Contemporary Analysis of Reexcision and Conversion to Mastectomy Rates and Associated Healthcare Costs for Women Undergoing Breast-Conserving Surgery.

PURPOSE: This study was designed to provide a comprehensive and up-to-date understanding of population-level reoperation rates and incremental healthcare costs associated with reoperation for patients who underwent breast-conserving surgery (BCS). METHODS: This is a retrospective cohort study using Merative™ MarketScan® commercial insurance data and Medicare 5% fee-for-service claims data. The study included females aged 18-64 years in the commercial cohort and females aged 18 years and older in the Medicare cohort, who underwent initial BCS for breast cancer in 2017-2019. Reoperation rates within a year of the initial BCS and overall 1-year healthcare costs stratified by reoperation status were measured. RESULTS: The commercial cohort included 17,129 women with a median age of 55 (interquartile range [IQR] 49-59) years, and the Medicare cohort included 6977 women with a median age of 73 (IQR 69-78) years. Overall reoperation rates were 21.1% (95% confidence interval [CI] 20.5-21.8%) for the commercial cohort and 14.9% (95% CI 14.1-15.7%) for the Medicare cohort. In both cohorts, reoperation rates decreased as age increased, and conversion to mastectomy was more prevalent among younger women in the commercial cohort. The mean healthcare costs during 1 year of follow-up from the initial BCS were $95,165 for the commercial cohort and $36,313 for the Medicare cohort. Reoperations were associated with 24% higher costs in both the commercial and Medicare cohorts, which translated into $21,607 and $8559 incremental costs, respectively. CONCLUSIONS: The rates of reoperation after BCS have remained high and have contributed to increased healthcare costs. Continuing efforts to reduce reoperation need more attention.

Performance of the Elixhauser Comorbidity Index in Predicting Mortality Among a National US Sample of Hospitalized Homeless Adults.

BACKGROUND: The Elixhauser Comorbidity Index (ECI) is widely used, but its performance in homeless populations has not been evaluated. OBJECTIVES: Using a national sample of inpatients, this study compared homeless and nonhomeless inpatients on common clinical diagnoses and evaluated ECI performance in predicting mortality among homeless inpatients. RESEARCH DESIGN: A retrospective study was conducted using 2019 National Inpatient Sample (NIS) data, the largest publicly available all-payer inpatient health care database in the United States. SUBJECTS: Among 4,347,959 hospitalizations, 78,819 (weighted 1.8%) were identified as homeless. MEASURES: The ECI consists of 38 medical conditions; homelessness was defined using the International Classification of Diseases Tenth Revision Clinical Modification (ICD-10-CM) diagnostic code, and clinical conditions were based on the Clinical Classifications Software Refined (CCSR) for ICD-10-CM. RESULTS: Leading clinical diagnoses for homeless inpatients included schizophrenia and other psychotic disorders (13.3%), depressive disorders (9.4%), and alcohol-related disorders (7.2%); leading diagnoses for nonhomeless inpatients were septicemia (10.2%), heart failure (5.2%), and acute myocardial infarction (3.0%). Metastatic cancer and liver disease were the most common ECI diagnoses for both homeless and nonhomeless inpatients. ECI indicators and summary scores were predictive of in-hospital mortality for homeless and nonhomeless inpatients, with all models yielding concordance statistics above 0.80, with better performance found among homeless inpatients. CONCLUSIONS: These findings underlie the high rates of behavioral health conditions among homeless inpatients and the strong performance of the ECI in predicting in-hospital mortality among homeless inpatients, supporting its continued use as a case-mix control method and predictor of hospital readmissions.

Increased IGFBP2 Levels by Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism in a TAA-Injured Rat Model via AMPK Signaling Pathway.

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 106) 8 weeks after the experiment started. The expression of the IGFBP2 gene and glucose metabolism factors (e.g., AMPK, GLUT4) was significantly increased in the PD-MSC group compared to the nontransplantation (NTx) group (* p < 0.05). The levels of follicular development markers and the sex hormones AMH, FSH, and E2 were also higher than those in the TAA group. Using ex vivo cocultivation, the mRNA and protein expression of IGFBP2, AMPK, and GLUT4 were significantly increased in the cocultivation with the PD-MSCs group and the recombinant protein-treated group (* p < 0.05). These findings suggest that the increased IGFBP2 levels by PD-MSCs play an important role in glucose metabolism and ovarian function through the IGFBP2-AMPK signaling pathway.

