To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery.
219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited from 1978–1981 and followed for up to 25 years. Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. The probability of recovery over time from multiple successive depressive episodes was examined with survival analytic techniques, including mixed-effects grouped-time survival models.
The median duration of major depressive episodes was 14 weeks, and over 70% recovered within 12 months of onset of the episode. The median duration of minor depressive episodes was 8 weeks, and approximately 90% recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first three major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient=0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio: 0.93, 95% CI: 0.89–0.98, p=0.002).
Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.
Valid, direct observation of medical student competency in clinical settings remains challenging and limits the opportunity to promote performance-based student advancement. The rationale for direct observation is to ascertain that students have acquired the core clinical competencies needed to care for patients. Too often student observation results in highly variable evaluations which are skewed by factors other than the student’s actual performance. Among the barriers to effective direct observation and assessment include the lack of effective tools and strategies for assuring that transparent standards are used for judging clinical competency in authentic clinical settings. We developed a web-based content management system under the name, Just in Time Medicine (JIT), to address many of these issues. The goals of JIT were fourfold: First, to create a self-service interface allowing faculty with average computing skills to author customizable content and criterion-based assessment tools displayable on internet enabled devices, including mobile devices; second, to create an assessment and feedback tool capable of capturing learner progress related to hundreds of clinical skills; third, to enable easy access and utilization of these tools by faculty for learner assessment in authentic clinical settings as a means of just in time faculty development; fourth, to create a permanent record of the trainees’ observed skills useful for both learner and program evaluation. From July 2010 through October 2012, we implemented a JIT enabled clinical evaluation exercise (CEX) among 367 third year internal medicine students. Observers (attending physicians and residents) performed CEX assessments using JIT to guide and document their observations, record their time observing and providing feedback to the students, and their overall satisfaction. Inter-rater reliability and validity were assessed with 17 observers who viewed six videotaped student-patient encounters and by measuring the correlation between student CEX scores and their scores on subsequent standardized-patient OSCE exams. A total of 3567 CEXs were completed by 516 observers. The average number of evaluations per student was 9.7 (±1.8 SD) and the average number of CEXs completed per observer was 6.9 (±15.8 SD). Observers spent less than 10 min on 43–50% of the CEXs and 68.6% on feedback sessions. A majority of observers (92%) reported satisfaction with the CEX. Inter-rater reliability was measured at 0.69 among all observers viewing the videotapes and these ratings adequately discriminated competent from non-competent performance. The measured CEX grades correlated with subsequent student performance on an end-of-year OSCE. We conclude that the use of JIT is feasible in capturing discrete clinical performance data with a high degree of user satisfaction. Our embedded checklists had adequate inter-rater reliability and concurrent and predictive validity.
Educational technology; Educational measurement; Medical students; Smart phones; Competency based assessment; Direct observation; Medical faculty; Clinical competence; iPhone; miniCEX
In a well-defined sample, we sought to determine what clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M).
We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder.
Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n = 21) was strongly associated with repeat episodes of H/M [hazard ratio (HR) = 2.01, 95% confidence interval (CI): 1.06–3.83, p = 0.03]. Those with treatment-associated episodes (n = 12) were less likely to experience subsequent episodes of H/M, though this was not significant in the multivariate model (HR = 0.25, 95% CI: 0.06–1.05, p = 0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode.
Family history of bipolar disorder influences course of illness even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes.
bipolar disorder; depressive disorder; antidepressants; prospective studies
There is widespread agreement that cancer gene discovery requires high-quality tumor samples. However, whether primary tumors or cultured samples are superior for cancer genomics has been a longstanding subject of debate. This debate has recently become more important because federally funded cancer genomics has been centralized under The Cancer Genome Atlas, which has chosen to focus exclusively on primary tumors. Here, we provide a data-driven “perspective” on the effect of sample type selection on cancer genomics research. We show that, in the case of glioblastoma multiforme, primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions. We also note that many of the most important oncogenes and tumor suppressor genes have been discovered through the use of cell lines and xenografts, and highlight the lack of published evidence supporting the dogma that ex vivo culture generates artifactual genetic lesions. Based on this analysis, we suggest that cancer genomics projects such as The Cancer Genome Atlas should include a variety of sample types such as xenografts and cell lines in their integrated genomic analysis of cancer.
