Physical exercise and cortical thickness in healthy controls: a pilot study.

OBJECTIVE: Physical exercise has showed potential in improving brain function and increase in cortical size. This study aims to assess the cortical changes that are associated with physical exercise. SUBJECTS AND METHODS: We investigated 45 subjects; 25 of them involved in exercise group and 20 in non-exercise group. The exercise group underwent 6 months of intervention consisting of 40 minutes (min) of aerobic exercise and 20 minutes of anaerobic exercise. Magnetic resonance imaging (MRI) scans were acquired from both groups to measure the thickness of the cortex and was assessed with FreeSurfer software. RESULTS: Exercise group demonstrated significantly increased cortical thickness in the left pericalcarine area, left superior parietal area, right rostral middle frontal and right lateral occipital gyrus compared to non-exercise group. CONCLUSIONS: Regular and continuous physical exercise can enhance brain structures. The current findings have important implications for understanding the effect of physical activity or fitness programs on the brains of healthy individuals and of patients with a range of conditions.

The effect of transcranial direct current stimulation combined with functional task training on motor recovery in stroke patients.

The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify pathological activity within the nervous system to achieve a therapeutic effect. Therapy including transcranial direct current stimulation (tDCS) has all shown promising results across a range of neurological and neuropsychiatric disorders. This article reviews the state-of-the-art of neuromodulation for stroke and discusses the opportunities and challenges available for clinicians and researchers interested in advancing neuromodulation therapy. The annual worldwide incidence of stroke ranges from 27.5 to 63 individuals per 100,000. Stroke, a major cause of adult disability, has devastating effects on patients and their caregivers, which has a tremendous socioeconomic impact on families and healthcare systems around the world. There are only a few treatments available for the improvement of motor function in stroke patients. The majority of these treatments are based on functional motor learning (ML) strategies. Both the mechanisms underlying stroke recovery and the effectiveness of neurorehabilitation interventions still remain poorly understood for widespread implementation, although it strongly depends on the quality of rehabilitation service to reach maximal post-stroke recovery.

ER Stress and Autophagy.

Eukaryotic cells respond to various types of stresses caused by changes in the extracellular environment. Intracellular factors, such as the accumulation of misfolded proteins in the endoplasmic reticulum (ER), also cause stress and activate the unfolded protein response (UPR), which induces the expression of chaperones and proteins involved in the recovery process. However, if the stress is excessive or sustained, and ER function cannot be restored, the UPR triggers apoptosis, thereby removing the affected cell. It is now apparent that ER stress is also a potent trigger for autophagy, a self-degradative process that has an adaptive function. This review surveys the intersection of ER stress and autophagy and highlights the potential therapeutic implications thereof.

Edge contacts of graphene formed by using a controlled plasma treatment.

Despite the fact that the outstanding properties of graphene are well known, the electrical performance of the material is limited by the contact resistance at the metal-graphene interface. In this study, we demonstrate the formation of "edge-contacted" graphene through the use of a controlled plasma processing technique that generates a bond between the graphene edge and the contact metal. This technique controls the edge structure of the bond and significantly reduces the contact resistance. This simple approach requires no additional post-processing and has been proven to be very effective. In addition, controlled pre-plasma processing was applied in order to produce CVD-graphene field effect transistors with an enhanced adhesion and improved carrier mobility. The contact resistance attained by using pre-plasma processing was 270 Ω µm, which is a decrease of 77%.

Evaluation of In-Stent Restenosis After Stent Implantation in the Vertebral Artery Ostium by Multislice Computed Tomography Angiography: Factors Affecting Accurate Diagnosis.

