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ImportanceThe BCG vaccine—used worldwide to prevent tuberculosis—confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non–muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses.ObjectiveTo evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event.Design, Setting, and ParticipantsThis cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023.Main Outcomes and MeasuresThe main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting.ResultsIn this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, −0.011; 95% CI, −0.019 to −0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, −0.056; 95% CI, −0.075 to −0.037).Conclusions and RelevanceIn this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

Aims: Bisphenol A (BPA)-based dental composites have commonly been used to fill dental cavities or seal pits and fissures on teeth. However, epidemiological evidence with regard to the BPA exposure from dental composites among children has rarely been reported. This study investigated whether there is a relationship between the BPA concentration in urine and the presence of composite restorations and sealants among South Korean children. Methods: Oral examinations and urine sample analyses were conducted on a total of 495 children aged 8–9 years. We classified the participants into four groups by the number of resin composites and sealant surfaces (0, 1–5, 6–10 and 11+). Results: BPA concentrations in urine were higher in children with 11 or more surfaces restored with sealants and resin composites than in those with zero restored surfaces, although no difference was seen in the group with 1–10 surfaces. After adjusting for gender and age, the urinary BPA concentration in children with 11 or more resin composite surfaces was 2.67 lg ⁄ g creatinine, which was higher than the concentration found in those with no filling surfaces ( P< 0.01). Conclusions: Having many dental composite filling surfaces on teeth may increase the urinary BPA concentration in children.

Human pluripotent stem cells show considerable promise for applications in regenerative medicine, including the development of cell replacement paradigms for the treatment of Parkinson's disease. Protocols have been developed to generate authentic midbrain dopamine (mDA) neurons capable of reversing dopamine-related deficits in animal models of Parkinson's disease. However, the generation of mDA neurons at clinical scale suitable for human application remains an important challenge. Here, we present an mDA neuron derivation protocol based on a two-step WNT signaling activation strategy that improves expression of midbrain markers, such as Engrailed-1 (EN1), while minimizing expression of contaminating posterior (hindbrain) and anterior (diencephalic) lineage markers. The resulting neurons exhibit molecular, biochemical, and electrophysiological properties of mDA neurons. Cryopreserved mDA neuron precursors can be successfully transplanted into 6-hydroxydopamine (6OHDA) lesioned rats to induce recovery of amphetamine-induced rotation behavior. The protocol presented here is the basis for clinical-grade mDA neuron production and preclinical safety and efficacy studies.

Environmental and genetic risk factors contribute to Parkinson’s Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho-STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases., The early molecular events that ultimately lead to neuronal cell death in pathologies such as Parkinson’s disease are poorly understood. Here the authors use pluripotent stem-cell-derived human midbrain neurons and chemical biology tools to gain molecular level insight into the events induced by toxic and genetic stresses that mimic those occurring during neurodegeneration.

Headache after traumatic brain injury (TBI) is a common symptom which includes moderate-to-severe pain more than 5 years after the injury and severely limits the quality of life. Some guidelines have indicated that there are several cases where headaches do not respond adequately to conventional therapies. Therefore, effective alternative approaches are needed. In this case report, we present a 74-year-old woman, who had persistent headache attributed to traumatic injury to the head and subjective cognitive impairment. By using the Korean Medical (KM) treatment blood stasis-removing therapy using Dangguixu-san and auriculotherapy, her headache improved markedly. Improvements in the cognitive function and hemorrhage were also observed. This case report suggests that KM treatments using Dangguixu-san and auriculotherapy may be an alternative therapeutic approach for headache after TBI.

Summary Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets., Highlights • Disease modeling study with patient (monogenic)-derived iPSC for Parkinson's disease • Disease phenotypes exhibited by PD iPSC-derived midbrain DA neurons involved • Mitochondria, α-synuclein, selective vulnerability, and neurotransmitter regulation • These phenotypes may interact synergistically throughout PD progression, Shim, Studer, and colleagues demonstrate that using a floor-plate-based differentiation strategy, Parkinson's disease (PD) patient iPSC-derived mDA neurons recapitulate several PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. The authors further propose that these phenotypes form a pathogenic loop contributing to disease.

