Association of long-term hyperglycaemia and insulin resistance with brain atrophy and cognitive decline: A longitudinal cohort study.

AIM: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline. MATERIALS AND METHODS: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits. RESULTS: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group. CONCLUSIONS: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline.

The Pathophysiology of Dystonic Tremors and Comparison With Essential Tremor.

There are two types of dystonic tremor syndromes (DTS), dystonic tremor (DT) and tremor associated with dystonia (TAWD), and neither is understood. DTS likely share some mechanisms with nontremulous dystonia, and there may also be overlaps with essential tremor (ET). We studied 21 ET (8 females, 13 males) and 22 DTS human patients (10 females, 12 males), including 13 human patients with DT (writer's cramp with writing tremor) and 9 human patients with tremor associated with dystonia (TAWD; cervical dystonia with hand tremor). Tremors were analyzed using accelerometry and surface EMG of the antagonist pairs of arm muscles during posture, simple kinetic movement, and writing. Cerebellar inhibition was performed to assess cerebello-thalamo-cortical involvement. DT exhibited higher variability of peak frequency and greater instability of tremor burst intervals over time (higher tremor stability index) than ET or TAWD regardless of tasks. Intermuscular coherence magnitude between the antagonist pairs increased during the writing task in DT, but not ET or TAWD. ET and TAWD exhibited different phase relationships of the temporal fluctuations of voluntary movement and tremor in the kinetic condition. A linear discriminant classifier based on these tremor parameters was able to distinguish the three groups with a classification accuracy of 95.1%. Cerebellar inhibition was significantly reduced in DT, but not in TAWD, compared with ET and healthy controls. Our study shows that the two DTS are distinct entities with DT closer to nontremorous dystonia and TAWD closer to ET.SIGNIFICANCE STATEMENT This study provides novel findings about characteristics and pathophysiology of the two different types of dystonic tremor syndromes compared with essential tremor. Patients with DTS are classified into DT who have dystonia and tremor in the same area, and tremor associated with dystonia (TAWD) who have dystonia and tremor elsewhere. Our results showed that DT exhibits increased tremor variability, instability, and intermuscular coherence, and decreased cerebello-thalamo-cortical inhibition compared with TAWD. Our study shows that DT and TAWD are distinct phenotypes, and that the physiological characteristics of DT are more similar to nontremorous dystonia, and TAWD is closer to ET.

Sarcopenia is associated with decreased gray matter volume in the parietal lobe: a longitudinal cohort study.

BACKGROUND: Substantial evidence supports an association between physical activity and cognitive function. However, the role of muscle mass and function in brain structural changes is not well known. This study investigated whether sarcopenia, defined as low muscle mass and strength, accelerates brain volume atrophy. METHODS: A total of 1284 participants with sarcopenic measurements and baseline and 4-year follow-up brain magnetic resonance images were recruited from the Korean Genome and Epidemiology Study. Muscle mass was represented as appendicular skeletal muscle mass divided by the body mass index. Muscle function was measured by handgrip strength. The low mass and strength groups were defined as being in the lowest quintile of each variable for one's sex. Sarcopenia was defined as being in the lowest quintile for both muscle mass and handgrip strength. RESULTS: Of the 1284 participants, 12·6%, 10·8%, and 5·4% were classified as the low mass, low strength, and sarcopenia groups, respectively. The adjusted mean changes of gray matter (GM) volume during 4-year follow-up period were - 9·6 mL in the control group, whereas - 11·6 mL in the other three groups (P < 0·001). The significantly greater atrophy in parietal GM was observed in the sarcopenia group compared with the control group. In a joint regression model, low muscle mass, but not muscle strength, was an independent factor associated with a decrease of GM volume. CONCLUSIONS: Sarcopenia is associated with parietal GM volume atrophy, in a middle-aged population. Maintaining good levels of muscle mass could be important for brain health in later adulthood.

Chronological Echocardiographic Changes in Healthy Term Neonates within Postnatal 72 Hours Using Doppler Studies.

