Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel-based morphometry study.

Recent morphometric magnetic resonance imaging (MRI) studies suggested the possibility that valproate (VPA) use is associated with parieto-occipital cortical thinning in patients with heterogeneous epilepsy syndromes. In this study, we examined the effect of VPA on the brain volume using a large number of homogenous patients with idiopathic generalized epilepsy. Voxel-based morphometry was used to compare regional gray matter (GM) volume between 112 patients currently taking VPA (VPA+ group), 81 patients not currently taking VPA (VPA- group), and 120 healthy subjects (control group). The VPA+ group showed a significant GM volume reduction in the bilateral cerebellum, hippocampus, insula, caudate nucleus, medial frontal cortex/anterior cingulate cortex, primary motor/premotor cortex, medial occipital cortex, and anteromedial thalamus, as compared to the control group. The VPA- group showed a significant GM volume reduction in the anteromedial thalamus and right hippocampus/temporal cortex, as compared to the control group. Compared to the VPA- group, the VPA+ group had a significant GM volume reduction in the bilateral cerebellum, primary motor/premotor cortex, and medial frontal cortex/anterior cingulate cortex. We have provided evidence that VPA use could result in GM volume reductions in the frontal cortex and cerebellum. Our findings should be acknowledged as a potential confounding factor in morphometric MRI studies that include subjects taking VPA.

Clinical characteristics and outcomes of atrial flutter in neonates.

BACKGROUND: Atrial flutter is an uncommon arrhythmia that can cause severe morbidity, including heart failure and even death in refractory cases. This study investigated the clinical characteristics, treatment, and long-term outcomes of patients with neonatal atrial flutter and its association with heart failure. METHODS: We retrospectively reviewed atrial flutter cases observed in our center between 1999 and 2021 and analyzed the clinical characteristics, treatment, and recurrence according to the presence of heart failure. RESULTS: The study comprised 15 patients with atrial flutter, with median bodyweight and gestational age of 2.7 kg, 37+4 weeks, respectively. Twelve patients were diagnosed with atrial flutter on the first day of life. The median atrial and ventricular rates were 440/min, 220/min, respectively. Four patients exhibited congestive heart failure. Episodic recurrence was noted in five patients and occurred at a higher rate in patients with congestive heart failure (p = 0.004). Antiarrhythmic drugs for maintenance treatment were administered more often in patients with heart failure (p = 0.011). Initial treatment included direct current cardioversion (n = 9), digoxin (n = 4), and observation (n = 2). Four patients treated with cardioversion experienced recurrence during the neonatal period, and none of those treated with digoxin experienced recurrence. The median follow-up duration was 7 years, during which no atrial flutter recurrence was evident. CONCLUSION: Neonates with congestive heart failure had a higher recurrence of atrial flutter. Direct current cardioversion is the most reliable treatment for neonatal atrial flutter, whereas digoxin may be a viable treatment option in refractory and recurrent cases.

Structural basis for recognition of the tumor suppressor protein PTPN14 by the oncoprotein E7 of human papillomavirus.

Human papillomaviruses (HPVs) are causative agents of various diseases associated with cellular hyperproliferation, including cervical cancer, one of the most prevalent tumors in women. E7 is one of the two HPV-encoded oncoproteins and directs recruitment and subsequent degradation of tumor-suppressive proteins such as retinoblastoma protein (pRb) via its LxCxE motif. E7 also triggers tumorigenesis in a pRb-independent pathway through its C-terminal domain, which has yet been largely undetermined, with a lack of structural information in a complex form with a host protein. Herein, we present the crystal structure of the E7 C-terminal domain of HPV18 belonging to the high-risk HPV genotypes bound to the catalytic domain of human nonreceptor-type protein tyrosine phosphatase 14 (PTPN14). They interact directly and potently with each other, with a dissociation constant of 18.2 nM. Ensuing structural analysis revealed the molecular basis of the PTPN14-binding specificity of E7 over other protein tyrosine phosphatases and also led to the identification of PTPN21 as a direct interacting partner of E7. Disruption of HPV18 E7 binding to PTPN14 by structure-based mutagenesis impaired E7's ability to promote keratinocyte proliferation and migration. Likewise, E7 binding-defective PTPN14 was resistant for degradation via proteasome, and it was much more effective than wild-type PTPN14 in attenuating the activity of downstream effectors of Hippo signaling and negatively regulating cell proliferation, migration, and invasion when examined in HPV18-positive HeLa cells. These results therefore demonstrated the significance and therapeutic potential of the intermolecular interaction between HPV E7 and host PTPN14 in HPV-mediated cell transformation and tumorigenesis.

