Association between scrub typhus encephalitis and diffusion tensor tractography detection of Papez circuit injury: A case report.

BACKGROUND: It is difficult to restore the cognitive functions of patients with impaired cognition caused by brain injury. Diffusion tensor imaging can visualize the integrity of neural tracts in the white matter (WM) three-dimensionally. It is unclear whether encephalitis following scrub typhus damages the WM. For the first time, we aimed to report diffusion tensor tractography (DTT) findings in a chronic patient with cognitive impairment following scrub typhus encephalitis, which revealed injury to the Papez circuit of the WM. CASE SUMMARY: A 70-year-old male patient was affected by encephalitis caused by scrub typhus that occurred 23 years ago. He had poor cognition and his clinical examination findings were as follows: Mini-Mental Status Examination score, 14; and handgrip strength (right/left, kg), 32.3/31.3. DTT revealed serious injuries of the left thalamocingulate tract and right mammillothalamic tract in the Papez circuit, and a partial injury of the anterior part of the fornix. CONCLUSION: Using DTT, we found a relationship between cognitive impairment and the integrity of the Papez circuit following scrub typhus.

Mechanism of cognitive impairment in chronic patients with putaminal hemorrhage: A diffusion tensor tractography.

It is not clear whether the fornix and cingulum are involved in cognition after putaminal hemorrhage (PH). We investigated structural changes and differences of the neural tracts, and the relationship between the integrity of the neural tracts and cognition not only at the affected but also at the unaffected side.Sixteen patients with left chronic putaminal hemorrhage and 20 healthy volunteers were enrolled. Using diffusion tensor tractography (DTT), we compared fiber number (FN), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) of the neural tracts between patient and control groups. The relationship between the neural tract parameters and neuropsychological results was also analyzed.The left fornix FN was significantly lower than the right fornix FN in the patient group. Except for the cingulum FA, the neural tracts parameters for both the affected and unaffected hemispheres differed significantly between the groups. The fornix FA and ADC at the affected side were significantly correlated with intelligence quotient (IQ), mini-mental status examination (MMSE), and short-term memory. Interestingly, the fornix ADC at the unaffected side was significantly correlated with MMSE. However, none of the cingulum parameters was correlated with neuropsychological results.The fornix integrity is critical for cognitive impairment after putaminal hemorrhage.

Therapeutic application of T regulatory cells in composite tissue allotransplantation.

With growing number of cases in recent years, composite tissue allotransplantation (CTA) has been improving the quality of life of patient who seeks reconstruction and repair of damaged tissues. Composite tissue allografts are heterogeneous. They are composed of a variety of tissue types, including skin, muscle, vessel, bone, bone marrow, lymph nodes, nerve, and tendon. As a primary target of CTA, skin has high antigenicity with a rich repertoire of resident cells that play pivotal roles in immune surveillance. In this regard, understanding the molecular mechanisms involved in immune rejection in the skin would be essential to achieve successful CTA. Although scientific evidence has proved the necessity of immunosuppressive drugs to prevent rejection of allotransplanted tissues, there remains a lingering dilemma due to the lack of specificity of targeted immunosuppression and risks of side effects. A cumulative body of evidence has demonstrated T regulatory (Treg) cells have critical roles in induction of immune tolerance and immune homeostasis in preclinical and clinical studies. Presently, controlling immune susceptible characteristics of CTA with adoptive transfer of Treg cells is being considered promising and it has drawn great interests. This updated review will focus on a dominant form of Treg cells expressing CD4+CD25+ surface molecules and a forkhead box P3 transcription factor with immune tolerant and immune homeostasis activities. For future application of Treg cells as therapeutics in CTA, molecular and cellular characteristics of CTA and immune rejection, Treg cell development and phenotypes, Treg cell plasticity and stability, immune tolerant functions of Treg cells in CTA in preclinical studies, and protocols for therapeutic application of Treg cells in clinical settings are addressed in this review. Collectively, Treg cell therapy in CTA seems feasible with promising perspectives. However, the extreme high immunogenicity of CTA warrants caution.

Comparison of serum biomarkers between patients with asthma and with chronic obstructive pulmonary disease.