Underutilization of Endovascular Therapy in Black Patients With Ischemic Stroke: An Analysis of State and Nationwide Cohorts.

BACKGROUND AND PURPOSE: Endovascular therapy (EVT) is a very effective treatment but relies on specialized capabilities that are not available in every hospital where acute ischemic stroke is treated. Here, we assess whether access to and utilization of this therapy has extended uniformly across racial and ethnic groups. METHODS: We conducted a retrospective, population-based study using the 2019 Texas Inpatient Public Use Data File. Acute ischemic stroke cases and EVT use were identified using the International Classification of Diseases, Tenth Revision (ICD-10) diagnosis and procedure codes. We examined EVT utilization by race/ethnicity and performed patient- and hospital-level analyses. To validate state-specific findings, we conducted patient-level analyses using the 2017 National Inpatient Sample for national estimates. To assess independent associations between race/ethnicity and EVT, multivariable modified Poisson regressions were fitted and adjusted relative risks were estimated accounting for patient risk factors and socioeconomic characteristics. RESULTS: Among 40 814 acute ischemic stroke cases in Texas in 2019, 54% were White, 17% Black, and 21% Hispanic. Black patients had similar admissions to EVT-performing hospitals and greater admissions to comprehensive stroke centers (CSCs) compared with White patients (EVT 62% versus 62%, P=0.21; CSCs 45% versus 39%, P<0.001) but had lower EVT rates (4.1% versus 5.3%; adjusted relative risk, 0.76 [0.66-0.88]; P<0.001). There were no differences in EVT rates between Hispanic and White patients. Lower rates of EVT among Black patients were consistent in the subgroup of patients who arrived in early time windows and received intravenous recombinant tissue-type plasminogen activator (adjusted relative risk, 0.77 [0.61-0.98]; P=0.032) and the subgroup of those admitted to EVT-performing hospitals in both non-CSC (3.0% versus 5.5, P<0.001) and CSC hospitals (7.9% versus 10.4%, P<0.001) while there were no differences between Whites and Hispanic patients. Nationwide sample data confirmed this finding of lower utilization of EVT among Black patients (adjusted relative risk, 0.87 [0.77-0.98]; P=0.024). CONCLUSIONS: We found no evidence of disparity in presentation to EVT-performing hospitals or CSCs; however, lower rates of EVT were observed in Black patients.

Machine Learning Automated Detection of Large Vessel Occlusion From Mobile Stroke Unit Computed Tomography Angiography.

BACKGROUND: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO. METHODS: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics. RESULTS: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5-196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80-0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71-0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts. CONCLUSIONS: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.

Structural basis of the fanconi anemia-associated mutations within the FANCA and FANCG complex.

Monoubiquitination of the Fanconi anemia complementation group D2 (FANCD2) protein by the FA core ubiquitin ligase complex is the central event in the FA pathway. FANCA and FANCG play major roles in the nuclear localization of the FA core complex. Mutations of these two genes are the most frequently observed genetic alterations in FA patients, and most point mutations in FANCA are clustered in the C-terminal domain (CTD). To understand the basis of the FA-associated FANCA mutations, we determined the cryo-electron microscopy (EM) structures of Xenopus laevis FANCA alone at 3.35 Å and 3.46 Å resolution and two distinct FANCA-FANCG complexes at 4.59 and 4.84 Å resolution, respectively. The FANCA CTD adopts an arc-shaped solenoid structure that forms a pseudo-symmetric dimer through its outer surface. FA- and cancer-associated point mutations are widely distributed over the CTD. The two different complex structures capture independent interactions of FANCG with either FANCA C-terminal HEAT repeats, or the N-terminal region. We show that mutations that disturb either of these two interactions prevent the nuclear localization of FANCA, thereby leading to an FA pathway defect. The structure provides insights into the function of FANCA CTD, and provides a framework for understanding FA- and cancer-associated mutations.

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1.

Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI-FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5' flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domain playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5' flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.

Automated prediction of final infarct volume in patients with large-vessel occlusion acute ischemic stroke.

