A widely distributed gene cluster compensates for uricase loss in hominids.

Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

Variation in Vaginal Hysterectomy Rates in an Integrated Healthcare System.

STUDY OBJECTIVE: To describe trends in minimally invasive hysterectomy (MIH) and assess patient, surgical, and provider characteristics associated with differences in vaginal versus laparoscopic rates within an integrated healthcare system. DESIGN: A retrospective cohort study. SETTING: Kaiser Permanente Northern California from 2008 to 2018. PATIENTS: Patients who underwent MIH for benign conditions excluding uterine prolapse and incontinence surgeries. INTERVENTIONS: Hysterectomies. MEASUREMENTS AND MAIN RESULTS: A total of 27518 hysterectomies were performed for benign indications. Of these, the proportion of MIH increased from 29.1% (2008) to 96.7% (2018) (p <.001). The proportion of vaginal hysterectomies (VHs) of all hysterectomies did not change significantly over the study period (p = .07); however, the proportion of VH among MIH cases decreased from a high of 50.6% in 2008 to 13.2% in 2018 (p <.001). VH rates were lower in obese and morbidly obese patients (p <.001 and p = .02, respectively) and in women with uterine weights >250 g (p <.001). The differences persisted after controlling for patient demographic, clinical, and surgery characteristics. Low surgical volume was inversely associated with VH (adjusted relative risk, 7.19; 95% confidence interval, 6.62-7.81; p <.001). VH rates ranged from 11.5% to 27.8% across service areas (hospitals). Service area remained a significant predictor of VH after controlling for patient (including body mass index and uterine weight) and surgery-related characteristics. Postoperative hospital stay decreased from 33.8 ± 16.4 hours (2008) to 6.1 ± 12.2 (2018) for VH. Operative time was shorter for VH than laparoscopic hysterectomies (LHs) (1.7 vs 2.5 hours; p <.001). Overall operative/perioperative complications were low and not significantly different (VH vs LH). CONCLUSION: As the proportion of MIH increased, LH became the preferred route despite similar rates of postoperative stay and intraoperative complications and shorter operative time for VH compared with LH. Service area and provider volume were independent predictors of MIH route, suggesting that training and evidence-based guidelines for route selection may help preserve VH rates.

Labor Induction Outcomes with Outpatient Misoprostol for Cervical Ripening among Low-Risk Women.

OBJECTIVE: In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies. STUDY DESIGN: We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity. RESULTS: We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals, p = 0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%, p = 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals, p < 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC, p < 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (p < 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (p < 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%, p < 0.001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%, p = 0.29). CONCLUSION: Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol. KEY POINTS: · Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..

Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.

BACKGROUND AND PURPOSE: The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan. METHODS: We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score-matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD. RESULTS: There were 48 828 patients matched and categorized equally into the pioglitazone group and the non-pioglitazone group. The number of PD patients in the pioglitazone group and the non-pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 [95% confidence interval (CI): 0.57-0.78], and this benefit was dose-dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64-0.94; P = 0.010). CONCLUSIONS: Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure-Activity Relationships.

Quantitative structure-activity relationships (QSAR) models are often seen as a "black box" because they are considered difficult to interpret. Meanwhile, qualitative approaches, e.g., structural alerts (SA) or read-across, provide mechanistic insight, which is preferred for regulatory purposes, but predictive accuracy of such approaches is often low. Herein, we introduce the chemistry-wide association study (CWAS) approach, a novel framework that both addresses such deficiencies and combines advantages of statistical QSAR and alert-based approaches. The CWAS framework consists of the following steps: (i) QSAR model building for an end point of interest, (ii) identification of key chemical features, (iii) determination of communities of such features disproportionately co-occurring more frequently in the active than in the inactive class, and (iv) assembling these communities to form larger (and not necessarily chemically connected) novel structural alerts with high specificity. As a proof-of-concept, we have applied CWAS to model Ames mutagenicity and Stevens-Johnson Syndrome (SJS). For the well-studied Ames mutagenicity data set, we identified 76 important individual fragments and assembled co-occurring fragments into SA both replicative of known as well as representing novel mutagenicity alerts. For the SJS data set, we identified 29 important fragments and assembled co-occurring communities into SA including both known and novel alerts. In summary, we demonstrate that CWAS provides a new framework to interpret predictive QSAR models and derive refined structural alerts for more effective design and safety assessment of drugs and drug candidates.

Clinical effectiveness of late maxillary protraction in cleft lip and palate: A methods paper.