BACKGROUND: This study evaluated echocardiographic changes in full-term healthy neonates during early transitional period from postnatal 0-72 hours at 12-hour intervals by echocardiography. METHODS: This was a prospective, observational, and longitudinal single-center cohort study. Morphometric, functional, systolic, diastolic, and tissue Doppler imaging (TDI) parameters (patent ductus arteriosus [PDA], aorta, superior vena cava [SVC], stroke volume [SV], cardiac output [CO], cardiac index [CI], early diastolic flow velocity [E], late diastolic flow velocity [A], early filling in TDI [E'], peak systolic annular velocity in TDI [S'], late velocity peak in TDI [A'], and myocardial performance index [MPI]) were evaluated in left ventricle (LV) and right ventricle (RV) with 56 newborns. RESULTS: Sizes and peak velocities of PDA before postnatal 24 hours were significantly changed than those after postnatal 24 hours. Aortic velocity time integral (VTI), systolic blood pressure (BP), LV SV/kg, LV CO/kg, LV CI, and SVC flow/LV CO before 24 hours showed significantly changes than those after 24 hours. Also, LV and RV MPI before 24 hours were significantly higher than those after 24 hours. LV E/E' was significantly higher than RV E/E'. CONCLUSION: Postnatal 24 hours is critical time for hemodynamic closure of PDA because aortic VTI, systolic BP, LV SV, LV CO, LV CI, and SVC flow/LV CO showed simultaneously significant changes after 24 hours at the same time as 24 hours of physiological closure of PDA. Chronological and dramatic changes of systolic, diastolic, and TDI parameters during early postnatal period can be used to compile normal baseline data of healthy full-term neonates.

Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation.

Motor surround inhibition is the neural mechanism that selectively favours the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) muscle as the target muscle, and the abductor digiti minimi, flexor carpi radialis and extensor carpi radialis muscles as surround muscles, during rest and tonic activation of the FDI muscle in 21 subjects. Cerebellar stimulation was performed under magnetic resonance imaging-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90-120% of the adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI muscle was selected for use during tonic activation. During selective tonic activation of the FDI muscle, CBI was significantly reduced only for the FDI muscle, and not for the surround muscles. Unconditioned motor evoked potential sizes were increased in all muscles during FDI muscle tonic activation as compared with rest, despite background electromyography activity increasing only for the FDI muscle. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle.

Higher mortality in metabolically obese normal-weight people than in metabolically healthy obese subjects in elderly Koreans.

OBJECTIVE: The purpose of this study was to investigate the impact of body mass index (BMI) and the presence of metabolic syndrome (MetS) on all-cause and cardiovascular mortality in elderly Korean men and women, and especially to compare metabolically obese normal-weight (MONW) and metabolically healthy obese (MHO) subjects. PATIENTS AND METHODS: A total of 2317 elderly people (over 60 years of age) were studied using follow-up data from the South-West Seoul (SWS) Study, a prospective cohort study. Mortality from all causes and cardiovascular disease (CVD) were evaluated according to the combination of the presence or absence of MetS and Asian-specific body mass index (BMI) criteria (BMI <23 kg/m²; normal weight, BMI 23-24·9 kg/m²; overweight, BMI ≥25 kg/m²; obesity). RESULTS: During a median follow-up of 10·3 years, 393 subjects died, including 126 from CVD. Among subjects with MetS, all-cause and CVD mortality were significantly higher in normal-weight subjects than overweight or obese individuals in Cox proportional-hazard models adjusted for confounding factors. Furthermore, among six groups with various MetS/BMI combinations, MONW individuals had the highest risk, whereas overweight subjects without MetS had the lowest risk of death from all causes and CVD [HR = 2·2 (95% CI = 1·4-3·4), HR = 3·0 (95% CI = 1·4-6·6) respectively]. Interestingly, all-cause mortality was significantly higher in MONW than MHO individuals. CONCLUSIONS: In contrast to MHO subjects, elderly individuals with the MONW phenotype exhibited greater all-cause mortality during 10 years of follow-up.