OBJECTIVE: In patients with large-vessel occlusion (LVO) acute ischemic stroke (AIS), determinations of infarct size play a key role in the identification of candidates for endovascular stroke therapy (EVT). An accurate, automated method to quantify infarct at the time of presentation using widely available imaging modalities would improve screening for EVT. Here, the authors aimed to compare the performance of three measures of infarct core at presentation, including an automated method using machine learning. METHODS: Patients with LVO AIS who underwent successful EVT at four comprehensive stroke centers were identified. Patients were included if they underwent concurrent noncontrast head CT (NCHCT), CT angiography (CTA), and CT perfusion (CTP) with Rapid imaging at the time of presentation, and MRI 24 to 48 hours after reperfusion. NCHCT scans were analyzed using the Alberta Stroke Program Early CT Score (ASPECTS) graded by neuroradiology or neurology expert readers. CTA source images were analyzed using a previously described machine learning model named DeepSymNet (DSN). Final infarct volume (FIV) was determined from diffusion-weighted MRI sequences using manual segmentation. The primary outcome was the performance of the three infarct core measurements (NCHCT-ASPECTS, CTA with DSN, and CTP-Rapid) to predict FIV, which was measured using area under the receiver operating characteristic (ROC) curve (AUC) analysis. RESULTS: Among 76 patients with LVO AIS who underwent EVT and met inclusion criteria, the median age was 67 years (IQR 54-76 years), 45% were female, and 37% were White. The median National Institutes of Health Stroke Scale score was 16 (IQR 12-22), and the median NCHCT-ASPECTS on presentation was 8 (IQR 7-8). The median time between when the patient was last known to be well and arrival was 156 minutes (IQR 73-303 minutes), and between NCHCT/CTA/CTP to groin puncture was 73 minutes (IQR 54-81 minutes). The AUC was obtained at three different cutoff points: 10 ml, 30 ml, and 50 ml FIV. At the 50-ml FIV cutoff, the AUC of ASPECTS was 0.74; of CTP core volume, 0.72; and of DSN, 0.82. Differences in AUCs for the three predictors were not significant for the three FIV cutoffs. CONCLUSIONS: In a cohort of patients with LVO AIS in whom reperfusion was achieved, determinations of infarct core at presentation by NCHCT-ASPECTS and a machine learning model analyzing CTA source images were equivalent to CTP in predicting FIV. These findings have suggested that the information to accurately predict infarct core in patients with LVO AIS was present in conventional imaging modalities (NCHCT and CTA) and accessible by machine learning methods.

Genetic Polymorphisms in miR-604A>G, miR-938G>A, miR-1302-3C>T and the Risk of Idiopathic Recurrent Pregnancy Loss.

The purpose of this study was to investigate whether polymorphisms in five microRNAs (miRNAs), miR-604A>G, miR-608C>G, 631I/D, miR-938G>A, and miR-1302-3C>T, are associated with the risk of idiopathic recurrent pregnancy loss (RPL). Blood samples were collected from 388 patients with idiopathic RPL (at least two consecutive spontaneous abortions) and 227 control participants. We found the miR-604 AG and AG + GG genotypes of miR-604, the miR-938 GA and GA + AA genotypes of miR-938, and the miR-1302-3CT and CT + TT genotypes of miR-1302-3 are less frequent than the wild-type (WT) genotypes, miR-604AA, miR-938GG, and miR-1302-3CC, respectively, in RPL patients. Using allele-combination multifactor dimensionality reduction (MDR) analysis, we found that eight haplotypes conferred by the miR-604/miR-608/miR-631/miR-938/miR-1302-3 allele combination, A-C-I-G-T, A-C-I-A-C, G-C-I-G-C, G-C-I-G-T, G-G-I-G-C, G-G-I-G-T, G-G-I-A-C, G-G-D-G-C, three from the miR-604/miR-631/miR-938/miR-1302-3 allele combination, A-I-G-T, G-I-G-C, G-I-A-T, one from the miR-604/miR-631/miR-1302-3 allele combination, G-I-C, and two from the miR-604/miR-1302-3 allele combination, G-C and G-T, were less frequent in RPL patients, suggesting protective effects (all p < 0.05). We also identified the miR-604A>G and miR-938G>A polymorphisms within the seed sequence of the mature miRNAs and aligned the seed sequences with the 3'UTR of putative target genes, methylenetetrahydrofolate reductase (MTHFR) and gonadotropin-releasing hormone receptor (GnRHR), respectively. We further found that the binding affinities between miR-604/miR-938 and the 3'UTR of their respective target genes (MTHFR, GnRHR) were significantly different for the common (miR-604A, miR-938G) and variant alleles (miR-604G, miR-938A). These results reveal a significant association between the miR-604A>G and miR-938G>A polymorphisms and idiopathic RPL and suggest that miRNAs can affect RPL in Korean women.

ATP-dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex.

