Cerebral Oxygenation and Autoregulation in Preterm Infants (Early NIRS Study).

OBJECTIVE: To determine if decreased cerebral oxygenation or altered cerebral autoregulation as measured by near-infrared spectroscopy (NIRS) in the first 96 postnatal hours is associated with an increased risk of death or severe neuroradiographic abnormalities in very preterm infants. STUDY DESIGN: The Early NIRS prospective, multicenter study enrolled very preterm infants with a birth weight of <1250 g from 6 tertiary neonatal intensive care units. Mean arterial blood pressure and cerebral oxygen saturation (Csat) were continuously monitored using a neonatal sensor until 96 hours of age. Moving window correlations between Csat and mean arterial blood pressure determined time periods with altered cerebral autoregulation, and percentiles of correlation were compared between infants with and without the adverse outcome of mortality or severe neuroradiographic abnormalities by early cranial ultrasound. RESULTS: Of 103 subjects with mean gestational age of 26 weeks, 21 (20%) died or had severe neuroradiographic abnormalities. Infants with adverse outcomes had a lower mean Csat (67 ± 9%) compared with those without adverse outcomes (72 ± 7%; P = .02). A Csat of <50% was identified as a cut-point for identifying infants with adverse outcome (area under the curve, 0.76). Infants with adverse outcomes were more likely to have significant positive or negative correlations between Csat and mean arterial blood pressure, indicating impaired cerebral autoregulation (P = .006). CONCLUSIONS: Early NIRS monitoring may detect periods of lower cerebral oxygenation and altered cerebral autoregulation, identifying preterm infants at risk for mortality or neuroradiographic injury. An improved understanding of the relationship between altered hemodynamics and cerebral oxygenation may inform future strategies to prevent brain injury.

Alterations in Anatomical Covariance in the Prematurely Born.

Preterm (PT) birth results in long-term alterations in functional and structural connectivity, but the related changes in anatomical covariance are just beginning to be explored. To test the hypothesis that PT birth alters patterns of anatomical covariance, we investigated brain volumes of 25 PTs and 22 terms at young adulthood using magnetic resonance imaging. Using regional volumetrics, seed-based analyses, and whole brain graphs, we show that PT birth is associated with reduced volume in bilateral temporal and inferior frontal lobes, left caudate, left fusiform, and posterior cingulate for prematurely born subjects at young adulthood. Seed-based analyses demonstrate altered patterns of anatomical covariance for PTs compared with terms. PTs exhibit reduced covariance with R Brodmann area (BA) 47, Broca's area, and L BA 21, Wernicke's area, and white matter volume in the left prefrontal lobe, but increased covariance with R BA 47 and left cerebellum. Graph theory analyses demonstrate that measures of network complexity are significantly less robust in PTs compared with term controls. Volumes in regions showing group differences are significantly correlated with phonological awareness, the fundamental basis for reading acquisition, for the PTs. These data suggest both long-lasting and clinically significant alterations in the covariance in the PTs at young adulthood.

Does prenatal stress alter the developing connectome?

Human neurodevelopment requires the organization of neural elements into complex structural and functional networks called the connectome. Emerging data suggest that prenatal exposure to maternal stress plays a role in the wiring, or miswiring, of the developing connectome. Stress-related symptoms are common in women during pregnancy and are risk factors for neurobehavioral disorders ranging from autism spectrum disorder, attention deficit hyperactivity disorder, and addiction, to major depression and schizophrenia. This review focuses on structural and functional connectivity imaging to assess the impact of changes in women's stress-based physiology on the dynamic development of the human connectome in the fetal brain.

Functional magnetic resonance connectivity studies in infants born preterm: suggestions of proximate and long-lasting changes in language organization.

Sophisticated neuroimaging strategies demonstrate alterations in functional connectivity at school age, adolescence, and young adulthood in individuals born preterm. Recent data suggest these alterations are present in the postnatal period prior to term-equivalent age in neonates born preterm. Likewise, functional organization increases across development, but the influence of preterm birth on this fundamental infrastructure is immediate and unchanging. This article briefly reviews the current methods of measuring functional connectivity throughout development in those born preterm, and the association of functional connectivity with language disorders. Taken together, these data suggest that the effects of preterm birth on the functional organization of language in the developing brain are both proximate and long-lasting.