Received: November 25, 2015 Revised: December 14, 2015 Accepted: December 18, 2015 Objectives: People with tension-type headache generally take pain relievers, but long term dependency causes problems as well as side effects. The present study aimed to provide clinical evidence of herbal medicine for tension-type headache by systematic review of randomized controlled trials on the effect of herbal medicine for tension-type headache. Methods: Randomized or quasi-randomized controlled trials that verified effects of herbal medicine intervention on patients with tension-type headache were included in the study. A literature search of English, Japanese, Chinese, Korean databases was performed. The selected literature were assessed by Jadad scale and Risk of Bias. Results: Herein, 40 reports were selected from a total of 157. Meta-analyses of 2 trials indicated that the effective rate was significantly higher in the herbal medicine treatment group, as compared to the placebo control (risk ratio: 1.49, 95% confidence interval (CI): 1.23 to 1.80, p

Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism mutations that perturb PFC neurogenesis and are correlated to abnormal WNT/βcatenin responses. Class 1 mutations (8 of 27) inhibit while class 2 mutations (5 of 27) enhance PFC neurogenesis. Remarkably, autism patient data reveal that individuals carrying subclass-specific mutations differ clinically in their corresponding language acquisition profiles. Our study provides a framework to disentangle genetic heterogeneity associated with autism and points toward converging molecular and developmental pathways of diverse autism-associated mutations.

Objectives: The purpose of this study is to investigate the research about using tuina therapy for depression and to determine its efficacy. Methods: All relevant articles were searched in the China National Knowledge Infrastructure using the terms `tuina` and `depression`. Results: Forty-one studies were selected, 34 randomized controlled trials (RCTs) and 7 prospective studies. The Chinese Classification of Mental Disorders and Hamilton Depression Rating Scale were used most frequently as diagnostic criteria and an assessment tool, respectively. Conduction exercise therapy was used in all studies; in contrast, Zheng Xing exercise therapy was used in only 1 study of depression patients with neck vertebrae disease. In 9 RCTs that showed scores of more than 2 points on a modified Jadad scale, tuina therapy had significant antidepressant efficacy compared with conventional treatment. However, more high-quality studies are required. Conclusions: Tuina therapy has a valid therapeutic effect on depression according to studies published in China; if evidence accumulates from high-quality studies, it can be considered a non-pharmacologic treatment for depression in Korean medicine, as well.

Parkinson’s disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions. This review discusses the role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD. Understanding the multi-faceted relationships between these events, with oxidative stress as a common denominator underlying these processes, is needed for developing better therapeutic strategies.

Summary Current challenges in capturing naive human pluripotent stem cells (hPSCs) suggest that the factors regulating human naive versus primed pluripotency remain incompletely defined. Here we demonstrate that the widely used Essential 8 minimal medium (E8) captures hPSCs at a naive-to-primed intermediate state of pluripotency expressing several naive-like developmental, bioenergetic, and epigenomic features despite providing primed-state-sustaining growth factor conditions. Transcriptionally, E8 hPSCs are marked by activated lipid biosynthesis and suppressed MAPK/TGF-β gene expression, resulting in endogenous ERK inhibition. These features are dependent on lipid-free culture conditions and are lost upon lipid exposure, whereas short-term pharmacological ERK inhibition restores naive-to-primed intermediate traits even in the presence of lipids. Finally, we identify de novo lipogenesis as a common transcriptional signature of E8 hPSCs and the pre-implantation human epiblast in vivo. These findings implicate exogenous lipid availability in regulating human pluripotency and define E8 hPSCs as a stable, naive-to-primed intermediate (NPI) pluripotent state.