The "Oriental" problem: trachoma and Asian immigrants in the United States, 1897-1910.

This essay examines the period between 1897 and 1910, when trachoma, a contagious eye disease, became an "Oriental" problem that justified exclusionary immigration policy against Asians entering the United States. It also investigates the ways in which the public fear and alleged threat of the eye disease destabilized and undermined the rights of Asian immigrants. Many scholars have explored the link between trachoma and southern and eastern European newcomers, in particular Jews, but they have not paid much attention to Chinese or Japanese immigrants, for whose exclusion trachoma played a significant role. This is primarily because the number of Asian immigrants was much smaller than that of their European counterparts and because the Chinese Exclusion Acts, which had already been in place, functioned as a stronger and more lasting deterrent to Asian immigration than exclusion or deportation through medical inspection. Moreover, into the 1910s, medical and scientific innovations for detecting parasitic diseases (e.g. hookworm) helped American authorities exclude Asians in larger numbers. Still, the analysis of the discourses surrounding trachoma and immigration from Asia, though short-lived, demonstrates the role of medical inspection in controlling and regulating Asian immigrants, in particular Chinese and Japanese, into the United States and in constructing their legal and political rights. In 1906, the fear of trachoma justified an order to segregate Japanese students from white children in San Francisco even at the cost of compromising their rights as citizens. Along with fierce criticisms against immigration officials by the American public, the 1910 investigation of the San Francisco Immigration Office problematized the admission of trachoma-afflicted Asian immigrants. Those critical of the Immigration Office and its implementation of American immigration policy called for exclusionary measures to limit the privileges of exempt classes and domiciled aliens and hinder the exertion of their rights to leave and reenter their adopted country. The two examples show that trachoma was a convenient excuse to condemn inefficient immigration policy and regulate allegedly diseased Asian bodies. In 1910, the federal government made a decision to relegate to steamship companies full responsibility for medical inspection at Asian ports. Since they had to pay a fine for every immigrant excluded at American borders for medical reasons, including trachoma, steamship companies carried out more rigorous examinations. With medical advancements and growing interest in parasitic diseases, trachoma soon lost its appeal to immigration authorities. However, the association of immigration, race, and disease has continued to provide a rationale for immigration control beyond American borders.

PTK2 is a potential biomarker and therapeutic target for EGFR- or TLRs-induced lung cancer progression via the regulation of the cross-talk between EGFR- and TLRs-mediated signals.

Protein tyrosine kinase 2 (PTK2), epidermal growth factor receptor (EGFR), and toll-like receptor (TLRs) are amplified in non-small cell lung cancer (NSCLC). However, the functional and clinical associations between them have not been elucidated yet in NSCLC. By using microarray data of non-small cell lung cancer (NSCLC) tumor tissues and matched normal tissues of 42 NSCLC patients, the genetic and clinical associations between PTK2, EGFR, and TLRs were analyzed in NSCLC patients. To verify the functional association, we generated PTK2-knockout (PTK2-KO) lung cancer cells by using CRISPR-Cas9 gene editing method, and performed in vitro cancer progression assay, including 3D tumor spheroid assay, and in vivo xenografted NSG (NOD/SCID/IL-2Rγnull) mouse assay. Finally, therapeutic effects targeted to PTK2 in lung cancer in response to EGF and TLR agonists were verified by using its inhibitor (Defactinib). In summary, we identified that up-regulated PTK2 might be a reliable marker for EGFR- or TLRs-induced lung cancer progression in NSCLC patients via the regulation of the cross-talk between EGFR- and TLRs-mediated signaling. This study provides a theoretical basis for the therapeutic intervention of PTK2 targeting EGFR- or TLRs-induced lung cancer progression.