Adaptive mechanisms of developing brain: cerebral lateralization in the prematurely-born.

Preterm birth results in alterations in neural connectivity, but the impact of prematurity on the functional organization of the developing brain has yet to be explored. To test the hypothesis that preterm birth alters cortical organization during the late second and third trimesters of gestation, we interrogated cerebral lateralization at rest in 26 very preterm subjects (birth weight 500-1500g) with no evidence of brain injury and 25 healthy term control subjects at term equivalent age. Employing an unbiased voxel-based measure of functional connectivity, these data demonstrated that cerebral lateralization is impaired in the prematurely-born. At term equivalent age, preterm neonates showed significantly less lateralization in regions subserving both receptive and expressive language, left Brodmann (BA) areas insula-BA22-BA21 and L BA45-BA47 (p<0.05 corrected for multiple comparisons for both). Exploratory region of interest analyses demonstrated significantly less inter-hemispheric connectivity from L BA22 to R BA22 in preterm infants compared to term controls (p<0.005) and from R BA22 to its homolog (p<0.005). L BA22, Wernicke's area, was more strongly connected to R BA39, foreshadowing neural networks for language in preterm subjects at school age, adolescence and young adulthood. For these very preterm neonates born at less than 30weeks' PMA, the degree of prematurity had no influence on lateralization in these differential regions.

Aqueous Levels of Angiopoietin-like 4 and Semaphorin 3E Correlate with Nonperfusion Area and Macular Volume in Diabetic Retinopathy.

OBJECTIVE: To investigate the aqueous levels of angiopoietin-like 4 (ANGPTL4), semaphorin 3E (Sema3E), and vascular endothelial growth factor (VEGF) in patients with diabetic retinopathy and to ascertain their association with diabetic retinopathy phenotypes. DESIGN: Prospective, nonrandomized, comparative case series. PARTICIPANTS: Of all 104 consecutive patients (104 eyes) who had intravitreal anti-VEGF injections from April 2012 through April 2013 for diabetic macular edema (DME), 51 had severe nonproliferative diabetic retinopathy (NPDR) and 53 had proliferative diabetic retinopathy (PDR). The controls were 54 consecutive nondiabetic patients who had undergone cataract surgery (54 eyes) during the same period. METHODS: The ANGPTL4, Sema3E, and VEGF levels in aqueous humor samples obtained before intravitreal injections were measured by enzyme-linked immunosorbent assay. Capillary nonperfusion area (NPA) was calculated from encircled angiography using the 7 standard field images described in the Early Treatment Diabetic Retinopathy Study protocol. Total macular volume (TMV) was measured by spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: Aqueous ANGPTL4, Sema3E, and VEGF levels in severe NPDR, PDR, and control groups and their correlations with each other, NPA, and TMV. RESULTS: The severe NPDR and PDR groups had higher aqueous levels of ANGPTL4 and VEGF than the control group (all P < 0.001). The PDR group had higher ANGPTL4 and VEGF levels than the severe NPDR group (both P < 0.001). The aqueous ANGPTL4 levels of all diabetic retinopathy patients correlated positively with NPA (r = 0.820, P = 0.003) and TMV (r = 0.824, P < 0.001). The control group had higher aqueous Sema3E levels than the NPDR and PDR groups (both P < 0.001). Aqueous Sema3E levels correlated negatively with VEGF levels in all subjects (r = -0.57, P = 0.025). CONCLUSIONS: The ANGPTL4 may be a candidate target in DME treatment and a biomarker of ischemic-induced retinopathy, including diabetic retinopathy.

Synthesis and conformational analysis of macrocyclic peptides consisting of both α-helix and polyproline helix segments.