To evaluate clinical features and CT findings of pneumatois intestinalis in recipients following liver transplantation and to determine whether certain clinical and CT findings enable differentiation of indolent pneumatois intestinalis from fulminant cases.This retrospective study was approved by our institutional review board, with informed consent waived. Among 2080 liver transplantation recipients at our institution between January 1998 and April 2008, 22 (1%) presented with pneumatois intestinalis on postoperative follow-up. Patients were divided into recovery and mortality groups, and then clinical features and CT findings were compared between two groups.Although indolent pneumatois intestinalis more frequently presented incidentally (61%) after 2 weeks of surgery (89%) than fulminant pneumatois intestinalis (0, 50%), there were no statistically significant differences (P=.14, .09). Right colon was affected in the recovery group without exception (n=18,100%), and all four patients (100%) in mortality group showed small bowel involvement (P.05). Caliber changes of superior mesenteric artery and vein in mortality group were significantly greater (49.6%, 67.0%) than those in recovery group (101.7%, 99.0%) (P.05, respectively). Pneumatois intestinalis in mortality group more commonly accompanied portomesenteric air-embolism, visceral infarction, hemorrhagic ascites, and small bowel ileus than indolent counterpart (P.05, respectively).Typical indolent pneumatois intestinalis is found incidentally later than 2 weeks of liver transplantation surgery, but there is some overlap between indolent and fulminant pneumatois intestinalis in terms of onset and mode of presentation. Among CT findings, grave signs are small bowel involvement, caliber changes in mesenteric vessels, portomesenteric air-embolism, visceral infarction, hemorrhagic ascites, and small bowel ileus.

Aging is a well-known risk factor associated with oral diseases. The aim of this cross-sectional study was to compare tooth loss and periodontal health between the relatively young elderly (65-74 years) and the old elderly (≥ 75 years) and to investigate the strength of the age effect on oral health status in the Korean elderly. Study population 65 years of age or older were selected from the participants of the Korean National Oral Health Survey (2006) (n = 1193). Oral examination was conducted by eight dentists trained in the World Health Organization (WHO) recommended examination procedure. The chi-square test, multiple regression analyses and multinomial logistic regression analyses were performed using SAS 9.1.3. The oral health status including decayed, missing, and filled teeth (DMFT), missing teeth, and residual teeth significantly differed between the young elderly and the old elderly (p0.01). Moreover, the regression coefficients of tooth loss linearly increased across different age groups (5-year intervals, starting at age 65 years) (p0.05). However, the odds ratios of periodontal health did not significantly differ across 5-year interval age groups. The findings that age and the number of missing teeth are significantly and linearly related could contribute to the development of oral health care and promotion programs for the elderly tailored to their own age.

DAAS is the diacetoxy acetal derivative of a-santonin and induces HL-60 cell differentiation into granulocytes. In this report, we investigated the structure-activity relationship (SAR) of DAAS derivatives in the differentiation of human HL-60 leukemia cells. Although its derivatives themselves had less effect on HL-60 cell differentiation than DAAS, the monoacetyl derivative, 2, mainly induced HL-60 cell differentiation. Moreover, compound 2 synergistically enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation when combined with 50 nM ATRA, a well-known differentiation inducer. This enhancing effect is similar to that of DAAS in ATRA-induced differentiation.

Several diacetoxy acetal analogues have been synthesized from santonin and assessed for their ability of inducing or enhancing the differentiation of human HL-60 leukemia cells. The compounds themselves had little effect on HL-60 cell differentiation. However, three analogues, 2a, 3a, and 5b, synergistically enhanced 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced HL-60 cell differentiation when combined with 5 nM of dihydroxyvitamin D3 [1,25-(OH)2D3], a well-known differentiation inducer. Especially, the compound 5b profoundly enhanced the 1,25-(OH)2D3]-induced HL-60 cell differentiation.