REST-dependent expression of TRF2 renders non-neuronal cancer cells resistant to DNA damage during oxidative stress.

REST is a neuronal gene silencing factor ubiquitously expressed in non-neuronal tissues. REST is additionally believed to serve as a tumor suppressor in non-neuronal cancers. Conversely, recent findings on REST-dependent tumorigenesis in non-neuronal cells consistently suggest a potential role of REST as a tumor promoter. Here, we have uncovered for the first time the mechanism by which REST contributes to cancer cell survival in non-neuronal cancers. We observed abundant expression of REST in various types of non-neuronal cancer cells compared to normal tissues. The delicate roles of REST were further evaluated in HCT116 and HeLa, non-neuronal cancer cell lines expressing REST. REST silencing resulted in decreased cell survival and activation of the DNA damage response (DDR) through a decrease in the level of TRF2, a telomere-binding protein. These responses were correlated with reduced colony formation ability and accelerated telomere shortening in cancer cells upon the stable knockdown of REST. Interestingly, REST was down-regulated under oxidative stress conditions via ubiquitin proteasome system, suggesting that sustainability of REST expression is critical to determine cell survival during oxidative stress in a tumor microenvironment. Our results collectively indicate that REST-dependent TRF2 expression renders cancer cells resistant to DNA damage during oxidative stress, and mechanisms to overcome oxidative stress, such as high levels of REST or the stress-resistant REST mutants found in specific human cancers, may account for REST-dependent tumorigenesis.

A Foundation for a "Cheerful Society": The Korean War and the Rise of Psychiatry.

One of the most remarkable medical achievements of the Korean War was the development of psychiatry. During the Korean War, soldiers and prisoners of war (POWs) experienced "gross stress reaction" and manifested poor concentration and memory as well as clinical depression and social alienation. Rest and relaxation rotations served as the primary treatment for their conditions. Civilians also bore the brunt of the war's effects. Delusions of grandeur and megalomania appear to have been common among Koreans, but there were few mental health facilities to provide treatment and care. Out of the furnace of war, psychiatry emerged as a newly specialized field, and in the 1950s, Korea became the very place where military psychiatry training under the U.S. military laid the groundwork for civilian psychiatry. This essay aims to enrich the study of mental illness during and after the Korean War by providing a more detailed picture of the mental problems experienced not only by veterans and POWs, but also by civilians in Korea. Examining mental health issues from this period is challenging due to the scarcity of resources for delving into the minds of the civilians involved. Taking military psychiatry as a starting point, this essay goes beyond existing scholarship to discuss psychiatry-related responses to the Korean War, including the influence of military psychiatry on civilian psychiatry, the endeavors of medical professionals and government policies, and contemporary expressions of mental distress during and after the war.

Acute Effect of Positive Airway Pressure on Heart Rate Variability in Obstructive Sleep Apnea.

Autonomic dysregulation is associated with cardiovascular consequences in obstructive sleep apnea (OSA). This study aimed to investigate the effect of acute continuous positive airway pressure (CPAP) treatment on autonomic activity and to identify factors contributing to heart rate variability (HRV) changes in OSA. Frequency domain HRV parameters were calculated and compared between the baseline polysomnography and during the CPAP titration in 402 patients with moderate to severe OSA. There were significant reductions in total power, very low-frequency band power, low-frequency band power, and high-frequency band power during the CPAP titration as compared to the baseline polysomnography. This tendency was pronounced in male patients with severe OSA. Multivariate analysis found that changes in the apnea-hypopnea index and oxygen saturation were significantly associated with changes in sympathetic and parasympathetic activity, respectively. This study demonstrated that HRV parameters significantly changed during the CPAP titration, indicating a beneficial effect of CPAP in the restoration of sympathetic and parasympathetic hyperactivity in OSA. Prospective longitudinal studies should determine whether long-term CPAP treatment aids in maintaining the long-lasting improvement of the autonomic functions, thereby contributing to the prevention of cardiovascular and cerebrovascular diseases in patients with OSA.

ß-arrestin 2 negatively regulates lung cancer progression by inhibiting the TRAF6 signaling axis for NF-κB activation and autophagy induced by TLR3 and TLR4.