[6]-Shogaol inhibits the production of proinflammatory cytokines via regulation of NF-κB and phosphorylation of JNK in HMC-1 cells.

[6]-Shogaol is a major bioactive component of Zingiber officinale. Although [6]-shogaol has a number of pharmacological activities including antipyretic, analgesic, antitussive and anti-inflammatory effects, the specific mechanisms of its anti-allergic effects have not been studied. In this study, we present the effects of [6]-shogaol on mast cell-mediated allergic reactions in vivo and in vitro. Sprague-Dawley rats received intradermal injections of anti-DNP IgE was injected into dorsal skin sites. After 48 h, [6]-shogaol was administered orally 1 h prior to challenge with DNP-HSA in saline containing 4% Evans blue through the dorsal vein of the penis. In addition, rat peritoneal mast cells (RPMCs) were cultured and purified to investigate histamine release. In vitro, we evaluated the regulatory effects of [6]-shogaol on the level of inflammatory mediators in phorbol 12-myristate 13-acetate plus calcium ionomycin A23187-stimulated human mast cells (HMC-1). [6]-Shogaol reduced the passive cutaneous anaphylaxis reaction compared to the control group, and histamine release decreased significantly following the treatment of RPMCs with [6]-shogaol. In HMC-1 cells, [6]-shogaol inhibited the production of TNF-α, IL-6 and IL-8, as well as the activation of nuclear factor-κB (NF-κB) and phosphorylation of JNK in compound 48/80-induced HMC-1 cells. [6]-shogaol inhibited mast cell-mediated allergic reactions by inhibiting the release of histamine and the production of proinflammatory cytokines with the involvement of regulation of NF-κB and phosphorylation of JNK.

Is essential tremor a degenerative or an electrical disorder? Electrical disorder.

Essential tremor (ET) is one of the most common movement disorders, yet we do not have a complete understanding of its pathophysiology. From a phenomenology standpoint, ET is an isolated tremor syndrome of bilateral upper limb action tremor with or without tremor in other body locations. ET is a pathological tremor that arises from excessive oscillation in the central motor network. The tremor network comprises of multiple brain regions including the inferior olive, cerebellum, thalamus, and motor cortex, and there is evidence that a dynamic oscillatory disturbance within this network leads to tremor. ET is a chronic disorder, and the natural history shows a slow progression of tremor intensity with age. There are reported data suggesting that ET follows the disease model of a neurodegenerative disorder, however whether ET is a degenerative or electrical disorder has been a subject of debate. In this chapter, we will review cumulative evidence that ET as a syndrome is a fundamentally electric disorder. The etiology is likely heterogenous and may not be primarily neurodegenerative.

Multimodal imaging of essential tremor and dystonic tremor.

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors. We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine). Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites. Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

Role of supplementary motor area in cervical dystonia and sensory tricks.

Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.

Night blood pressure variability, brain atrophy, and cognitive decline.

Background: Although blood pressure variability (BPV) has emerged as a novel risk factor for Alzheimer's disease, few studies have examined the effects of night BPV on brain structure and function. This study investigated the association of night BPV with brain atrophy and cognitive function changes. Methods: The analysis included 1,398 participants with valid ambulatory blood pressure (BP) monitoring at baseline and both baseline and 4-year follow-up brain magnetic resonance images who were recruited from the Korean Genome and Epidemiology Study. Participants underwent a comprehensive neuropsychological test battery. BPV was derived from ambulatory BP monitoring and calculated as a standard deviation (SD) of 24-h and daytime and nighttime BP. Results: During the median follow-up of 4.3 years, increased SD of night systolic or diastolic BP was an indicator of total brain volume reduction, while daytime BPV or night average BP was not associated with total brain volume changes. High SD of night systolic BP was associated with reduced gray matter (GM) volume, independent of average night BP, and use of antihypertensive drugs. It also was associated with a reduction of temporal GM volume, mostly driven by atrophy in the left entorhinal cortex and the right fusiform gyrus. In cognitive performance, high variability of night systolic BP was associated with a decrease in visual delayed recall memory and verbal fluency for the category. Conclusion: Increased night BPV, rather than night mean BP, was associated with reduced brain volume and cognitive decline. High night BPV could be an independent predictor for rapid brain aging in a middle-aged population.

