Reduced cortical thickness in subjects at clinical high risk for psychosis and clinical attributes.

OBJECTIVES: Although neuroanatomical abnormalities in subjects at clinical high risk for psychosis have been considered a putative biomarker of psychosis, relevance of cortical thickness alterations remains contested due to discrepant findings. Inconsistencies persist in Asian clinical high risk studies, despite their advantageous settings well-controlled for confounds. Attributes of cortical thickness alterations in clinical high risk subjects warrant further examination. METHODS: We examined cortical thickness at the whole-brain level in 74 clinical high risk subjects and 34 demographically matched healthy controls recruited from Seoul Youth Clinic, South Korea. Clinical symptoms were assessed using the Scale of Prodromal Symptoms, and their associations with cortical thickness were explored using partial correlation analysis. RESULTS: Compared to healthy control, clinical high risk exhibited significant cortical thinning in bilateral prefrontal cortex and inferior parietal lobule clusters. Reduced thickness in the left prefrontal cortex cluster was associated with more severe Scale of Prodromal Symptoms general symptoms scores and the right inferior parietal lobule cluster with Scale of Prodromal Symptoms disorganization symptoms. CONCLUSIONS: Thickness deficits found in the present clinical high risk sample demonstrated a degree of consistency with those reported in the previous Seoul Youth Clinic study. While inconsistencies reported between the present and previous Seoul Youth Clinic samples may reflect markedly decreased rate of converters, consistencies may be relevant to clinical attributes beyond transition, such as the prevalence of comorbidities. Particular recruitment strategies employed for sample selections should also be considered for findings in Asian clinical high risk samples. Our results suggest potential utility of cortical thickness alterations in clinical high risk subjects beyond the frame of transition.

Effect of smoking on the association of HHEX (rs5015480) with diabetes among Korean women and heavy smoking men.

BACKGROUND: Several genome-wide association studies (GWAS) for serum fasting glucose levels have reported HHEX as possibly causal. The objective of this study was to examine the joint effect of smoking on the association of diabetes with the HHEX rs5015480 polymorphism among Korean subjects. METHODS: This replication study included a total of 4240 individuals, and multivariate linear regression and multiple logistic regression models were used. We examined the combined effect of smoking on the relationship between HHEX rs5015480 and diabetes. RESULTS: The rs5015480 SNP in the HHEX gene was related to the mean FBS level (effect per allele, 1.572 mg/dL, p = 0.0122). Females with the CC genotype had a 2.68 times higher (range, 1.05-6.82 times) risk of diabetes than those with the TT/TC genotype. Although the association was stronger in female subjects (OR, 4.46; 95% CI, 1.15-17.3, p = 0.0304) among healthy individuals (N = 2461), the association between HHEX and diabetes was much stronger in male heavy smokers (OR, 4.03; 95% CI, 1.19-13.6, p = 0.0247) than in nonsmokers (p = 0.9709) and ex-smokers (p = 0.2399). The interaction of smoking was also statistically significant (P for interaction =0.0182). CONCLUSIONS: This study clearly demonstrates that a genetic variant in HHEX influences fasting glucose levels in Korean women and male heavy smokers.

Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration.

Blood vessels and nerve fibers are distributed throughout the entirety of skeletal tissue, and play important roles during bone development and fracture healing by supplying oxygen, nutrients, and cells. However, despite the successful development of bone mimetic materials that can replace damaged bone from a structural point of view, most of the available bone biomaterials often do not induce sufficient formation of blood vessels and nerves. In part, this is due to the difficulty of integrating and regulating multiple tissue types within artificial materials, which causes a gap between native skeletal tissue. Therefore, understanding the anatomy and underlying interaction mechanisms of blood vessels and nerve fibers in skeletal tissue is important to develop biomaterials that can recapitulate its complex microenvironment. In this perspective, we highlight the structure and osteogenic functions of the vascular and nervous system in bone, in a coupled manner. In addition, we discuss important design criteria for engineering vascularized, innervated, and neurovascularized bone implant materials, as well as recent advances in the development of such biomaterials. We expect that bone implant materials with neurovascularized networks can more accurately mimic native skeletal tissue and improve the regeneration of bone tissue.

Microfluidic Production of Biodegradable Microcapsules for Sustained Release of Hydrophilic Actives.