OBJECTIVE: Asthma and chronic obstructive pulmonary disease (COPD) have distinct pathophysiological mechanisms but sometimes share similar clinical manifestations. Distinguishing between these diseases is important. This study compared the profiles of serum biomarkers between patients with asthma and those with COPD. METHODS: Serum levels of the chitinase like protein YKL-40, periostin, interleukin (IL)-18, and chemokine (C--C motif) ligand 18 (CCL18) were measured in asthma patients (n = 20), COPD patients (n = 16), and normal controls (n = 20). RESULTS: Serum levels of YKL-40 were higher in COPD patients [median (range), 55 (17-565) versus 208 (74-922) ng/mL, p < 0.0001], but no differences were observed between asthma and COPD patients after adjusting for age and forced expiratory volume in 1 s (FEV1). No differences in serum levels of periostin, IL-18, or CCL18 were observed between the patient groups. Total IgE and airway hypersensitivity were negatively correlated (r = -0.485, p = 0.007). CCL18 levels were related to patients' age in asthmatic patients (r = -0.562, p = 0.010). Serum levels of CCL18 and IL-18 were positively correlated in patients with COPD (r = 0.696, p = 0.003). CONCLUSIONS: No differences in the serum profiles of periostin, IL-18, or CCL18 were observed between patients with asthma and those with COPD. Serum levels of YKL-40 were not different between asthma and COPD patients after adjusting for age and FEV1. There were negative correlation between CCL18 and age in patients with asthma and positive correlation between IL-18 and CCL18 in patients with COPD.

Lipoprotein-associated phospholipase A2 is related to plaque stability and is a potential biomarker for acute coronary syndrome.

PURPOSE: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) binds to low-density lipoprotein. The levels of Lp-PLA2 reflect the plaque burden, and are upregulated in acute coronary syndrome (ACS). We investigated the diagnostic value of Lp-PLA2 levels and found that it might be a potential biomarker for ACS. MATERIALS AND METHODS: We classified 226 study participants into three groups: patients without significant stenosis (control group), patients with significant stenosis with stable angina (SA group), and patients with ACS (ACS group). RESULTS: Lp-PLA2 and high-sensitivity C-reactive protein (hs-CRP) levels were significantly greater in the ACS group than in the SA group (p=0.044 and p=0.029, respectively). Multivariate logistic regression analysis revealed that Lp-PLA2 levels are significantly associated with ACS (odds ratio=1.047, p=0.013). The addition of Lp-PLA2 to the ACS model significantly increased the global χ² value over traditional risk factors (28.14 to 35.602, p=0.006). The area under the receiver operating characteristic curve for Lp-PLA2 was 0.624 (p=0.004). The addition of Lp-PLA2 level to serum hs-CRP concentration yielded an integrated discrimination improvement of 0.0368 (p=0.0093, standard error: 0.0142) and improved the ability to diagnose ACS. CONCLUSION: Lp-PLA2 levels are related to plaque stability and might be a diagnostic biomarker for ACS.

Anatomical location and somatotopic organization of the corticospinal tract in the corona radiata of the normal human brain: a diffusion tensor tractography study.

The anatomical location and somatotopic organization of the corticospinal tract (CST) in the corona radiata (CR) of the normal human brain have not been studied using diffusion tensor tractography so far. In this study, the anatomical location and somatotopic organization of the CST in the CR were evaluated by determining the highest probabilistic locations and distances between the upper and lower extremities in the slices of upper and lower CR in the brain. In the mediolateral direction, the average of the highest probabilistic locations for the upper and lower extremities were 40.27 and 37.16% at the upper CR level and 38.19 and 37.14% at the lower CR level, respectively. In the anteroposterior direction, the average of the highest probabilistic locations for the upper and lower extremities were 62.52 and 75.65% at the upper CR level and 60.19 and 68.12% at the lower CR level, respectively. The average distances between upper and lower extremities for the mediolateral direction were 2.41 mm at the upper CR level and 1.21 mm at the lower CR level. The average distances between upper and lower extremities for the anteroposterior direction were 5.23 mm at the upper CR level and 4.47 mm at the lower CR level, respectively. Our findings suggest that the anatomical location and somatotopic organization for the upper extremity are located anterolaterally to the lower extremity in the CR of a normal human brain and distances between the upper and lower extremities become decreased as the CST descends from the upper to the lower CR level.