ß-arrestin 2 (ARRB2) is functionally implicated in cancer progression via various signaling pathways. However, its role in lung cancer remains unclear. To obtain clinical insight on its function in lung cancer, microarray data from lung tumor tissues (LTTs) and matched lung normal tissues (mLNTs) of primary non-small cell lung cancer (NSCLC) patients (n = 37) were utilized. ARRB2 expression levels were markedly decreased in all 37 LTTs compared to those in matched LNTs of NSCLC patients. They were significantly co-related to enrichment gene sets associated with oncogenic and cancer genes. Importantly, Gene Set Enrichment Analysis (GSEA) between three LTTs with highly down-regulated ARRB2 and three LTTs with lowly down-regulated ARRB2 revealed significant enrichments related to toll-like receptor (TLR) signaling and autophagy genes in three LTTs with highly down-regulated ARRB2, suggesting that ARRB2 was negatively involved in TLR-mediated signals for autophagy induction in lung cancer. Biochemical studies for elucidating the molecular mechanism revealed that ARRB2 interacted with TNF receptor-associated factor 6 (TRAF6) and Beclin 1 (BECN1), thereby inhibiting the ubiquitination of TRAF6-TAB2 to activate NF-κB and TRAF6-BECN1 for autophagy stimulated by TLR3 and TLR4, suggesting that ARRB2 could inhibit the TRAF6-TAB2 signaling axis for NF-κB activation and TRAF6-BECN1 signaling axis for autophagy in response to TLR3 and TLR4. Notably, ARRB2-knockout (ARRB2KO) lung cancer cells exhibited marked enhancements of cancer migration, invasion, colony formation, and proliferation in response to TLR3 and TLR4 stimulation. Altogether, our current data suggest that ARRB2 can negatively regulate lung cancer progression by inhibiting TLR3- and TLR4-induced autophagy.

FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB.

BACKGROUND: Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed. METHODS: We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout (FFAR2KO) A549 and FFAR2KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation. RESULTS: The clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2DownTLR2UpTLR3Up lung tumor tissues (LTTs) vs. FFAR2upTLR2DownTLR3Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2KO A549 and FFAR2KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines. CONCLUSION: Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.

Inactivation of glycogen synthase kinase-3ß is required for osteoclast differentiation.

Glycogen synthase kinase-3ß (GSK-3ß) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3ß in osteoblasts is well characterized as a negative regulator of ß-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3ß inactivation upon receptor activator of NF-κB ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3ß activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3ß (GSK3ß-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3ß (GSK3ß-K85R) or small interfering RNA (siRNA)-mediated GSK-3ß silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3ß further confirmed the negative role of GSK-3ß in osteoclast formation. We also show that overexpression of the GSK3ß-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3ß-S9A mutant show an osteopetrotic phenotype due to impaired osteoclast differentiation. Further, osteoclast precursor cells from the transgenic mice show defects in expression and nuclear localization of NFATc1. These findings demonstrate a novel role for GSK-3ß in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling.

Cardioprotective effects of diet with different grains on lipid profiles and antioxidative system in obesity-induced rats.

In the present study, the nutritional quality of four grains including adlay (AD), buckwheat (BW), glutinous barley (GB), and white rice (WR) were evaluated in terms of plasma lipid parameters, gut transit time, and thickness of the aortic wall in rats. The rats were then raised for 4 weeks on the high-fat diet based on the American Institute of Nutrition-93 (AIN-93 G) diets containing 1 % cholesterol and 20 % dietary lipids. Forty male rats were divided into 4 groups and raised for 4 weeks with a diet containing one of the following grains: WR, AD, BW, or WB. The level of thiobarbituric acid-reactive substances (TBARS) in liver was shown to be higher in rats by the order of those fed WR, AD, GB, and BW. This indicates that other grains decreased oxidative stress in vivo more than WR. The superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase levels in the AD, BW, and GB groups were significantly higher than those in the WR group (p < 0.05). Plasma lipid profiles differed significantly according to grain combination, and decreased aortic wall thickness was consistent with the finding of decreased plasma low-density lipoprotein cholesterol (LDL-C) (p < 0.05) and increased high-density lipoprotein (HDL-C) in rats fed AD, BW, and GB (p < 0.001). The antioxidant and hypolipidemic capacities of grains are quite high, especially those of adlay, buckwheat, and glutinous barley. In conclusion, this study has demonstrated that the whole grains had a cardioprotective effect. This effect was related to several mechanisms that corresponded to lowering plasma lipids, decreasing TBARS, and increasing antioxidant activities.