ATP-dependent DNA end recognition and nucleolytic processing are central functions of the Mre11/Rad50 (MR) complex in DNA double-strand break repair. However, it is still unclear how ATP binding and hydrolysis primes the MR function and regulates repair pathway choice in cells. Here,Methanococcus jannaschii MR-ATPγS-DNA structure reveals that the partly deformed DNA runs symmetrically across central groove between two ATPγS-bound Rad50 nucleotide-binding domains. Duplex DNA cannot access the Mre11 active site in the ATP-free full-length MR complex. ATP hydrolysis drives rotation of the nucleotide-binding domain and induces the DNA melting so that the substrate DNA can access Mre11. Our findings suggest that the ATP hydrolysis-driven conformational changes in both DNA and the MR complex coordinate the melting and endonuclease activity.

Neonatal Intensive Care Variation in Medicaid-Insured Newborns: A Population-Based Study.

OBJECTIVE: To assess the contribution of maternal and newborn characteristics to variation in neonatal intensive care use across regions and hospitals. STUDY DESIGN: This was a retrospective population-based live birth cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 2 subcohorts: very low birth weight (VLBW) singletons and late preterm singletons. Crude and risk-adjusted neonatal intensive care unit (NICU) admission rates, intensive and intermediate special care days, and imaging procedures were calculated across Neonatal Intensive Care Regions (n = 21) and hospitals (n = 100). Total Medicaid payments were calculated. RESULTS: Overall, 11.5% of live born, 91.7% of VLBW, and 37.6% of infants born late preterm were admitted to a NICU, receiving an average of 2 days, 58 days, and 5 days of special care with payments per newborn inpatient episode of $5231, $128 075, and $10 837, respectively. There was little variation across regions and hospitals in VLBW NICU admissions but marked variation for NICU admissions in late preterm newborn infants and for special care days and imaging rates in all cohorts. The variation decreased slightly after health risk adjustment. There was moderate substitution of intermediate for intensive care days across hospitals (Pearson r VLBW -0.63 P < .001; late preterm newborn -0.53 P < .001). CONCLUSIONS: Across all risk groups, the variation in NICU use was poorly explained by differences in newborn illness levels and is likely to indicate varying practice styles. Although the "right" rates are uncertain, it is unlikely that all of these use patterns represent effective and efficient care.

Role of Prices, Utilization, and Health in Explaining Texas Medicaid Newborn Care Spending Variation.

BACKGROUND: Newborn care is one of the most frequent types of hospitalization and Medicaid covers over 50% of all births nationwide. However, little is known about regional variation in Medicaid newborn care spending and its drivers. OBJECTIVES: To measure the contribution of market-level prices, utilization, and health risk on regional variation in spending among newborn Medicaid population in Texas. RESEARCH DESIGN AND METHODS: The study used 2014 Texas Medicaid newborn claims and encounters linked to birth and death certificate data. Newborn care spending was defined as Medicaid payments per newborn hospital stay, including hospital transfers, from birth through discharge home or death. Spending was further categorized into inpatient facility and related professional spending. Variation in spending across neonatal intensive care regions was decomposed into price and utilization, accounting for input price and health risk differences. RESULTS: Newborn care spending across Texas regions varied significantly (coefficient of variation, 0.31), with most of the variation attributed to spending on inpatient facility services (91%). Both price (41%) and utilization (27%) played a role in explaining this variation, after adjusting for health status (29%) and input price (4%). Though most regions with the highest spending indexes had high price and utilization indexes, some had high spending driven mostly by high prices and others by high utilization. CONCLUSIONS: Significant regional variations in price, utilization, and health status exist in Medicaid newborn care across Texas in 2014. Disentangling the effect of each driver is important to address spending variation and improve efficiency in newborn care.

A 13-Week Repeated Oral Dose Toxicity Study of ChondroT in Sprague-Dawley Rats.