Can the multiple mini-interview predict academic achievement in medical school?

PURPOSE: The purpose of this study was to determine whether the multiple mini-interview (MMI) predicts academic achievement for subjects in a medical school curriculum. METHODS: Of 49 students who were admitted in 2008, 46 students finished the entire medical education curriculum within 4 years. We calculated the Pearson correlation coefficients between the total MMI score of the 46 graduates and their academic achievements in all subjects of the curriculum. RESULTS: The correlation coefficients between total MMI score and academic achievement in Medical Interview and History Taking, Problem-Based Learning, Doctoring I, and Clinical Practice of Surgery ranged from 0.4 to 0.7, indicating that they were moderately related. The values between total MMI score and achievement in Research Overview, Technical and Procedural Skills, Clinical Performance Examinations 1 and 3, Clinical Practice of Laboratory Medicine and Psychiatry, Neurology, and Orthopedics ranged from 0.2 to 0.4, which meant that they were weakly related. CONCLUSION: MMI score can predict medical student' academic achievement in subjects in the medical humanities and clinical practice.

Mitral valve endothelial cells with osteogenic differentiation potential.

OBJECTIVE: Cardiac valvular endothelium is unique in its ability to undergo endothelial-to-mesenchymal transformation, a differentiation process that is essential for valve development and has been proposed as mechanism for replenishing the interstitial cells of mature valves. We hypothesized that the valvular endothelium contains endothelial cells that are direct precursors to osteoblastic valvular interstitial cells (VICs). METHODS AND RESULTS: Clonal cell populations from ovine mitral valve leaflets were isolated by single cell plating. Mitral valvular endothelial and mesenchymal clones were tested for osteogenic, adipogenic, and chondrogenic differentiation, determined by the expression of lineage-specific markers. Mitral valvular endothelial clones showed a propensity for osteogenic, as well as chondrogenic differentiation that was comparable to a mitral valvular VIC clone and to bone marrow-derived mesenchymal stem cells. Osteogenic differentiation was not detected in nonvalvular endothelial cells. Regions of osteocalcin expression, a marker of osteoblastic differentiation, were detected along the endothelium of mitral valves that had been subjected in vivo to mechanical stretch. CONCLUSIONS: Mitral valve leaflets contain endothelial cells with multilineage mesenchymal differentiation potential, including osteogenic differentiation. This unique feature suggests that postnatal mitral valvular endothelium harbors a reserve of progenitor cells that can contribute to osteogenic and chondrogenic VICs.

Proteomic analysis of human small cell lung cancer tissues: up-regulation of coactosin-like protein-1.

Small cell lung cancer (SCLC) is the leading cause of cancer death, with a high propensity for aggressiveness and metastasis even in an early stage. Thus, identification of biomarkers as early diagnostics and treatment is needed. In this study, we investigated differentially regulated proteins between human SCLC tissues and normal bronchial epithelium by proteomic analysis using two-dimensional electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Seven proteins and protein isoforms, including, γ-actin, tubulin α-1B, laminin B1, coactosin-like protein-1 (COTL-1), ubiquitin carboxyl-terminal esterase L1, ubiquitin-conjugating enzyme E2-25K, and carbonic anhydrase 1, were up-regulated more than 2 fold in SCLC tissues. In particular, up-regulated COTL-1 expression was validated by Western blot analysis, immunohistochemistry, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Moreover, most SCLC tissues (93%; 28/30) were COTL-1-positive in immunohistochemistry, whereas only 16% (10/64) of nonsmall cell lung cancer (NSLC) tissues were. Taken together, this SCLC proteomic data may help in establishing a human SCLC proteome database. COTL-1 may be a biomarker or a therapeutic target in SCLC patients.

Characterization of the cytokine profile of platelet rich plasma (PRP) and PRP-induced cell proliferation and migration: Upregulation of matrix metalloproteinase-1 and -9 in HaCaT cells.