Christians, at any given time in history, have definable geographic locations and a demographic or statistical centre. A single geographic point is here identified as the statistical "centre of gravity" of Christianity for each of 25 different dates in Christian history, beginning with AD 33 (the traditional date for the origin of the church) and projecting to AD 2100 (one hundred years into the future). The methodology for locating these points utilizes demographic and religious affiliation statistics relating to 21 United Nations regions. By connecting these points, a line is formed that can be viewed as the "trajectory" of global Christianity. In the early Christian centuries the trajectory moved around the eastern Mediterranean but, after AD 600, the trajectory was astonishingly consistent, moving both north and west until AD 1500 when it began to move slowly to the south. After 1900, the trajectory moved precipitously to the south, and then, after AD 1970, definitively back to the east. By AD 2100, the statistical centre of gravity of Christianity is likely to be in northern Nigeria. This trajectory is tracked in detail throughout Christian history, and historical comments and interpretation are provided, with one map, one graphic, and two tables. Brief consideration is given to the implications of the present southeastern trajectory of Christianity for theology, translation and mission. ********** One of the most significant features of Christianity, apart from its theology, ethics and ecclesiastical structures, is the number and location of its followers. These followers, called "Christians", are individuals, and they have distinct ethnic identities, speak identifiable languages, and make their homes in specific geographic locations, (1) Throughout the history of Christianity, whole villages, tribes and peoples have embraced the Christian message. Consequently, groups of followers, including their ethnicity and language, can be named, located, listed, counted, mapped and tracked over time. As a result, Christians as a whole, at any given time in history, have a definable geographic boundary and a demographic or statistical centre. In practical terms, a single geographic point on earth can be seen as the statistical "centre of gravity (2)" of all Christian followers at any given date, and the place where the numbers of all Christians living to its north, its south, its east and its west are exactly the same. (3) The demographic history of Christianity is viewed precisely through this lens in Map 1: "Trajectory of the statistical centre of gravity of global Christianity, AD 33-AD 2100." (p. 167) A single geographic point has been identified in Table 1 (p. 179) as the statistical centre of gravity of Christianity for each of 25 different dates in Christian history, beginning with AD 33 (the traditional date for the origin of the church), and projecting to AD 2100 (one hundred years into the future). The methodology, which employs current United Nations (UN) regional boundaries for arriving at the location of these points, is found in the appendix (cf. pages 177f). The points have been connected in order to approximate a "trajectory" of the demographic centre of gravity of Christianity throughout its history. A more detailed and precise trajectory could also be drawn up utilizing data on 238 countries instead of 21 regions. Again, one could consider the world's 13,000 ethnolinguistic peoples as the basic demographic units for yet more detailed demographic analysis. [ILLUSTRATION OMITTED] Documenting the statistical centre of gravity of Christianity Table 1 "Global Christianity's statistical centre of gravity, AD 33-AD 2100" (cf. page 179) provides more information on each of the dates analysed in Map 1, and on the line connecting them. Column 1 lists 25 different years, from AD 33 to AD 2100, in which Christian demography is examined. Columns 2-8 refer exactly to the date in column 1, whereas columns 9-11 refer to the period leading up to that date. …

Breast cancer is the most prevalent malignancy among women, occurring in approximately one in eight women in Western countries (1). The BRCA1 and BRCA2 genes contribute 5~10% in genetic breast cancer and women with these mutations have a 60~80% risk of developing breast cancer by the age of 70 (2). To reduce this risk, close surveillance for the earlier detection of breast cancer at the most favorable stage is necessary. The strategy for the surveillance of high-risk women should differ from that of the general population. Screening of high-risk women should begin at a younger age, and clinical breast examinations and annual mammography should begin at 25-35 years of age (3, 4). Findings of several studies indicate that contrast-enhanced MRI is useful for screening highrisk women (5, 6). In addition, the American Cancer INTRODUCTION

Objective To evaluate our early experience using self-expanding stents to treat atherosclerotic vertebral artery ostial stenosis (VAOS), with respect to technical feasibility and clinical and imaging follow-up results. Materials and Methods A total of 20 lesions in 20 patients underwent stenting of the VAOS using a self-expanding stent (Precise RX; Cordis Neurovascular, Miami Lakes, FL). Two patients were asymptomatic. We analyzed the technical success rate, causes of technical failure, occurrence of any vascular or neurological event, and the occurrence of any neurological abnormality or in-stent restenosis (ISR) seen on follow-up. The imaging follow-up was performed with Doppler ultrasound (DUS) as a primary screening modality. Results One instance of technical failure was caused by failure of the guidewire passage. The stent diameter was 5 mm, and post-stenting balloon dilatations were necessary in all cases. Stent misplacement requiring placement of an additional stent occurred in four cases. Following a 14.8 month average clinical follow-up time, two patients showed anterior circulation ischemia, which was not attributed to the VAOS we treated. Following a 13.7 month average DUS follow-up, five patients showed a mild degree of diffuse or focal intimal thickening in the stent lumen; however, none of the stenosis showed luminal loss of more than 50% and no stent fracture was noted. Conclusion The use of self-expanding stents for treating VAOS was technically feasible and helped to improve artery patency during our limited follow-up interval.