OBJECTIVES: A prospective parallel cohort trial was conducted to compare outcomes of patients treated with maxillary protraction vs LeFort 1 maxillary advancement surgery. SETTING AND SAMPLE POPULATION: The primary site for the clinical trial is Children's Hospital Los Angeles; the satellite test site is Seattle Children's Hospital. All patients have isolated cleft lip and palate and a skeletal Class III malocclusion. MATERIAL AND METHODS: A total of 50 patients, ages 11-14, will be recruited for the maxillary protraction cohort. The maxillary surgery cohort consists of 50 patients, ages 16-21, who will undergo LeFort 1 maxillary advancement surgery. Patients with additional medical or cognitive handicaps were excluded from the study. RESULTS: Current recruitment of patients is on track to complete the study within the proposed recruitment period. CONCLUSION: This observational trial is collecting information that will examine dental, skeletal, financial and quality-of-life issues from both research cohorts.

The influence of comorbid disorders on the episodicity of bipolar disorder in youth.

OBJECTIVE: Bipolar disorder (BP) frequently co-occurs with other psychiatric disorders. We examine whether course of anxiety disorders (ANX), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), and substance use disorders (SUD) influence likelihood of recovery and recurrence of depression and mania in BP youth. METHOD: Weekly ratings of psychiatric disorder intensity were obtained from 413 participants of the Course and Outcome of BP Youth project, followed for an average of 7.75 years. Multiple-event Cox proportional hazards regression analyses examined worsening of comorbid disorders as predictors of mood episode recovery and recurrence. RESULTS: Increased severity in ANX and SUD predicted longer time to recovery and less time to next depressive episode, and less time to next manic episode. Multivariate models with ANX and SUD found that significant effects of ANX remained, but SUD only predicted longer time to depression recovery. Increased severity of ADHD and DBD predicted shorter time to recurrence for depressive and manic episodes. CONCLUSION: There are significant time-varying relationships between the course of comorbid disorders and episodicity of depression and mania in BP youth. Worsening of comorbid conditions may present as a precursor to mood episode recurrence or warn of mood episode protraction.

Borderline personality disorder in transition age youth with bipolar disorder.

OBJECTIVE: To determine the longitudinal impact of borderline personality disorder (BPD) on the course and outcome of bipolar disorder (BP) in a pediatric BP sample. METHOD: Participants (N = 271) and parents from the Course and Outcome of Bipolar Youth (COBY) study were administered structured clinical interviews and self-reports on average every 8.7 months over a mean of 93 months starting at age 13.0 ± 3.1 years. The structured interview for DSM-IV personality disorders (SIDP-IV) was administered at the first follow-up after age 18 to assess for symptoms of BPD. BPD operationalized at the disorder, factor, and symptom level, was examined as a predictor of poor clinical course of BP using all years of follow-up data. RESULTS: The number of BPD symptoms was significantly associated with poor clinical course of BP, above and beyond BP characteristics. Affective dysregulation was most strongly associated with poor course at the factor level; the individual symptoms most strongly associated with poor course were dissociation/stress-related paranoid ideation, impulsivity, and affective instability. CONCLUSION: BPD severity adds significantly to the burden of BP illness and is significantly associated with a more chronic and severe course and outcome beyond what can be attributable to BP characteristics.

Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells.

OBJECTIVES: This study tested whether or not gene expression in human marrow stromal fibroblast (MSF) cells depends on light wavelength and energy density. MATERIALS AND METHODS: Primary cultures of isolated human bone marrow stem cells (hBMSC) were exposed to visible red (VR, 633 nm) and infrared (IR, 830 nm) radiation wavelengths from a light emitting diode (LED) over a range of energy densities (0.5, 1.0, 1.5, and 2.0 Joules/cm2) Cultured cells were assayed for cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content. mRNA was analyzed by microarray and compared among different wavelengths and energy densities. Mesenchymal and epithelial cell responses were compared to determine whether responses were cell type specific. Protein array analysis was used to further analyze key pathways identified by microarrays. RESULT: Different wavelengths and energy densities produced unique sets of genes identified by microarray analysis. Pathway analysis pointed to TGF-beta 1 in the visible red and Akt 1 in the infrared wavelengths as key pathways to study. TGF-beta protein arrays suggested switching from canonical to non-canonical TGF-beta pathways with increases to longer IR wavelengths. Microarrays suggest RANKL and MMP 10 followed IR energy density dose-response curves. Epithelial and mesenchymal cells respond differently to stimulation by light suggesting cell type-specific response is possible. CONCLUSIONS: These studies demonstrate differential gene expression with different wavelengths, energy densities and cell types. These differences in gene expression have the potential to be exploited for therapeutic purposes and can help explain contradictory results in the literature when wavelengths, energy densities and cell types differ.