PURPOSE: Few articles have evaluated vertebral artery ostium stents using multislice computed tomography (CT). The purpose of our study was to evaluate the diagnostic performance of 64- and 16-slice CT for detecting significant in-stent restenosis after vertebral artery ostium stenting, and to identify factors affecting the accurate diagnosis by CT. METHODS: We reviewed 57 stents scanned using 64-slice CT and 34 stents using 16-slice CT. The accuracy of CT for diagnosing significant in-stent restenosis (≥ 50% diameter narrowing) was calculated using conventional angiography as a reference standard. Possible factors influencing the diagnostic performance of CT were analyzed, such as CT scanner, image quality, and stent characteristics. RESULTS: With 64-slice CT, 46 (80.7%) of 57 stents were classified as evaluable, while with 16-slice CT, 28 (82.3%) of 34 stents were classified as evaluable. No stents with diameters ≤ 2.75 mm were evaluable. The respective results for 64- versus 16-slice CT were sensitivity 87.5% (95% confidence interval [CI] 47.3-99.7%) versus 100% (95% CI 15.8-100.0%), specificity 94.7% (95% CI 82.3%-99.4%) versus 96.2% (95% CI 80.4-99.9%). Factors reducing the accurate diagnosis were those associated with poor image quality, a diameter ≤ 2.75 mm, and drug-eluting stent type (p < 0.05). CONCLUSIONS: 64-slice and 16-slice CT scans are adequate in stents with diameters > 2.75 mm for the evaluation of in-stent restenosis after stent implantation in the vertebral artery ostium.

Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations.

This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>107 IU/mL). Twenty-one women received LMV (treated group) for an average of 53 days (range 22-88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment (EOT) HBV DNA in four (18%) LMV-treated women remained at >10(7) IU/mL (± 0.5 log IU/mL), no mother-to-baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra-deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63-5.92%) at EOT, but one LMV-treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug-resistant viral variants emerged.

Feasibility study on development of Cerenkov fiber-optic dosimeter for radiotherapy application.

To obtain real-time dose information in photon-beam therapy using a clinical linear accelerator, we fabricated a novel Cerenkov fiber-optic dosimeter using two plastic optical fibers without employing a scintillator. In this study, the light intensity and spectrum of Cerenkov radiation induced by a high-energy photon beam were measured as functions of the irradiation angle and the length difference between the two plastic optical fibers in the dosimeter probe. Also, we obtained a percentage depth dose curve for a 6 MV photon beam with a field size of 10 × 10 cm(2) according to the depth of the solid water phantom. Based on the results of this study, it is anticipated that the proposed Cerenkov fiber-optic dosimeter can be developed as a useful dosimeter to accurately obtain dose information prior to conducting radiotherapy.

Restriction fragment mass polymorphism (RFMP) analysis based on MALDI-TOF mass spectrometry for detecting antiretroviral resistance in HIV-1 infected patients.

Viral genotype assessment is important for effective clinical management of HIV-1 infected patients, especially when access and/or adherence to antiretroviral treatment is reduced. In this study, we describe development of a matrix-assisted laser desorption/ionization-time of flight mass spectrometry-based viral genotyping assay, termed restriction fragment mass polymorphism (RFMP). This assay is suitable for sensitive, specific and high-throughput detection of multiple drug-resistant HIV-1 variants. One hundred serum samples from 60 HIV-1-infected patients previously exposed to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were analysed for the presence of drug-resistant viruses using the RFMP and direct sequencing assays. Probit analysis predicted a detection limit of 223.02 copies/mL for the RFMP assay and 1268.11 copies/mL for the direct sequencing assays using HIV-1 RNA Positive Quality Control Series. The concordance rates between the RFMP and direct sequencing assays for the examined codons were 97% (K65R), 97% (T69Ins/D), 97% (L74VI), 97% (K103N), 96% (V106AM), 97% (Q151M), 97% (Y181C), 97% (M184VI) and 94% (T215YF) in the reverse transcriptase coding region, and 100% (D30N), 100% (M46I), 100% (G48V), 100% (I50V), 100% (I54LS), 99% (V82A), 99% (I84V) and 100% (L90M) in the protease coding region. Defined mixtures were consistently and accurately identified by RFMP at 5% relative concentration of mutant to wild-type virus while at 20% or greater by direct sequencing. The RFMP assay based on mass spectrometry proved to be sensitive, accurate and reliable for monitoring the emergence and early detection of HIV-1 genotypic variants that lead to drug resistance.

Development of a fibre-optic dosemeter to measure the skin dose and percentage depth dose in the build-up region of therapeutic photon beams.