Family Caregivers of People with Dementia Associate with Poor Health-Related Quality of Life: A Nationwide Population-Based Study.

Despite the growing awareness of poor health-related quality of life (HRQoL) in family caregivers of people with dementia (PWD), their relationship has rarely been explored with population-based samples. The current cross-sectional study aimed to determine the detrimental impact of informal dementia caregiving on HRQoL by using nationally representative population-based samples from the Korean Community Health Survey. Demographics, socioeconomic, and physical and mental health-related characteristics as well as HRQoL measured by the Korean version of the European Quality of Life Questionnaire Five Dimension (EQ-5D) were compared between 9563 family caregivers of PWD and 186,165 noncaregivers. Caregivers had lower index scores and higher frequency of some/extreme problems in all five dimensions of the EQ-5D compared with noncaregivers. Logistic regression adjusting for potential confounding factors found that caregivers had a higher frequency of poor HRQoL (lowest quartile of EQ-5D index) than noncaregivers (adjusted odds ratio [95% confidence interval] = 1.46 [1.39-1.53]). Compared to noncaregivers, caregivers had a higher frequency of some/extreme problems in each dimension of the EQ-5D: mobility (1.30 [1.21-1.40]), self-care (1.62 [1.46-1.80]), usual activity (1.39 [1.29-1.51]), pain/discomfort (1.37 [1.31-1.45]), and anxiety/depression (1.51 [1.42-1.61]). A one-to-one propensity score matching analysis confirmed that poor HRQoL was more frequently found in caregivers compared to noncaregivers (1.38 [1.29-1.48]). Our results indicated that family caregivers of PWD are significantly associated with overall poor HRQoL, underscoring the detrimental impact of informal dementia caregiving on HRQoL. Given the high frequency of poor HRQoL in dementia caregivers and the important recognition of its serious consequences on physical and mental health, clinicians should take into consideration efficient interventions to improve health and HRQoL for family caregivers of PWD.

Validation of Cancer Diagnosis Based on the National Health Insurance Service Database versus the National Cancer Registry Database in Korea.

PURPOSE: This study aimed to assess the feasibility of operational definitions of cancer patients in conducting cancer-related studies using the claims data from the National Health Insurance Service (NHIS). MATERIALS AND METHODS: Cancer incidence data were obtained from the Korean Central Cancer Registry, the NHIS primary diagnosis, and from the rare and intractable disease (RID) registration program. RESULTS: The operational definition with higher sensitivity for cancer patient verification was different by cancer type. Using primary diagnosis, the lowest sensitivity was found in colorectal cancer (91.5%; 95% confidence interval [CI], 91.7 to 92.0) and the highest sensitivity was found in breast cancer (97.9%; 95% CI, 97.8 to 98.0). With RID, sensitivity was the lowest in liver cancer (91.9%; 95% CI, 91.7 to 92.0) and highest in breast cancer (98.1%; 95% CI, 98.0 to 98.2). In terms of the difference in the date of diagnosis in the cancer registration data, > 80% of the patients showed a < 31-day difference from the RID definition. CONCLUSION: Based on the NHIS data, the operational definition of cancer incidence is more accurate when using the RID registration program claims compared to using the primary diagnosis despite the relatively lower concordance by cancer type requires additional definitions such as treatment.

"Insanity Is the Price of Modern Civilization": The Discourse of Civilization and the Asian Insane in Modern America.