Clinical Features and Evolution of Blepharospasm: A Multicenter International Cohort and Systematic Literature Review.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features. Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region. Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34-40%) and depression (21-24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety. Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

Effect of Toll-like receptor 4 gene polymorphisms on work-related respiratory symptoms and sensitization to wheat flour in bakery workers.

BACKGROUND: Bakery workers are exposed to flour allergens and endotoxins, which interact to induce allergic responses and respiratory symptoms. We hypothesized that Toll-like receptor 4 (TLR4) may be involved in the development of work-related respiratory symptoms and sensitization to wheat flour. OBJECTIVE: To investigate the genetic contribution of TLR4 to respiratory symptoms and sensitization to wheat flour in bakery workers, we performed a genetic association study of TLR4 in Korean bakery workers. METHODS: A total of 381 workers completed a questionnaire regarding work-related symptoms. Skin prick tests with common and occupational allergens were done, and specific antibodies to wheat flour were measured by enzyme-linked immunosorbent assay. Two single-nucleotide polymorphisms (SNPs) of the TLR4 gene (-2027A>G and -1608T>C) were genotyped, and the functional effects of the polymorphisms were analyzed using the luciferase reporter and electrophoretic mobility shift assay. RESULTS: Homozygotes for the -2027G and -1608C alleles exhibited a lower prevalence of work-related lower respiratory symptoms than carriers of the -2027AA/AG (P = .007) and -1608TT/TC (P =.021) genotypes. Furthermore, haplotype analysis indicated that workers with the haplotype 2, ht2 [GC], had fewer work-related lower respiratory symptoms (P = .021). The ht2 [GC] construct showed lower promoter activity than the haplotype 1, ht1[AT], in both BEAS-2B (P = .001) and U937 cells (P = .007). CONCLUSION: Bakery workers carrying the TLR4 variants are at lower risk of developing work-related chest symptoms. This finding suggests that the TLR4 gene may be involved in allergic sensitization to wheat flour as well as endotoxin-induced respiratory symptoms in endotoxin-allergen-exposed workers and that carriers of TLR4 variants are less affected by environmental exposure.

Sensory tricks modulate corticocortical and corticomuscular connectivity in cervical dystonia.

OBJECTIVE: To examine interactions between cortical areas and between cortical areas and muscles during sensory tricks in cervical dystonia (CD). METHODS: Thirteen CD patients and thirteen age-matched healthy controls performed forewarned reaction time tasks, sensory tricks, and two tasks replicating aspects of the tricks (moving necks/arms). Control subjects mimicked sensory tricks. Corticocortical and corticomuscular coherence values were calculated from surface electrodes placed over motor, premotor, and sensory cortical areas and dystonic muscles. RESULTS: During initial preparation (after the warning stimulus), the only between-task difference was found in the γ-band corticocortical coherence (higher during tricks than during voluntary neck movements). With movements (before/after the imperative stimulus), the γ-band coherence of CD patients significantly increased during tricks but decreased during voluntary movements, while opposite trends were observed in healthy subjects. Additionally, the α- and ß-band coherence decreased in healthy subjects during movements. Between the two patient subgroups (typical vs. forcible tricks), only those with typical tricks showed significant decrease in corticomuscular coherence during tricks. CONCLUSIONS: Observed changes in the corticocortical coherence suggest that sensory tricks improve cortical function, which reduces corticomuscular connectivity and the dystonia. SIGNIFICANCE: We demonstrated that sensory tricks fundamentally affect sensorimotor integration in CD, both in movement preparation and execution.