BACKGROUND: ChondroT, a new herbal medication, consists of Angelica grosseserrata Maxim., Lonicera japonica Thunb., Angelica gigas Nakai, Clematis terniflora var. manshurica (Rupr.) Ohwi, and Phellodendron amurense Rupr. (6:4:4:4:3). Our previous studies have shown that ChondroT exhibits significant anti-arthritic and anti-inflammatory effects. In this study, we aimed to assess the toxicological safety assessment of ChondroT. METHODS: This study was designed to assess the safety of ChondroT after repeated oral administration. Male and female Sprague-Dawley rats were treated with ChondroT at oral doses of 0, 500, 1000, and 2000 mg/kg for 13 weeks. Mortality, clinical signs, body weight changes, food consumption, ophthalmological findings, urinalysis, hematological and blood-chemical parameters, necropsy findings, organ weights, and histological markers were recorded throughout the study period. Rats were also monitored for an additional 4 weeks to determine the recovery time. RESULTS: No death occurred and no significant changes in food consumption, ophthalmologic findings, and urinalysis were found. Although there were alterations in clinical signs, body weights, hematological parameters, blood-chemical parameters, necropsy findings, organ weights, and histological markers, they were not considered to be toxicologically significant. CONCLUSIONS: The results suggest that the no-observed adverse effects level (NOAEL) was 2000 mg/kg/day for the test substance. ChondroT, a new complex herbal medication composed of five plants, can therefore be used safely at the NOAEL.

Anti-osteoarthritic effects of ChondroT in a rat model of collagenase-induced osteoarthritis.

BACKGROUND: Previously, we reported that ChondorT showed significant anti-arthritis and anti-inflammatory effects. ChondroT, a new herbal medication, consists of the water extracts of Osterici Radix, Lonicerae Folium, Angelicae Gigantis Radix, Clematidis Radix, and Phellodendri Cortex (6:4:4:4:3). The objective of this study was to investigate the effects of ChondroT in collagenase-induced osteoarthritis rat model. METHODS: Osteoarthritis was induced by the injection of collagenase into the right knee joint cavity of rats. The samples were divided into seven groups [intact (n = 6), control (n = 6), indomethacin (n = 6), Joins tab (n = 6), ChondroT50 (n = 6), ChondroT100 (n = 6), and ChondroT200 (n = 6)]. The control group was administered normal saline, indomethacin group was administered indomethacin (2 mg/kg), and Joins tab group was administered Joins Tab (20 mg/kg). The ChondroT50, ChondroT100, and ChondroT200 groups were administered 50, 100, and 200 mg/kg of ChondroT, respectively. All oral administrations were initiated 7 days after the induction of arthritis and were continued for a total of 12 days. At the end of the experiment, serum aminotransferase, albumin, blood urea nitrogen, creatinine, leukocyte, and inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6] were analyzed. Hematoxylin and eosin (H&E) and safranin O-fast green staining of the articular structures of the knee joint were performed. RESULTS: TNF-α and IL-1ß decreased in the ChondroT100 and ChondroT200 groups compared with those in the control group. IL-6 and aspartate aminotransferase decreased in the ChondroT50, ChondroT100, and ChondroT200 groups compared with that in the control group. Albumin, WBC and lymphocytes decreased in the ChondroT100 and ChondroT200 groups compared with those in the control group. In H&E stain, synoviocytes, cartilage lacunae, and chondrocytes were well preserved in the ChondroT100 and ChondroT200 groups, and safranin O-fast staining showed a clear reaction of proteoglycans in the ChondroT100 and ChondroT200 groups. CONCLUSIONS: Based on these results, it can be proposed that ChondroT has anti-osteoarthritic effects on collagenase-induced rat model.

Structure of the ArgRS-GlnRS-AIMP1 complex and its implications for mammalian translation.

In higher eukaryotes, one of the two arginyl-tRNA synthetases (ArgRSs) has evolved to have an extended N-terminal domain that plays a crucial role in protein synthesis and cell growth and in integration into the multisynthetase complex (MSC). Here, we report a crystal structure of the MSC subcomplex comprising ArgRS, glutaminyl-tRNA synthetase (GlnRS), and the auxiliary factor aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)/p43. In this complex, the N-terminal domain of ArgRS forms a long coiled-coil structure with the N-terminal helix of AIMP1 and anchors the C-terminal core of GlnRS, thereby playing a central role in assembly of the three components. Mutation of AIMP1 destabilized the N-terminal helix of ArgRS and abrogated its catalytic activity. Mutation of the N-terminal helix of ArgRS liberated GlnRS, which is known to control cell death. This ternary complex was further anchored to AIMP2/p38 through interaction with AIMP1. These findings demonstrate the importance of interactions between the N-terminal domains of ArgRS and AIMP1 for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex.

Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes.

Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes. Stimulation by serum of many immediate early genes is greatly reduced by IPMK deletion. IPMK stimulates expression of these genes, an influence also displayed by catalytically inactive IPMK. IPMK acts by binding directly to SRF and thereby enhancing interactions of SRF with the serum response element of diverse genes.

Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration.

This study reports the physical and functional interplay between Fas-associated factor 1 (FAF1), a death-promoting protein, and parkin, a key susceptibility protein for Parkinson's disease (PD). We found that parkin acts as an E3 ubiquitin ligase to ubiquitinate FAF1 both in vitro and at cellular level, identifying FAF1 as a direct substrate of parkin. The loss of parkin function due to PD-linked mutations was found to disrupt the ubiquitination and degradation of FAF1, resulting in elevated FAF1 expression in SH-SY5Y cells. Moreover, FAF1-mediated cell death was abolished by wild-type parkin, but not by PD-linked parkin mutants, implying that parkin antagonizes the death potential of FAF1. This led us to investigate whether FAF1 participates in the pathogenesis of PD. To address this, we used a gene trap mutagenesis approach to generate mutant mice with diminished levels of FAF1 (Faf1(gt/gt)). Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of PD, we found that FAF1 accumulated in the substantia nigra pars compacta (SNc) of MPTP-treated PD mice, and that MPTP-induced dopaminergic cell loss in the SNc was significantly attenuated in Faf1(gt/gt) mice versus Faf1(+/+) mice. MPTP-induced reduction of locomotor activity was also lessened in Faf1(gt/gt) mice versus Faf1(+/+) mice. Furthermore, we found that FAF1 deficiency blocked PD-linked biochemical events, including caspase activation, ROS generation, JNK activation and cell death. Taken together, these results suggest a new role for FAF1: that of a positive modulator for PD.

Predictors of pulmonary tuberculosis treatment outcomes in South Korea: a prospective cohort study, 2005-2012.

BACKGROUND: Tuberculosis remains an important health concern in many countries. The aim of this study was to identify predictors of unfavorable outcomes at the end of treatment (EOT) and at the end of study (EOS; 40 months after EOT) in South Korea. METHODS: New or previously treated tuberculosis patients were recruited into a prospective observational cohort study at two hospitals in South Korea. To identify predictors of unfavorable outcomes at EOT and EOS, logistic regression analysis was performed. RESULTS: The proportion of multidrug-resistant tuberculosis (MDR-TB) was 8.2% in new cases and 57.9% in previously treated cases. Of new cases, 68.6% were cured, as were 40.7% of previously treated cases. At EOT, diabetes, ≥3 previous TB episodes, ≥1 significant regimen change, and MDR-TB were significantly associated with treatment failure or death. At EOS, age ≥35, body-mass index (BMI) <18.5, diabetes, and MDR-TB were significantly associated with treatment failure, death, or relapse. Among cases that were cured at EOT, age ≥50 and a BMI <18.5 were associated with subsequent death or relapse during follow-up to EOS. Treatment interruption was associated with service sector employees or laborers, bilateral lesions on chest X-ray, and previous treatment failure or treatment interruption history. CONCLUSIONS: Risk factors for poor treatment outcomes at EOT and EOS include both patient factors (diabetes status, age, BMI) and disease factors (history of multiple previous treatment episodes, MDR-TB). In this longitudinal, observational cohort study, diabetes mellitus and MDR-TB were risk factors for poor treatment outcomes and relapse. Measures to help ensure that the first tuberculosis treatment episode is also the last one may improve treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00341601.

Dammarane triterpenes from the leaves of Panax ginseng enhance cellular immunity.

In our search for immune stimulating materials from natural source, bioassay-guided fractionation of a methanol extract of Panax ginseng leaves led to the isolation of three dammarane triterpenes (1-3), including two previously unknown compounds 27-demethyl-(E,E)-20(22),23-dien-3ß,6α,12ß-trihydroxydammar-25-one (1) and 3ß,20(S)-dihydroxydammar-24-en-12ß,23ß-epoxy-20-O-ß-D-glucopyranoside (2). Their structures were elucidated on the basis of spectroscopic methods, chemical transformation, and by the comparison with those of literature data. Compounds 1-3 significantly increased interleukin-12 expression in LPS-activated mouse peritoneal macrophage at a concentration of 100 ng/mL. Furthermore, compound 1 strongly increased the Th1 response-mediated cytokine IL-2, and decreased Th2 response-mediated cytokines IL-4 and IL-6 expression at 100 ng/mL on ConA-activated splenocytes. This study indicated that compound 1 showed a better effect on cellular immunity, and provided new chemical entities as promising lead compounds for the treatment of cellular immunity-related diseases.