Examining debates on the link between civilization and insanity in the late nineteenth and early twentieth-century United States, this essay engages the discourse of civilization to discuss the ways in which insanity among Asian immigrants, in particular Chinese and Japanese, was understood, defined and debated. During the period, insanity was regarded as a disease of civilization, which had been increasing due to the struggles of modern life. While Americans witnessed insanity among the "colored" and Asians, they argued that these groups had lower rates of insanity than white Americans and European immigrants because they belonged to lower positions on the civilization scale. Though not explicitly racialist or even racist, the discourse of civilization ordered the international world and drew a clear color line between white westerners and non-white others. At the same time, American missionaries and medical professionals stationed in China and Japan, who were there to see and learn about insanity in Asia, reaffirmed the existing medical understandings of insanity and offered a knowledge base for American psychiatrists who would encounter the Asian insane at their mental institutions. The alleged rarity of mental troubles for Chinese and Japanese was not considered an asset; the insanity debates confirmed the non-white, non-American status of Asian immigrants, rendering them forever foreign. Moreover, their very distance from western civilization explained why Asians in America seemed to have suffered less from mental disturbances and how they could resist the debilitating effects of civilization and migration.

A Real-World, Population-Based Retrospective Analysis of Therapeutic Survival for Recurrent Localized Renal Cell Carcinoma After Nephrectomy.

We retrospectively analyzed therapeutic strategies and risk factors for overall survival (OS) in disease recurrence following curative nephrectomy for localized renal cell carcinoma (loRCC) using the Korean National Cancer Registry Database. We selected 1295 recurrent loRCC patients who underwent either partial or radical nephrectomy from 2007-2013. Patients were excluded for age <19 years, secondary RCC, multiple primary tumors, other SEER stages except for a localized or regional stage, postoperative recurrence within 3-month, and non-nephrectomized cases. Four therapeutic groups were statistically analyzed for OS and risk factors: surgery (OP, 12.0%), other systemic therapy (OST, 59.5%), radiotherapy (RT, 2.8%), and targeted therapy (TT, 25.8%). The overall mortality rate for recurrent loRCC was 32.5%, including 82.4% for RCC-related deaths. The baseline comparison among groups showed statistical differences for the diagnostic age of cancer and the SEER stage (p<0.05). Multivariate analysis of OS showed significance for the TT (hazard ratio [HR]: 6.27), OST (HR: 7.05), and RT (HR: 7.47) groups compared with the OP group, along with significance for the sex, SEER stage, and the time from nephrectomy to treatment for disease recurrence (p<0.05). The median OS curve showed a significantly better OS in the OP group (54.9 months) compared with the TT, OST, and RT groups (41.7, 42.9, and 38.0 months, respectively; p<0.001). In conclusion, the surgery-treated group had the best OS among the different therapeutic strategies for recurrent loRCC after nephrectomy, and the importance of the time from nephrectomy to secondary treatment was a significant prognostic factor.

Role of Synovial Exosomes in Osteoclast Differentiation in Inflammatory Arthritis.

This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were co-incubated with CD14+ mononuclear cells from healthy donors without macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclast differentiation was evaluated via tartrate-resistant acid phosphatase (TRAP) staining and activity and F-actin ring formation. RANKL expression on synovial exosomes was assessed using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Synovial exosomes were the lowest in OA patients; these induced osteoclastogenesis in the absence of M-CSF and RANKL. Osteoclastogenesis was significantly higher with more exosomes in RA (p = 0.030) than in OA patients, but not in AS or gout patients. On treating macrophages with a specified number of synovial exosomes from RA/AS patients, exosomes induced greater osteoclastogenesis in RA than in AS patients. Synovial exosomal RANKL levels were significantly higher in RA (p = 0.035) than in AS patients. Synovial exosome numbers vary with the type of inflammatory arthritis. Synovial exosomes from RA patients may bear the disease-specific "synovial signature of osteoclastogenesis."

The reversible developmental unipotency of germ cells in chicken.