Sensory tricks in cervical dystonia correlate with enhanced brain activity during motor preparation.

INTRODUCTION: Although sensory tricks are well known as the maneuvers that temporarily relieve dystonic symptoms in patients with cervical dystonia (CD), the underlying neurophysiological mechanisms remain unclear. We aimed to investigate brain potentials related to sensory tricks in patients with CD. METHODS: Thirteen patients with CD and 13 age-matched healthy volunteers participated. The experiment consisted of three conditions (moving the neck, moving an arm, and performing sensory tricks) presented in different blocks in random order in a contingent negative variation (CNV) paradigm. Warning and trigger stimuli (S1 and S2) were presented to the participants, who were instructed to prepare to perform the specific task for each condition after S1, and then to perform the task after S2. Early and late components of the CNV were measured. RESULTS: The late CNVs in patients with CD were significantly larger than those in healthy participants in Fz, FCz, Cz, and C3 electrodes. Only in patients with CD, the late CNVs were significantly greater for the 'sensory tricks' condition compared to the 'move neck' condition in Fz and C3 electrodes. CONCLUSION: The late CNV is increased during sensory tricks in patients with CD, suggesting that sensory tricks may affect mechanisms related to the motor preparatory phase in the premotor and primary motor areas. Sensory tricks may normalize impaired motor preparation in dystonia, leading to improved dystonic symptoms.

In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7.

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p < 0.05, FWE corrected; Hedge's g > 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p < 0.05, FWE corrected; Hedge's g > 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = -0.66, p = 0.104, FDR corrected) and global white matter pFA (r = -0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Glutathione Peroxidase 3 as a Biomarker of Recurrence after Lung Cancer Surgery.

We aimed to examine the usefulness of serum glutathione peroxidase 3 (GPx3) as a biomarker of lung cancer recurrence after complete resection. We prospectively collected serial serum samples at the baseline, as well as 3, 6 and 12 months after surgery from complete resection cases in 2013. GPx3 levels were measured by enzyme-linked immunosorbent assay. Statistical tests including t-tests and Cox proportional hazard regression analyses were performed. Totally, 135 patients were enrolled, and 39 (28.9%) showed relapse during the median follow-up period (63.60 months; range, 0.167-81.867). The mean GPx3 change was significantly higher in the recurrence group at 6 months (0.32 ± 0.38 vs. 0.15 ± 0.29, p = 0.016) and 12 months (0.40 ± 0.37 vs. 0.13 ± 0.28, p = 0.001). The high GPx3 change group showed significantly higher 60-months recurrence rates than the low group (48.1% vs. 25.2% at 3 months, p = 0.005; 54.5% vs. 28.9% at 6 months, p = 0.018; 38.3% vs. 18.3% at 12 months, p = 0.035). High GPx3 change at 3 months were independent risk factors of recurrence (hazard ratio (HR) 3.318, 95% confidence interval (CI), 1.582-6.960, p = 0.002) and survival (HR 3.150, 95% CI, 1.301-7.628, p = 0.011). Therefore, serum GPx3 changes after surgery may be useful predictive biomarkers for recurrence in lung cancer. Larger-scale validation studies are warranted to confirm these findings.

Differential circulating and visceral fat microRNA expression of non-obese and obese subjects.