Pathogen reduction treatment alters the immunomodulatory capacity of buffy coat-derived platelet concentrates.

BACKGROUND: Storage of platelet concentrates (PCs) after Mirasol pathogen reduction technology (PRT) treatment changes platelet (PLT) surface marker expression and secretion of immunomodulatory factors. Given that PLTs are known to participate in immune function, PRT may alter the way PLTs interact with the immune cells of a recipient upon transfusion. As such, the aim of this study was to assess the effects of PRT treatment on the functional ability of PLTs to interact with peripheral blood mononuclear cells (PBMNCs). STUDY DESIGN AND METHODS: Buffy coat-derived PCs were pooled and split to obtain matched pairs. One unit was treated using the Mirasol PRT system, while the control PC remained untreated. After 5 days of storage, either the PLTs or the PLT supernatants from the PCs were cocultured with PBMNCs, with or without lipopolysaccharide (LPS). The immunomodulatory factors secreted into culture medium after coculture were examined. RESULTS: PRT-treated PLTs and PLT supernatant significantly increased the interleukin (IL)-8 concentration, which was manifested only in the presence of LPS. Conversely, PRT-treated PLTs secreted less soluble P-selectin (sCD62P) upon coculture with PBMNCs. CONCLUSION: PRT-treatment induced differential secretion of IL-8 and sCD62P during coculture, which may be attributed to either bioactive substances present in PLT supernatant or as a result of cell-cell interactions.

Prospective study of risk factors for suicidal behavior in individuals with anxiety disorders.

BACKGROUND: Anxiety disorders are very common and increase risk for suicide attempts. Little is known about predictors of increased risk specifically among individuals with anxiety disorders. The purpose of this study was to investigate whether specific anxiety disorders and other co-morbid psychiatric disorders, physical health, or work or social functioning increased the future likelihood of a suicide attempts among individuals with anxiety disorders. Method In this prospective study, 676 individuals with an anxiety disorder were followed for an average of 12 years. RESULTS: As hypothesized, we found that post-traumatic stress disorder, major depressive disorder (MDD), intermittent depressive disorder (IDD), epilepsy, pain, and poor work and social functioning all predicted a shorter time to a suicide attempt in univariate analyses. In multivariate analyses, baseline MDD and IDD were independent predictors of time to suicide attempt, even when controlling for a past history of suicide attempt. No specific anxiety disorder was an independent predictor of time to attempt in this anxiety-disordered sample. Adding baseline physical health variables and social functioning did not improve the ability of the model to predict time to suicide attempt. CONCLUSIONS: Mood disorders and past history of suicide attempts are the most powerful predictors of a future suicide attempt in this sample of individuals, all of whom have an anxiety disorder.

Prospective predictors of adolescent suicidality: 6-month post-hospitalization follow-up.

BACKGROUND: The aim of this study was to examine prospective predictors of suicide events, defined as suicide attempts or emergency interventions to reduce suicide risk, in 119 adolescents admitted to an in-patient psychiatric unit for suicidal behaviors and followed naturalistically for 6 months. Method Structured diagnostic interviews and self-report instruments were administered to adolescent participants and their parent(s) to assess demographic variables, history of suicidal behavior, psychiatric disorders, family environment and personality/temperament. RESULTS: Baseline variables that significantly predicted time to a suicide event during follow-up were Black race, high suicidal ideation in the past month, post-traumatic stress disorder (PTSD), childhood sexual abuse (CSA), borderline personality disorder (BPD), low scores on positive affectivity, and high scores on aggression. In a multivariate Cox regression analysis, only Black race, CSA, positive affect intensity and high aggression scores remained significant. CONCLUSIONS: Our findings suggest the following for adolescent populations: (1) in a very high-risk population, risk factors for future attempts may be more difficult to ascertain and some established risk factors (e.g. past suicide attempt) may not distinguish as well; and (2) cross-cutting constructs (e.g. affective and behavioral dysregulation) that underlie multiple psychiatric disorders may be stronger predictors of recurrent suicide events than psychiatric diagnoses. Our finding with respect to positive affect intensity is novel and may have practical implications for the assessment and treatment of adolescent suicide attempters.

