-based derivative, KZ-41, that protects from radiation injury. Further preclinical efficacy studies were conducted to determine the radiomitigating activity of KZ-41. C57BL/6 mice received total body irradiation (TBI-LD₈₀/₃₀, ¹³⁷Cs; ∼2 min) followed by either normal saline or KZ-41 (100 mg/kg sc ∼26 h post-TBI). KZ-41 increased 30-day survival by approximately 45% compared with vehicle controls (P < 0.05). To further investigate the potential radiomodulating mechanisms of KZ-41, we developed a combined radiation and vascular injury model. C57BL/6 mice surgically fixed with dorsal windows for dermal vasculature imaging received either sham or TBI (¹³⁷Cs; 6 Gray). Postcapillary venule injury was induced (24, 48, 72, and 96 h post-TBI) followed by imaging at 5 min and 24 h to assess clot formation and blood flow. Impairment in flow (P < 0.05) and clot formation (P < 0.05) were observed as early as 48 and 72 h, respectively. Thus, vascular injury 72 h post-TBI was used to evaluate intervention (KZ-41; 100 mg/kg i.p. at 12, 36, and 60 h post-TBI) on radiation-induced changes in both flow and clot formation. KZ-41, although not improving flow, increased clot formation (P < 0.05). Platelet counts were lower in both irradiated groups compared with sham controls (P < 0.05). In summary, KZ-41 exerts radiomitigating activity in lethally irradiated mice. Imaging results suggest KZ-41 exerts radiomitigating activity through mechanisms involving promotion of initial clot formation and vascular flow restoration. The imaging model described herein is useful for further examination of radiation-induced vascular injury repair mechanisms., (© 2013 Wiley Periodicals, Inc.)

Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States and is a contributing factor to one third of all injury related deaths annually. According to the CDC, approximately 75% of all reported TBIs are concussions or considered mild in form, although the number of unreported mild TBIs (mTBI) and patients not seeking medical attention is unknown. Currently, classification of mTBI or concussion is a clinical assessment since diagnostic imaging is typically inconclusive due to subtle, obscure, or absent changes in anatomical or physiological parameters measured using standard magnetic resonance (MR) or computed tomography (CT) imaging protocols. Molecular imaging techniques that examine functional processes within the brain, such as measurement of glucose uptake and metabolism using [(18)F]fluorodeoxyglucose and positron emission tomography (FDG-PET), have the ability to detect changes after mTBI. Recent technological improvements in the resolution of PET systems, the integration of PET with magnetic resonance imaging (MRI), and the availability of normal healthy human databases and commercial image analysis software contribute to the growing use of molecular imaging in basic science research and advances in clinical imaging. This review will discuss the technological considerations and limitations of FDG-PET, including differentiation between glucose uptake and glucose metabolism and the significance of these measurements. In addition, the current state of FDG-PET imaging in assessing mTBI in clinical and preclinical research will be considered. Finally, this review will provide insight into potential critical data elements and recommended standardization to improve the application of FDG-PET to mTBI research and clinical practice.

Object: Pediatric patients with sickle cell anemia (SCA) carry a significant risk of developing moyamoya syndrome (MMS) and brain ischemia. The authors sought to review the safety and efficacy of pial synangiosis in the treatment of MMS in children with SCA by performing a comprehensive review of all previously reported cases in the literature., Methods: The authors retrospectively reviewed the clinical and radiographic records in 17 pediatric patients with SCA treated at the Morgan Stanley Children's Hospital of New York (MSCHONY) who developed radiological evidence of MMS and underwent pial synangiosis between 1996 and 2012. The authors then added any additional reported cases of pial synangiosis for this population in the literature for a combined analysis of clinical and radiographic outcomes., Results: The combined data consisted of 48 pial synangiosis procedures performed in 30 patients. Of these, 27 patients (90%) presented with seizure, stroke, or transient ischemic attack, whereas 3 (10%) were referred after transcranial Doppler screening. At the time of surgery, the median age was 12 years. Thirteen patients (43%) suffered an ischemic stroke while on chronic transfusion therapy. Long-term follow-up imaging (MR angiography or catheter angiography) at a mean of 25 months postoperatively was available in 39 (81%) treated hemispheres. In 34 (87%) of those hemispheres there were demonstrable collateral vessels on imaging. There were 4 neurological events in 1590 cumulative months of follow-up, or 1 event per 33 patient-years. In the patients in whom complete data were available (MSCHONY series, n = 17), the postoperative stroke rate was reduced more than 6-fold from the preoperative rate (p = 0.0003)., Conclusions: Pial synangiosis in patients with SCA, MMS, and brain ischemia appears to be a safe and effective treatment option. Transcranial Doppler and/or MRI screening in asymptomatic patients with SCA is recommended for the diagnosis of MMS.