Macrocycles are interesting molecules because their topological features and constrained properties significantly affect their chemical, physical, biological, and self-assembling properties. In this report, we synthesized unique macrocyclic peptides composed of both an α-helix and a polyproline segment and analyzed their conformational properties. We found that the molecular stiffness of the rod-like polyproline segment and the relative orientation of the two different helical segments strongly affect the efficiency of the macrocyclization reaction. Conformational analyses showed that both the α-helix and the polyproline II helix coexisted within the macrocyclic peptides and that the polyproline segment exerts significant effect on the overall helical stability and conformation of the α-helical segment.

Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates.

Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.

Prognostic significance of the intratumoral heterogeneity of (18) F-FDG uptake in oral cavity cancer.

BACKGROUNDS: We evaluated the prognostic value of the intratumoral heterogeneity of (18) F-FDG uptake in oral cavity cancer. MATERIALS AND METHODS: We enrolled 45 patients who underwent pretreatment (18) F-FDG PET/CT. The intratumoral heterogeneity of (18) F-FDG uptake was represented as the heterogeneity factor (HF), defined as the derivative (dV/dT) of a volume-threshold function for a primary tumor. We measured the maximum standardized uptake value (SUVmax ) and volumetric PET parameters. The relationship between HF and clinical parameters, as well as other PET parameters, was evaluated. RESULTS: The HF was significantly correlated with SUVmax (r = -0.353, P = 0.017), metabolic tumor volume (r = -0.708, P < 0.0001), and total lesion glycolysis (r = -0.709, P < 0.0001). A multivariate analysis revealed not only cervical lymph node metastasis (hazard ratio = 5.983; P = 0.022) but also HF (hazard ratio = 2.49 × 10(-4) ; P = 0.002) to be independent predictors of overall survival. Those patients with HF < -0.13 showed a worse prognosis than those with HF ≥ -0.13 (P = 0.005). CONCLUSIONS: The intratumoral heterogeneity of (18) F-FDG uptake may be a significant prognostic factor for overall survival in addition to cervical lymph node metastasis in oral cavity cancer. J. Surg. Oncol. 2014 110:702-706. © 2014 Wiley Periodicals, Inc.

Artificial keloid skin models: understanding the pathophysiological mechanisms and application in therapeutic studies.

Keloid is a type of scar formed by the overexpression of extracellular matrix substances from fibroblasts following inflammation after trauma. The existing keloid treatment methods include drug injection, surgical intervention, light exposure, cryotherapy, etc. However, these methods have limitations such as recurrence, low treatment efficacy, and side effects. Consequently, studies are being conducted on the treatment of keloids from the perspective of inflammatory mechanisms. In this study, keloid models are created to understand inflammatory mechanisms and explore treatment methods to address them. While previous studies have used animal models with gene mutations, chemical treatments, and keloid tissue transplantation, there are limitations in fully reproducing the characteristics of keloids unique to humans, and ethical issues related to animal welfare pose additional challenges. Consequently, studies are underway to create in vitro artificial skin models to simulate keloid disease and apply them to the development of treatments for skin diseases. In particular, herein, scaffold technologies that implement three-dimensional (3D) full-thickness keloid models are introduced to enhance mechanical properties as well as biological properties of tissues, such as cell proliferation, differentiation, and cellular interactions. It is anticipated that applying these technologies to the production of artificial skin for keloid simulation could contribute to the development of inflammatory keloid treatment techniques in the future.

Dual Growth Factor Delivery Using Photo-Cross-Linkable Gelatin Hydrogels for Effectively Reinforced Regeneration of the Rotator Cuff Tendon.