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

Fetal heart rate patterns and the incidence of adverse events after oral misoprostol administration for cervical ripening among low-risk pregnancies.

OBJECTIVE: Though misoprostol is commonly used for inpatient cervical ripening, its use in outpatient settings has been limited by safety concerns. This study was conducted to assess the association between early fetal heart tracing (FHT) and maternal tocodynamometry patterns and the incidence of adverse fetal and pregnancy outcomes after the administration of oral misoprostol for cervical ripening. METHODS: We conducted a retrospective cohort study of 9908 low-risk patients at ≥37 weeks gestation who received oral misoprostol for cervical ripening prior to rupture of membranes between 01/01/2012 and 12/31/2017 at Kaiser Permanente Northern California hospitals as inpatients. We excluded patients who received a different agent for cervical ripening or had any need for additional inpatient monitoring, including hypertensive disorders of pregnancy, diabetes, or intrauterine growth restriction. Abnormal FHT, abnormal uterine activity, and adverse pregnancy or fetal-related events documented in the electronic health record in the four hours after administration of the first and second doses of misoprostol were assessed using descriptive statistics. RESULTS: We found that 0.9% of patients experienced tachysystole after the first dose of misoprostol (0.6% without decelerations; 0.3% with decelerations). The incidence of variable decelerations only and other FHT abnormalities (i.e. bradycardia, late or prolonged decelerations, or absent or minimal variability) in the first hour after misoprostol administration were 7.1% and 6.7% respectively, and diminished over time. The need for tocolytic use was 0.2% in the first hour and declined over time to 0.03% in the fourth hour after the first dose. Urgent cesarean delivery occurred in 0.1% of patients after receiving the first dose of misoprostol. Patients who did not experience variable, prolonged, or late decelerations in the first hour after the initial misoprostol dose were less likely to have such FHT abnormalities in the subsequent three hours compared to patients who had other FHT abnormalities (11.8% among patients with no FHT abnormalities vs. 43.7% among patients with other FHT abnormalities; p <.001). The overall trends in outcomes over time were similar after the second dose of misoprostol. CONCLUSION: The risk of short-term adverse outcomes associated with misoprostol is low among relatively low-risk patients. FHT abnormalities occurred in up to 32% of patients in the first four hours of monitoring post-misoprostol. Patients with no FHT abnormalities in the first hour after receiving misoprostol had a low risk of developing adverse outcomes and FHT abnormalities on continued monitoring, while patients with any type of deceleration in the first hour were at higher risk of adverse outcomes and FHT abnormalities. Our data may inform the development of protocols for cervical ripening that allow reduced monitoring for a subset of low-risk patients, however, more research is needed to validate findings and develop clinical protocols.

Patient and Visit Characteristics Associated With Physical Restraint Use in the Emergency Department.

Objective Physical restraints are used in emergency departments (EDs) to address behavioral emergencies in situations in which less restrictive methods have failed. The objective of this study was to evaluate for associations between patient/visit characteristics and physical restraint use. Study Design This study was designed as a cross-sectional, retrospective study of all encounters at Kaiser Permanente Northern California EDs from January 1, 2016, to December 31, 2019, to evaluate differences in patient and visit characteristics between visits involving physical restraint use and those without. Methods Using electronic health record data, this study identified physical restraint use among ED encounters and extracted demographic, clinical, and facility characteristics. The authors calculated odds ratios for physical restraint placement, adjusting for patient and visit characteristics and accounting for within-patient clustering. Results Among 4,410,816 encounters (representing 1,791,673 patients), 6369 encounters (0.1%) involved physical restraint use among 5,554 patients (0.3%). Variables associated with the lowest odds of physical restraint included female sex, presentation to the ED in more recent years, and presence of intentional self-harm/suicidal ideation. Variables associated with the highest odds of physical restraint included higher visit acuity and weekend presentations to the ED. Discussion This study, which leveraged a large, diverse patient sample generalizable to the Northern California population, found several patient and visit characteristics associated with physical restraint use in the ED. Conclusion Results of this study may help identify patient groups and situational factors that are most likely to lead to physical restraint use and structural factors contributing to disparities in care, thereby informing interventions to reduce physical restraint use when possible.

BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML.