BACKGROUND: The underlying rationale of platelet rich plasma (PRP) therapy is that an injection of concentrated PRP at the site of injury may promote tissue repair via cytokine release from platelets. The molecular mechanisms of PRP therapy in the skin wound healing process are not well understood at present, and would benefit from clarification. METHODS: PRP was stimulated with angonists for 5 min, and cytokine profile analysis was performed. To investigate the wound healing activity of PRP, cell proliferation and migration analyses were performed in skin cells. The effects of PRP were analyzed on the expression and activity of matrix metalloproteinase (MMP)-1, -2, -9, and the activation of transcription factors. RESULTS: Thrombin was found to be a strong stimulator of PRP activation to release growth factors and chemokines. PRP induced cell proliferation and migration in HUVECs, HaCaT cells, and HDFs, as well as MMP-1and MMP-9 expression in HaCaT cells, but PRP did not have a significant effect on the expression or activity of MMPs in HDFs. The transcription factors, including signal transducer and activator of transcription-3 (STAT-3) were found to be phosphorylated following PRP treatment in HaCaT cells. CONCLUSION: In this study, we have identified the cytokine profile of activated PRP after agonist stimulation. We have shown that PRP plays an active role in promoting the proliferation and migration of skin cells via the regulation of MMPs, and this may be applicable to the future development of PRP therapeutics to enhance skin wound healing.

Homoisoflavanone inhibits UVB-induced skin inflammation through reduced cyclooxygenase-2 expression and NF-kappaB nuclear localization.

BACKGROUND: Since the generation of reactive oxygen species (ROS) and release of inflammatory mediators play a major role in UVB-induced inflammation, vigorous attempts have been made for the pharmacological management of these molecules as well as for uncovering the molecular signaling pathways. Homoisoflavanone (5,7-dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-chroman-4-one, HIF) extracted from Cremastra appendiculata has anti-angiogenic activities, but its effect on inflammation was unknown. OBJECTIVE: To investigate the anti-inflammatory effects of HIF on the skin and the underlying molecular mechanisms. METHODS: HaCaT cells were irradiated by UVB (10 mJ/cm(2)) with or without HIF. Prostaglandin E(2) (PGE(2)) level was measured by enzyme immunoassay. Activation of MAPK and production of cyclooxygenase-2 (COX-2) were determined by Western blot analysis. Localization of nuclear factor kappa B (NF-kappaB) was assessed by immunofluorescence microscopy. Hairless mice were stimulated with UVB or chemical stimulants to induce inflammatory responses in skin. RESULTS: Pretreatment with HIF inhibited the production of intracellular ROS induced by UVB irradiation in HaCaT cells. Further analysis revealed a decrease in the level of MAPK activation and down-regulation of COX-2 expression. In addition, HIF attenuated the nuclear localization of NF-kappaB, resulting in the suppression of inflammatory molecules such as IL-6, IL-8, and TNF-alpha. Finally, topical treatment with HIF inhibited ear edema induced by UVB, 12-O-tetradecanoylphorbol-13-acetate (TPA), arachidonic acid (AA), or croton oil. CONCLUSION: HIF has a strong protective effect against proinflammatory responses, implying the possibility of preventive application for inflammatory skin diseases.

Capsiate inhibits ultraviolet B-induced skin inflammation by inhibiting Src family kinases and epidermal growth factor receptor signaling.

Capsiate, one of the major capsaicinoids, is nonpungent and present in sweet pepper. We investigated the effects of capsiate on the ultraviolet B (UVB)-induced inflammatory response in skin and its molecular mechanisms. Capsiate-pretreated human keratinocytes inhibited intracellular reactive oxygen species (ROS), which activate the mitogen-activated protein kinase and nuclear factor-kappaB (NF-kappaB) pathways. Therefore, we determined the effects of capsiate on these pathways. Capsiate inhibited UVB-induced cyclooxygenase-2 (COX-2) expression, extracellular signal-related kinase 1/2 phosphorylation, nuclear translocation of NF-kappaB, and the expression of proinflammatory cytokines and potent angiogenic factors, including vascular endothelial cell growth factor and matrix metalloproteinase-2 (MMP-2) and MMP-9. In addition, capsiate inhibited UVB-induced epidermal growth factor receptor (EGFR) activation, which reduces the levels of proinflammatory cytokines and angiogenic factors. We also investigated the photoprotective effects of capsiate in vivo. Topical treatment with capsiate significantly decreased UVB-induced skin damage and inhibited the expression of COX-2, proinflammatory cytokines, and angiogenic factors, including platelet/endothelial cell adhesion molecule-1 and intercellular adhesion molecule-1. Inhibition of Src kinase activity and ROS may inhibit the EGFR activation. Therefore, capsiate may protect the skin from UVB-induced adverse effects and these results provide a molecular basis for understanding its effects on inflammation and angiogenesis.