Rotator cuff tears are currently treated with drugs (steroids and nonsteroidal anti-inflammatory drugs) and surgery. However, the damaged rotator cuff requires a considerable amount of time to regenerate, and the regenerated tissue cannot restore the same level of function as that before the damage. Although growth factors can accelerate regeneration, they are difficult to be used alone because of the risk of degradation and the difficulties in ensuring their sustained release. Thus, hydrogels such as gelatin are used, together with growth factors. Gelatin is a biocompatible and biodegradable hydrogel derived from collagen; therefore, it closely resembles the components of native tissues and can retain water and release drugs continuously, while also showing easily tunable mechanical properties by simple modifications. Moreover, gelatin is a natural biopolymer that possesses the ability to form hydrogels of varying compositions, thereby facilitating effective cross-linking. Therefore, gelatin can be considered to be suitable for rotator-to-tendon healing. In this study, we designed photo-cross-linkable gelatin hydrogels to enhance spacing and adhesive effects for rotator cuff repair. We mixed a ruthenium complex (Ru(II)bpy32+) and sodium persulfate into gelatin-based hydrogels and exposed them to blue light to induce gelation. Basic fibroblast growth factor and bone morphogenetic protein-12 were encapsulated in the gelatin hydrogel for localized and sustained release into the wound, thereby enhancing the cell proliferation. The effects of these dual growth factor-loaded hydrogels on cell cytotoxicity and tendon regeneration in rotator cuff tear models were evaluated using mechanical and histological assessments. The findings confirmed that the gelatin hydrogel was biocompatible and that treatment with the dual growth factor-loaded hydrogels in in vivo rotator cuff tear models promoted regeneration and functional restoration in comparison with the findings in the nontreated group. Therefore, growth factor-loaded gelatin-based hydrogels may be suitable for the treatment of rotator cuff tears.

Quarter-Annulus Si-Photodetector with Equal Inner and Outer Radii of Curvature for Reflective Photoplethysmography Sensors.

Reflection-type photoplethysmography (PPG) pulse sensors used in wearable smart watches, true wireless stereo, etc., have been recently considered a key component for monitoring biological signals such as heart rate, SPO3, and blood pressure. Typically, the optical front end (OFE) of these PPG sensors is heterogeneously configured and packaged with light sources and receiver chips. In this paper, a novel quarter-annulus photodetector (NQAPD) with identical inner and outer radii of curvature has been developed using a plasma dicing process to realize a ring-type OFE receiver, which maximizes manufacturing efficiency and increases the detector collection area by 36.7% compared to the rectangular PD. The fabricated NQAPD exhibits a high quantum efficiency of over 90% in the wavelength of 500 nm to 740 nm and the highest quantum efficiency of 95% with a responsivity of 0.41 A/W at the wavelength of 530 nm. Also, the NQAPD is shown to increase the SNR of the PPG signal by 5 to 7.6 dB compared to the eight rectangular PDs. Thus, reflective PPG sensors constructed with NQAPD can be applied to various wearable devices requiring low power consumption, high performance, and cost-effectiveness.

Structural control of self-assembled peptide nanostructures to develop peptide vesicles for photodynamic therapy of cancer.

Vesicles such as liposomes, polymersomes, and exosomes have been widely used as drug delivery carriers; however, peptide vesicles (peptidesomes) despite their potential utility are far less well developed. Peptidesomes are distinctive because peptides play dual roles as a self-assembly building block and a bioactive functional unit. In order for peptidesomes to become successful nanodrugs, the issues related to differences in nanostructural properties between in vitro and in vivo conditions should be addressed. Here, we delineate a multivariate approach to feedback control the structures of peptide building blocks, nanoparticle size, drug loading process, nanoparticle aggregation, cytotoxicity, cell targeting capability, endosome disruption function, protease resistance, and in vivo performance, which eventually enabled the successful development of a highly efficacious peptidesome for in vivo cancer therapy. This study lays the groundwork for the successful in vivo translation of peptide nanodrugs.

A comparative study of the traditional medicine systems of South Korea and Taiwan: Focus on administration, education and license.