In this study, a fibre-optic dosemeter (FOD) using an organic scintillator with a diameter of 0.5 mm for photon-beam therapy dosimetry was fabricated. The fabricated dosemeter has many advantages, including water equivalence, high spatial resolution, remote sensing and real-time measurement. The scintillating light generated from an organic-dosemeter probe embedded in a solid-water stack phantom is guided to a photomultiplier tube and an electrometer via 20 m of plastic optical fibre. Using this FOD, the skin dose and the percentage depth dose in the build-up region according to the depths of a solid-water stack phantom are measured with 6- and 15-MV photon-beam energies with field sizes of 10 × 10 and 20 × 20 cm(2), respectively. The results are compared with those measured using conventional dosimetry films. It is expected that the proposed FOD can be effectively used in radiotherapy dosimetry for accurate measurement of the skin dose and the depth dose distribution in the build-up region due to its high spatial resolution.

CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis.

The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA.

BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice.

We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15-20% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.

Fracture in long bones stabilised by telescopic intramedullary rods in patients with osteogenesis imperfecta.

We investigated the fracture-free survival of long bones stabilised by a telescopic intramedullary rod (TIMR) in patients with osteogenesis imperfecta with respect to the remodelling status of fracture or osteotomy sites and TIMR regions, in order to identify risk factors for fracture. A total of 44 femora and 28 tibiae in 25 patients with a mean age of 5.0 years (1.9 to 10.5) at presentation were studied. There were six patients with Sillence type I, five with type III, 13 with type IV and one with type V osteogenesis imperfecta. All received bisphosphonate treatment at the same stage during the mean follow-up of 7.3 years (0.5 to 18.1). The fracture-free survival was estimated at 6.2 years (95% confidence interval 5.1 to 7.3) by Kaplan-Meier analysis. More than half the fracture or osteotomy sites remained in a less-remodelled state at the latest follow-up or time of fracture. Of the 33 fractures, 29 (87.9%) occurred in long bones containing a less-remodelled site, and these fractures were located at this site. The relative fracture risk at the rod tip was significantly greater than in any other TIMR region (p < 0.001), and this was higher in bone segments having a less-remodelled site. This study shows a persistent fracture risk in TIMR-stabilised long bones, especially at less-remodelled fracture or osteotomy sites and at the rod tip.

Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia.

Hepatocyte growth factor (HGF) has been shown to induce angiogenesis in vivo and has potential as a candidate gene for 'therapeutic angiogenesis'. In vivo, two isoforms of HGF, HGF723 and HGF728, consisting of 723 and 728 amino acids, are generated through alternative splicing between exons 4 and 5, but the biological effects of their coexpression have not yet been elucidated. In this study, we generated a series of genomic-complementary DNA (cDNA) hybrids of the HGF gene by inserting various truncated intron 4 into the junction of exons 4 and 5 of HGF cDNA and analyzed the biological activities of these hybrid constructs. We showed that: (1) the hybrid called HGF-X7, which contained 1502 base pairs of intron 4, could drive a higher level of HGF expression than other hybrid constructs and cDNAs of each isoform alone; (2) the pCK vector was most efficient for the gene expression of HGF-X7; (3) coexpression of both isoforms of HGF could more efficiently induce the migration of human umbilical vein endothelial cell (HUVEC) and of the mouse myoblast cell line C2C12 myoblasts than a single isoform of HGF and human vascular endothelial growth factor (VEGF)165 at a given concentration; (4) intramuscular administration of pCK-HGF-X7 resulted in transient and localized HGF expression in the injected muscle without an increase in the HGF protein levels in other tissues including serum; and (5) intramuscular injection of pCK-HGF-X7 could more efficiently increase the number of angiographically recognizable collateral vessels, as well as improve an intra-arterial Doppler wire-measured blood flow in the rabbit model of hindlimb ischemia when compared with the identical vector encoding VEGF165 gene. These results showed that transfer of the genomic-cDNA hybrid of the HGF gene could be used as a potential therapeutic approach to human vascular diseases.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.