Biodegradable microcapsules with a large aqueous lumen and ultrathin membrane are microfluidically designed for sustained release of hydrophilic bioactives using water-in-oil-in-water double-emulsion drops as a template. As a shell phase, an organic solution of poly(lactic-co-glycolic acid) is used, which is consolidated to form a biodegradable membrane. The encapsulants stored in the lumen are released over a long period of time as the membranes degrade. The period can be controlled in a range of -three to five months at neutral pH condition by adjusting membrane thickness, providing highly sustained release and potentially enabling the programed release of multiple drugs. At acidic or basic condition, the degradation is accelerated, leading to the release in the period of approximately two months. As the membrane is semipermeable, the microcapsules respond to the osmotic pressure difference across the membrane. The microcapsules are inflated in hypotonic condition and deflated in hypertonic condition. Both conditions cause cracks on the membrane, resulting in the fast release of encapsulants in a day. The microcapsules implanted in mice also show sustained release, despite the period is decreased to a month. It is believed that the microcapsules are promising for the in vivo sustained release of drugs for high and long-term efficacy.

Controlling Smectic Liquid Crystal Defect Patterns by Physical Stamping-Assisted Domain Separation and Their Use as Templates for Quantum Dot Cluster Arrays.

Controlling the organization of self-assembling building blocks over a large area is crucial for lithographic tools based on the bottom-up approach. However, the fabrication of liquid crystal (LC) defect patterns with a particular ordering still remains a challenge because of the limited close-packed morphologies of LC defects. Here, we introduce a multiple-stamping domain separation method for the control of the dimensions and organization of LC defect structures. Prepatterns with various grid shapes on planar polyimide (PI) surfaces were fabricated by pressing a line-shaped stamp into the PI surfaces in two different directions, and then these surfaces were used to prepare LC defect structures confined to these grid domains. The dimensions of the LC defect structures, namely, the equilibrium diameter and the center to center spacing, are controlled by varying the line spacing of the stamps and the film thickness. A variety of arrangements of LC defects, including square, rhombic, hexagonal, and other oblique lattices, can be obtained by simply varying the stamping angle (Ω) between the first and second stamping directions. Furthermore, we demonstrate that the resulting controllable LC defect arrays can be used as templates for generating various patterns of nanoparticle clusters by trapping quantum dots (QDs) within the cores of the LC defects.

Anisotropic microparticles created by phase separation of polymer blends confined in monodisperse emulsion drops.

Anisotropic microparticles are promising as a new class of colloidal or granular materials due to their advanced functionalities which are difficult to achieve with isotropic particles. However, synthesis of the anisotropic microparticles with a highly controlled size and shape still remains challenging, despite their intense demands. Here, we report a microfluidic approach to create uniform anisotropic microparticles using phase separation of polymer blends confined in emulsion drops. Two different polymers are homogeneously dissolved in organic solvent at low concentration, which is microfluidically emulsified to produce oil-in-water emulsion drops. As the organic solvent diffuses out, small domains are formed in the emulsion drops, which are then merged, forming only two distinct domains. After the drops are fully consolidated, uniform anisotropic microparticles with two compartments are created. The shape of the resulting microparticles is determined by combination of a pair of polymers and type of surfactant. Spherical microparticles with eccentric core and incomplete shell are prepared by consolidation of polystyrene (PS) and poly(lactic acid) (PLA), and microparticles with single crater are formed by consolidation of PS and poly(methyl methacrylate) (PMMA); both emulsions are stabilized with poly(vinyl alcohol) (PVA). With surfactants of triblock copolymer, acorn-shaped Janus microparticles are obtained by consolidating emulsion drops containing PS and PLA. This microfluidic production of anisotropic particles can be further extended to any combination of polymers and colloids to provide a variety of structural and chemical anisotropy.

Osmocapsules for direct measurement of osmotic strength.