BACKGROUND: Traditional medicine (TM) is widely used in South Korea and Taiwan, and both societies have similar systems for the management of TM. This study aimed to compare the TM systems in South Korea and Taiwan. METHODS: We searched for studies on the TM systems and collected statistical data from the websites of relevant government agencies in both countries. Interviews were conducted with experts on TM and officials from government agencies. The two TM systems were described and examined in terms of policies, resources, utilization, licensing, and educational systems. RESULTS: Both South Korea and Taiwan have a dual system that separates the administration, licensing and educational systems between TM and Western Medicine (WM), and the TM systems are well established and highly standardized. Comparing with South Korea, however, Taiwan has a more flexible dual medical system in which education courses for producing dual licensure are provided. Additionally, in the system in Taiwan, dual license holders can use both TM and WM methods without limitations and WM doctors can apply acupuncture under some circumstances. Because of the strict dual medical system in South Korea, TM and WM conflict with each other on most health issues. CONCLUSION: Both South Korea and Taiwan have the advantages of preserving TM, as TM and WM are systemically independent and together provide a more holistic approach. The institutionalization of TM in South Korea and Taiwan may be a good reference for countries considering modernization of their TM.

Diabetes and Alzheimer's Disease: Mechanisms and Nutritional Aspects.

Blood glucose homeostasis is well maintained by coordinated control of various hormones including insulin and glucagon as well as cytokines under normal conditions. However, chronic exposure to diabetic environment with high fat/high sugar diets and physical/mental stress can cause hyperglycemia, one of main characteristics of insulin resistance, metabolic syndrome, and diabetes. Hyperglycemia impairs organogenesis and induces organ abnormalities such as cardiac defect in utero. It is a risk factor for the development of metabolic diseases in adults. Resulting glucotoxicity affects peripheral tissues and vessels, causing pathological complications including diabetic neuropathy, nephropathy, vessel damage, and cardiovascular diseases. Moreover, chronic exposure to hyperglycemia can deteriorate cognitive function and other aspects of mental health. Recent reports have demonstrated that hyperglycemia is closely related to the development of cognitive impairment and dementia, suggesting that there may be a cause-effect relationship between hyperglycemia and dementia. With increasing interests in aging-related diseases and mental health, diabetes-related cognitive impairment is attracting great attention. It has been speculated that glucotoxicity can result in structural damage and functional impairment of brain cells and nerves, hemorrhage of cerebral blood vessel, and increased accumulation of amyloid beta. These are potential mechanisms underlying diabetes-related dementia. Nutrients and natural food components have been investigated as preventive and/or intervention strategy. Among candidate components, resveratrol, curcumin, and their analogues might be beneficial for the prevention of diabetes-related cognitive impairment. The purposes of this review are to discuss recent experimental evidence regarding diabetes and cognitive impairment and to suggest potential nutritional intervention strategies for the prevention and/or treatment of diabetes-related dementia.

Diffusion-weighted MR imaging of unusual white matter lesion in a patient with Menkes disease.

We report here on the diffusion-weighted imaging of unusual white matter lesions in a case of Menkes disease. On the initial MR imaging, the white matter lesions were localized in the deep periventricular white matter in the absence of diffuse cortical atrophy. The lesion showed diffuse high signal on the diffusion-weighted images and diffuse progression and persistent hyperintensity on the follow up imaging. Our case suggests that the white matter lesion may precede diffuse cortical atrophy in a patient with Menkes disease.

Fabrication of Multicomponent Multivesicular Peptidoliposomes and Their Directed Cytoplasmic Delivery.

A novel self-assembly strategy for the formation of multicomponent and multicompartment vesicles via the hierarchical assembly of the cyclic peptide and lipid building blocks is reported. The primary driving force underlying the formation of dual-component (i.e., peptide and lipid) heteromultivesicular vesicles (hMVVs) is the differential thermostability between the supramolecular building blocks. Furthermore, the combination of the differential thermostability and charge-based separation further enables the fabrication of the hMVVs that incorporate up to four different components (i.e., two different building blocks and two different encapsulated molecules). The quadruple-component hMVVs consist of cyclic peptides, lipids, negatively charged green fluorescent probes (GFPr), and positively charged red fluorescent probes (RFPr). Intracellular delivery study shows that cellular localization of hMVVs is directed by the function of hMVV envelopes, and the nuclear localization signal (NLS) of peptide vesicles appears to use different cellular pathways depending on the site of action (i.e., extracellular space or cytoplasm). This study provides the hierarchical peptide-based hMVVs with sophisticated architectures and cell delivery characteristics, thus making a step toward artificial cells or viruses.