BACKGROUND & AIMS: Altered microRNA (miRNA) expression is associated with the pathophysiology of obesity; however, little is known about the miRNAs commonly dysregulated in the blood and visceral fat tissue of obese patients. This study compared the circulating and visceral fat miRNA expression in subjects with and without obesity. METHODS: For the circulating miRNA study, 20 healthy control and 30 obese subjects were recruited. For the tissue miRNA expression study, omental fat tissue was collected in ten female subjects each in the control and obese groups. MiRNA expression was measured by TaqMan low-density arrays. Metabolic risk factors were measured. Target genes for selected miRNAs were analyzed using informatics tools and a functional network map was constructed. RESULTS: 11 miRNAs were down-regulated (miR-133a, -139-5p, -15b, -26a, -301, -30b, -30c, -374, -451, -570, and -636), and one was up-regulated (miR-155) in both depots in obese subjects. These miRNAs had significant associations with BMI, waist circumference, and fat mass. Among them, miR-15b, miR-26a, miR-301, miR-30b, and miR-30c had more predicted obesity-related target genes than other miRNAs. In particular, miR-15b had numerous target genes associated with adipogenesis, mammalian target of rapamycin (mTOR) signaling, diabetes and insulin resistance, and mitochondrial function. CONCLUSIONS: It is suggested that the miRNA alteration in the serum and visceral fat has pathophysiological implications for obesity. Our study identified dysregulated miRNAs that may be novel therapeutic targets to combat obesity.

Differential expression of p63 isoforms in normal skin and hyperproliferative conditions.

BACKGROUND: The p63 is regarded as a potential stem cell marker. METHODS: Expression of p63 isoforms was examined in normal skin and hyperproliferative conditions including psoriasis and artificial skin equivalents (SEs). Rapidly adhering (RA) and slowly adhering (SA) cells were isolated, and Western blotting was performed. RESULTS: Expression of p63 (4A4) and p63 (H-137) is similar in all conditions, although there is some variation in psoriasis. However, expression of p63alpha (C-12) is markedly different. In normal skin, p63alpha (C-12)-positive cells were scattered in whole epidermis. But in psoriasis, p63alpha (C-12)-positive cells were observed at the tips of rete ridges. In SEs, p63alpha (C-12)-positive cells were not well observed. Western blot results showed that the RA cells express p63 (4A4) and p63 (H-137) strongly compared with SA or nonadhering (NA) cells. In contrast, SA or NA cells strongly express p63alpha (C-12). CONCLUSIONS: Results suggest that both p63 (4A4) and p63 (H-137) can detect epidermal stem cells. But, p63 (H-137) seemed to be a better marker because p63 (H-137)-positive cells were more localized at basal layer. In addition, it can be said that p63alpha (C-12) can detect TAp63, which is important in differentiation of epidermis. Furthermore, it is concluded that molecular control of TAp63 is especially disorganized in hyperproliferative condition including psoriasis and SEs.

Effect of light on blinking in patients with idiopathic isolated blepharospasm.

OBJECTIVE: Melanopsin may be involved in the pathophysiology of photophobia in idiopathic isolated blepharospasm. We assessed the efficacy of blocking wavelengths of melanopsin absorption to reduce blinking in blepharospasm as a possible surrogate for photophobia. METHODS: Twenty-one participants (11 blepharospasm and 10 healthy controls) were studied. There were three sessions: (1) a baseline condition to measure the blink rate (BR) without intervention; (2) two conditions where the participants received intermittent light stimuli with high or low intensity without wearing study lenses; (3) four conditions in which the participants received intermittent light stimuli with high intensity while wearing one of four different lenses: tinted lenses with neutral gray or FL-41, or coated lenses that block 480-nm or 590-nm wavelength. The primary outcome measure was the BR. RESULTS: The blepharospasm group blinked more frequently than controls in dim room conditions. Patients reported greater photosensitivity compared to controls based on the questionnaire and exhibited a higher BR with intermittent light stimuli. The BR decreased for both groups when using 480-nm and 590-nm blocking lenses. In the patients, 480-nm and 590-nm blocking lenses reduced the mean BR by 9.6 blink/min and 10.3 blink/min, respectively, while in the control group, the mean BR decreased by 4.4 blink/min and 4.3 blink/min, respectively. CONCLUSIONS: Blepharospasm patients had increased BR with light stimuli which decreased with 590-nm and 480-nm blocking lenses. The 480-nm- and 590-nm- coated lenses might have therapeutic potential in treating photophobia although BR does not appear to be an optimal biomarker for photophobia.