Opposing actions of Notch1 and VEGF in post-natal cardiac valve endothelial cells.

The endothelium of the cardiac valves is unique compared the rest of the vasculature in its ability to undergo an endothelial-to-mesenchymal transformation (EMT) in vitro in response to transforming growth factor-beta (TGF-beta). EMT is a critical event during embryonic valve development, and both VEGF-A and Notch1 have been shown to function in this process. Here we investigate the effects of VEGF-A and Notch1 on EMT in clonal endothelial cell (EC) populations isolated from adult aortic valve leaflets. VEGF-A inhibited TGF-beta-induced EMT. Endothelial growth, however, was not affected by VEGF-A or TGF-beta. A positive role for Notch1 was revealed in three experiments: (1) TGF-beta induced Notch1 mRNA in valve ECs, (2) a gamma-secretase inhibitor of Notch1 signaling blocked EMT, and (3) overexpression of a ligand-independent form of Notch1 induced EMT. These results demonstrate, for the first time, that VEGF-A and Notch1 play opposing roles in regulating EMT in post-natal valve endothelium.

Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-beta2.

In situ analysis of fetal semilunar valve leaflets has revealed cells coexpressing endothelial and mesenchymal markers along the endothelium, with diminished frequency seen in adult valves. To determine whether such cells are progenitor cells, we isolated clonal populations from human pulmonary valves. The clones expressed endothelial markers but showed potential to further differentiate into endothelium in response to vascular endothelial growth factor (VEGF)-A. When exposed to transforming growth factor (TGF)-beta2, individual clones adopted a mesenchymal phenotype to varying degrees and expressed markers of endothelial to mesenchymal transformation (EMT). Both VEGF- and TGFbeta2-induced phenotypic changes were partially reversible, indicating the plasticity of these cells. When challenged with VEGF or TGFbeta2, a hierarchy of endothelial/mesenchymal potential could be seen among the clonal populations: cells initially closer to an endothelial phenotype showed a strong response to TGFbeta2 that could be inhibited by VEGF, whereas cells closer to a mesenchymal phenotype responded to TGFbeta2 but were resistant to endothelial-inducing effects of VEGF. These findings suggest the presence of bipotential valve progenitor cells with ability to differentiate into either endothelial or interstitial cells of the valve leaflet. Understanding the differentiation potential and function of these cells may be important for understanding heart valve disease and may also be applied to current paradigms for creating tissue-engineered heart valves.

The validity and reliability of a Computerized Dementia Screening Test developed in Korea.

OBJECTIVE: This study was done to verify the validity and the reliability of the newly developed Computerized Dementia Screening Test (CDST) to be easily used in the primary care setting of Korea. DESIGN: Comparison of the results of CDST between 103 healthy control subjects and 41 patients who were diagnosed as having mild cognitive impairment or early dementia, having a clinical dementia rate of 0.5-1 from one health examination center and two neurology clinics in university hospitals. MEASUREMENTS: In order to estimate the criterion-related validity, logistic regression analysis for dementia was done using the four individual test results of CDST, age and educational level. The correlation between Korean Mini-Mental State Examination (K-MMSE) and the predicted probability of mild cognitive impairment and early dementia from the logistic regression was measured to verify its validity. The reliability of CDST was measured by test-retest reliability. RESULTS: The sensitivity and specificity of CDST were 75.6% and 94.2%, respectively, if the cut-off point was set to be 0.5 in the logistic regression model. The Pearson's Correlation Coefficient between K-MMSE and the predicted probability of mild cognitive impairment and early dementia from the logistic regression analysis was 0.59 (P<0.001). The overall test-retest reliability using the predicted probability of dementia from the logistic regression analysis of CDST was 0.89 (P=0.01). CONCLUSION: The validity and reliability of CDST is adequate for use as a screening tool to identify mild cognitive impairment and early dementia in Korean primary care.