Tumors of the central nervous system are challenging to treat due to the limited effectiveness and associated toxicities of chemotherapy and radiation therapy. For tumors that can be removed surgically, extent of malignant tissue resection has been shown to correlate with disease progression, recurrence, and survival. Thus, improved technologies for real-time brain tumor imaging are critically needed as tools for guided surgical resection. We previously engineered a novel peptide that binds with high affinity and unique specificity to α V β 3 , α V β 5 , and α 5 β 1 integrins, which are present on tumor cells, and the vasculature of many cancers, including brain tumors. In the current study, we conjugated this engineered peptide to a near infrared fluorescent dye (Alexa Fluor 680), and used the resulting molecular probe for non-invasive whole body imaging of patient-derived medulloblastoma xenograft tumors implanted in the cerebellum of mice. The engineered peptide exhibited robust targeting and illumination of intracranial medulloblastoma following both intravenous and intraperitoneal injection routes. In contrast, a variant of the engineered peptide containing a scrambled integrin-binding sequence did not localize to brain tumors, demonstrating that tumor-targeting is driven by specific integrin interactions. Ex vivo imaging was used to confirm the presence of tumor and molecular probe localization to the cerebellar region. These results warrant further clinical development of the engineered peptide as a tool for image-guided resection of central nervous system tumors.

Diabetes is a serious chronic illness that involves individuals, couples, and families in complex reciprocal interactions with the illness and other life dimensions. A major issue in diabetes management is how well the patient is able to follow the established medical regimen of selfcare. Situated within personal, physical, and social contexts, the meaning that a couple creates and the emotions they feel in their adaptation to living with diabetes and its demanding regimen can be viewed as the couple's relationship with diabetes., (© 2012 American Association for Marriage and Family Therapy.)

The neurotensin receptor-3 also known as sortilin is part of the new receptor family of vacuolar protein sorting 10 protein domain. Growing evidence show that the vacuolar protein sorting 10 protein domain family is implicated as a genetic risk factor for neurodegenerative diseases such as Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, in addition to links associated with type 2 diabetes mellitus, lysosomal disorders, cardiovascular disease and atherosclerosis. In fact, sortilin expression is elevated in many human cell lines controlling the trafficking and release of neurotrophins. Hence, not surprisingly the imbalance of neurotrophin signaling is implicated in several human diseases. The fine regulation of the growth factor, brain derived nerve factor by sortilin mediates both neuronal and tumor cell survival, whereas in Alzheimer's disease sortilin mediated beta secretase-1 trafficking increases the cleavage of the beta-amyloid precursor protein. Perturbation of the autocrine/paracrine loop of neurotrophins in combination with the cell surface interaction of sortilin with neurotensin receptor 1 or 2 or tyrosine kinase receptor A or B are dramatically upregulated in both neurodegenerative diseases and cancer. In cardiovascular diseases, the circulatory low-density lipoprotein is closely correlated with sortilin expression in hepatocytes. Herein, this review discusses the multifaceted role played by sortilin and its interacting partners in human disease which could be interesting novel target(s) in drug discovery. Nevertheless, completely challenging the function of sortilin could prove unfavorable given the important universal role of sortilin plays in the body. Hence, metabolism disorders could be relieved with specific targeted therapeutic challenge of sortilin function.

Background: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF., Methods: A randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group., Results: At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035)., Conclusions: These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.