BACKGROUND: Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML. METHODS: The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-097, were investigated using in vitro and in vivo assays. RESULTS: The 50% inhibitory concentration (IC(50)) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 nM, and the 50% growth inhibition concentrations (GC(50)s) were 21±7 and 46±14 nM for MOLM-13 and MV4-11 cells, respectively. BPR1J-097 inhibited FLT3/signal transducer and activator of transcription 5 phosphorylation and triggered apoptosis in FLT3-driven AML cells. BPR1J-097 also showed favourable pharmacokinetic property and pronounced dose-dependent tumour growth inhibition and regression in FLT3-driven AML murine xenograft models. CONCLUSION: These results indicate that BPR1J-097 is a novel small molecule FLT-3 inhibitor with promising in vivo anti-tumour activities and suggest that BPR1J-097 may be further developed in preclinical and clinical studies as therapeutics in AML treatments.

Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenstrom macroglobulinemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy.

T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8(+)CD57(+) T-cell receptor Vbeta-positive (TCRVbeta(+))-restricted cytotoxic T-cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report that CTL clones with varying TCRVbeta repertoire are present in 70% of patients with Waldenström macroglobulinemia (WM; n = 20). Previous nucleoside analog (NA) therapy, associated with increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVbeta expansions (chi(2) = 11.6; P < .001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVbeta expansions had received NA. Clonality of CD3(+)CD8(+)CD57(+)TCRVbeta(+)-restricted CTLs was confirmed by TCRVbeta CDR3 size analysis and direct sequencing. The differential expression of CD3(+)CD8(+)CD57(+)TCRVbeta(+) cells was profiled using DNA microarrays and validated at mRNA and protein level. By gene set enrichment analysis, CTL clones expressed not only genes from cytotoxic pathways (GZMB, PRF1, FGFBP2) but also genes that suppress apoptosis, inhibit proliferation, arrest cell-cycle G1/S transition, and activate T cells (RAS, CSK, and TOB pathways). Proliferation tracking after stimulation confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity, and nature of clonal CTLs in WM and highlight mechanisms that cause anergy in these cells.

Comparison of alternative models for personality disorders, II: 6-, 8- and 10-year follow-up.

BACKGROUND: Several conceptual models have been considered for the assessment of personality pathology in DSM-5. This study sought to extend our previous findings to compare the long-term predictive validity of three such models: the five-factor model (FFM), the schedule for nonadaptive and adaptive personality (SNAP), and DSM-IV personality disorders (PDs). METHOD: An inception cohort from the Collaborative Longitudinal Personality Disorder Study (CLPS) was followed for 10 years. Baseline data were used to predict long-term outcomes, including functioning, Axis I psychopathology, and medication use. RESULTS: Each model was significantly valid, predicting a host of important clinical outcomes. Lower-order elements of the FFM system were not more valid than higher-order factors, and DSM-IV diagnostic categories were less valid than dimensional symptom counts. Approaches that integrate normative traits and personality pathology proved to be most predictive, as the SNAP, a system that integrates normal and pathological traits, generally showed the largest validity coefficients overall, and the DSM-IV PD syndromes and FFM traits tended to provide substantial incremental information relative to one another. CONCLUSIONS: DSM-5 PD assessment should involve an integration of personality traits with characteristic features of PDs.

The association of personality disorders with the prospective 7-year course of anxiety disorders.

BACKGROUND: This study prospectively examined the natural clinical course of six anxiety disorders over 7 years of follow-up in individuals with personality disorders (PDs) and/or major depressive disorder. Rates of remission, relapse, new episode onset and chronicity of anxiety disorders were examined for specific associations with PDs. METHOD: Participants were 499 patients with anxiety disorders in the Collaborative Longitudinal Personality Disorders Study, who were assessed with structured interviews for psychiatric disorders at yearly intervals throughout 7 years of follow-up. These data were used to determine probabilities of changes in disorder status for social phobia (SP), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder and panic disorder with agoraphobia. RESULTS: Estimated remission rates for anxiety disorders in this study group ranged from 73% to 94%. For those patients who remitted from an anxiety disorder, relapse rates ranged from 34% to 67%. Rates for new episode onsets of anxiety disorders ranged from 3% to 17%. Specific PDs demonstrated associations with remission, relapse, new episode onsets and chronicity of anxiety disorders. Associations were identified between schizotypal PD with course of SP, PTSD and GAD; avoidant PD with course of SP and OCD; obsessive-compulsive PD with course of GAD, OCD, and agoraphobia; and borderline PD with course of OCD, GAD and panic with agoraphobia. CONCLUSIONS: Findings suggest that specific PD diagnoses have negative prognostic significance for the course of anxiety disorders underscoring the importance of assessing and considering PD diagnoses in patients with anxiety disorders.