Monodisperse microcapsules with ultra-thin membranes are microfluidically designed to be highly sensitive to osmotic pressure, thereby providing a tool for the direct measurement of the osmotic strength. To make such osmocapsules, water-in-oil-in-water double-emulsion drops with ultra-thin shells are prepared as templates through emulsification of core-sheath biphasic flow in a capillary microfluidic device. When photocurable monomers are used as the oil phase, the osmocapsules are prepared by in-situ photopolymerization of the monomers, resulting in semipermeable membranes with a relatively large ratio of membrane thickness to capsule radius, approximately 0.02. These osmocapsules are buckled by the outward flux of water when they are subjected to a positive osmotic pressure difference above 125 kPa. By contrast, evaporation-induced consolidation of middle-phase containing polymers enables the production of osmocapsules with a small ratio of membrane thickness to capsule radius of approximately 0.002. Such an ultra-thin membrane with semi-permeability makes the osmocapsules highly sensitive to osmotic pressure; a positive pressure as small as 12.5 kPa induces buckling of the capsules. By employing a set of distinct osmocapsules confining aqueous solutions with different osmotic strengths, the osmotic strength of unknown solutions can be estimated through observation of the capsules that are selectively buckled. This approach provides the efficient measurement of the osmotic strength using only a very small volume of liquid, thereby providing a useful alternative to other measurement methods which use complex setups. In addition, in-vivo measurement of the osmotic strength can be potentially accomplished by implanting these biocompatible osmocapsules into tissue, which is difficult to achieve using conventional methods.

Combination of phytochemicals, including ginsenoside and curcumin, shows a synergistic effect on the recovery of radiation-induced toxicity.

Radiotherapy is commonly used to treat solid cancers located in the pelvis. A considerable number of patients experience proctitis of varying severity, even for a considerable period after radiotherapy. These side effects are often long-lasting or progressively worsen despite multiple therapeutic efforts and are a primary cause of an unexpectedly low quality of life, even after successful cancer treatment. Therefore, this study evaluated the individual and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate compounds in treating radiation-induced proctitis. While the candidate compounds did not affect the proliferation and migration of cancer cells, they promoted the recovery of cell activity, including motility. They exhibited anti-inflammatory effects on human dermal fibroblasts or human umbilical vein endothelial cells within in vitro disease models. When each compound was tested, curcumin and ginsenoside were the most effective in cell recovery and promoted the migration of human dermal fibroblasts and cell restoration of human umbilical vein endothelial cells. The combination of ginsenoside and curcumin resulted in cell migration recovery of approximately 54%. In addition, there was a significant improvement in the length of the endothelial tube, with an increase of approximately 25%, suggesting that the ginsenoside-curcumin-containing combination was the most effective against radiation-induced damage. Furthermore, studies evaluating the effects of combined treatments on activated macrophages indicated that the compounds effectively reduced the secretion of inflammatory cytokines, including chemokines, and alleviated radiation-induced inflammation. In conclusion, our study provides valuable insights into using curcumin and ginsenoside as potential compounds for the effective treatment of radiation-induced injuries and highlights the promising therapeutic benefits of combining these two compounds.

Mesenchymal stem cells enhance CCL8 expression by podocytes in lupus-prone MRL.Faslpr mice.

Nephritis is common in systemic lupus erythematosus patients and is associated with hyper-activation of immune and renal cells. Although mesenchymal stem cells (MSCs) ameliorate nephritis by inhibiting T and B cells, whether MSCs directly affect renal cells is unclear. To address this issue, we examined the direct effect of MSCs on renal cells with a focus on chemokines. We found that expression of CCL2, CCL3, CCL4, CCL5, CCL8, CCL19, and CXCL10 increased 1.6-5.6-fold in the kidney of lupus-prone MRL.Faslpr mice with advancing age from 9 to 16 weeks. Although MSCs inhibited the increase in the expression of most chemokines by 52-95%, they further increased CCL8 expression by 290%. Using renal cells, we next investigated how MSCs enhanced CCL8 expression. CCL8 was expressed by podocytes, but not by tubular cells. MSCs enhanced CCL8 expression by podocytes in a contact-dependent manner, which was proved by transwell assay and blocking with anti-VCAM-1 antibody. Finally, we showed that CCL8 itself activated MSCs to produce more immunosuppressive factors (IL-10, IDO, TGF-ß1, and iNOS) and to inhibit more strongly IFN-γ production by T cells. Taken together, our data demonstrate that MSCs activate podocytes to produce CCL8 in a contact-dependent manner and conversely, podocyte-derived CCL8 might potentiate immunosuppressive activity of MSCs in a paracrine fashion. Our study documents a previously unrecognized therapeutic mechanism of MSCs in nephritis.

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Objective: Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. Methods: A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Results: Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. Conclusion: The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.