We recently developed bimodal germline chimera production approaches by transfer of primordial germ cells (PGCs) or embryonic germ cells (EGCs) into embryos and by transplantation of spermatogonial stem cells (SSCs) or germline stem cells (GSCs) into adult testes. This study was undertaken to investigate the reversible developmental unipotency of chicken germ cells using our established germline chimera production systems. First, we transferred freshly isolated SSCs from adult testis or in vitro cultured GSCs into stage X and stage 14-16 embryos, and we found that these transferred SSCs/GSCs could migrate to the recipient embryonic gonads. Of the 527 embryos that received SSCs or GSCs, 135 yielded hatchlings. Of 17 sexually mature males (35.3%), six were confirmed as germline chimeras through testcross analysis resulting in an average germline transmission efficiency of 1.3%. Second, PGCs/EGCs, germ cells isolated from embryonic gonads were transplanted into adult testes. The EGC transplantation induced germline transmission, whereas the PGC transplantation did not. The germline transmission efficiency was 12.5 fold higher (16.3 vs 1.3%) in EGC transplantation into testis (EGCs to adult testis) than that in SSC/GSC transfer into embryos (testicular germ cells to embryo stage). In conclusion, chicken germ cells from different developmental stages can (de)differentiate into gametes even after the germ cell developmental clock is set back or ahead. Use of germ cell reversible unipotency might improve the efficiency of germ cell-mediated germline transmission.

Total scores of the CERAD neuropsychological assessment battery: validation for mild cognitive impairment and dementia patients with diverse etiologies.

OBJECTIVES: This study aimed to validate the two total scores (TS-I and TS-II) of the Consortium to Establish a Registry for Alzheimer Disease neuropsychological battery (CERAD-NP) for a large elderly population including mild cognitive impairment (MCI) and dementia patients with various etiologic backgrounds. The authors also investigated whether the addition of frontal-executive function score can improve the discrimination accuracy of the total scores for dementia and MCI. DESIGN, SETTING, AND PARTICIPANTS: One thousand three hundred thirty-six normal comparison (NC), 583 dementia (420 AD, 111 non-AD dementia, and 52 mixed AD with non-AD dementia), and 250 MCI (223 amnestic and 27 nonamnestic MCI) individuals living in the community were included (all aged 60 years and older). RESULTS: Both TS-I and TS-II were highly correlated with other global cognitive and functional scales. Both total scores showed, though modest, superior NC versus MCI discrimination ability to Mini-Mental State Examination (MMSE). Their discrimination ability for NC versus dementia was excellent and significantly better, especially in discriminating very mild dementia, than MMSE. The addition of frontal-executive test score to TS-I or TS-II did not make a significant improvement in dementia or MCI discrimination ability. Both of them also showed higher test-retest and interrater reliability than MMSE or any individual neuropsychological tests in the CERAD-NP. CONCLUSION: These results strongly support the validity and usefulness of CERAD total scores for early detection and progression monitoring of MCI and dementia in clinical and research settings.

Nonlinear Hammett plots in pyridinolysis of 2,4-dinitrophenyl X-substituted benzoates: change in RDS versus resonance contribution.

Second-order rate constants (k(OH)-) have been measured for nucleophilic substitution reactions of 2,4-dinitrophenyl X-substituted benzoates (1a-j) with Z-substituted pyridines in 80 mol% H(2)O/20 mol% DMSO at 25.0 +/- 0.1 degrees C. The Hammett plots for the reactions of 1a-j with pyridines consist of two intersecting straight lines, i.e., a large rho value for the reactions of substrates (1a-c) possessing an electron-donating group (EDG) in the benzoyl moiety and a small one for substrates (1e-j) bearing an electron-withdrawing group (EWG). The nonlinear Hammett plots have been attributed to stabilization of the ground state of substrates 1a-c through resonance interactions between the electron-donating substituent and the carbonyl functionality, since the corresponding Yukawa-Tsuno plots exhibit excellent linear correlations with large r values. It has been shown that substrates are not unusually more reactive than would be expected from the Hammett substituent constants, but rather, substrates 1a-c exhibit lower reactivity than would be predicted. The Brønsted-type plots for pyridinolysis of 1a-j are linear with beta(nuc) = 0.74-0.98, indicating that the reaction proceeds through a stepwise mechanism in which the second step is the RDS. It has been concluded that the electronic nature of the substituent X in the benzoyl moiety does not influence the RDS, but the degree of bond formation (or the effective charge on the nucleophilic site) in the transition state becomes more significant as the substituent X changes from a strong EDG to a strong EWG.