Patients (30–50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.
Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5–3 mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of ≤10 on the Montgomery–Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.
Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR = 3.33, p = .011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS ≤ 10) compared to 24% of the placebo augmentation group (CMH(1) = 6.48, p = .011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.
Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
Antidepressants; Antipsychotic; Clinical drug studies; Mood disorders – unipolar
The phenomenology of bipolar I disorder affects treatment and prognosis.
To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.
Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model.
Five US academic medical centers.
Two hundred nineteen subjects with bipolar I disorder.
Main Outcome Measures
Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter.
The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR]=0.746; 95% confidence interval [CI], 0.578–0.963; P=.02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR=0.917; 95% CI, 0.886–0.948; P<.001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR=1.713; 95% CI, 1.373–2.137; P<.001), hypomania (HR=4.502; 95% CI, 3.466–5.849; P<.001), or minor depression (HR = 2.027; 95% CI, 1.622–2.534; P<.001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR=0.438; 95% CI, 0.351–0.548; P<.001).
The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.
There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.
Bipolar (type I or II) patients with an MDE at intake (N=142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.
Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.
The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.
The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
It is well established that the presence of prominent anxiety within depressive episodes portends poorer outcomes. Important questions remain as to which anxiety features are important to outcome and how sustained their prognostic effects are over time.
To examine the relative prognostic importance of specific anxiety features and to determine whether their effects persist over decades and apply to both unipolar and bipolar conditions.
Participants with unipolar (n = 476) or bipolar (n = 335) depressive disorders were intensively followed for a mean of 16.7 years (s.d. = 8.5).
The number and severity of anxiety symptoms, but not the presence of pre-existing anxiety disorders, showed a robust and continuous relationship to the subsequent time spent in depressive episodes in both unipolar and bipolar depressive disorder. The strength of this relationship changed little over five successive 5-year periods.
The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.
Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50
) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50
and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50
, showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress – all characteristics of the international students. Local students exhibited significantly lower SNR50
scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50
and the students’ Visual/Verbal Learning Style (r = −0.023). Standard multiple regression was carried out to assess the relationship between language proficiency and verbal working memory (SNR50
) using 5 variables of L2 proficiency, with the results showing that the variance in SNR50
was significantly predicted by this model (r2 = 0.335). Hierarchical multiple regression was then used to test the ability of three independent variable measures (SNR50
, age of acquisition of English and English proficiency) to predict academic performance as the dependent variable in a factor analysis model which predicted significant performance differences in an assessment requiring communications skills (p = 0.008), but not on a companion assessment requiring knowledge of procedural skills, or other assessments requiring factual knowledge. Thus, impaired vWM for an L2 appears to affect specific communications-based assessments in university medical students.
Medical education; International students; Working memory; Speech in noise; Assessment; OSCE; English as a second language
anxiety; bipolar disorder; symptom persistence
This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age-grouping, and whether age of onset plays an independent role in symptom persistence.
Participants in the NIMH Collaborative Depression Study who completed at least twenty years of follow-up and who met study criteria for bipolar I or schizoaffective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18–29 years, n = 56), middle (30–44 years, n = 68) and oldest (greater than 44 years, n = 24) groups.
The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the twenty years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, though correlations were stronger for depressive symptoms and for shorter intervals.
Regardless of age at onset, the passage of decades in bipolar illness appears to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and appears to reflect traits that manifest early an individual’s illness.
major depression; age periods; age of onset; symptom persistence
The meaningful use (MU) of electronic medical records (EMRs) is being implemented in three stages. Key objectives of stage one include electronic analysis of data entered into structured fields, using decision-support tools (e.g., checking drug–drug interactions [DDI]) and electronic information exchange.
The authors assessed the performance of medical students on 10 stage-one MU tasks and measured the correlation between students’ MU performance and subsequent end-of-clerkship professionalism assessments and their grades on an end-of-year objective structured clinical examination.
Two-hundred and twenty-two third-year medical students on the internal medicine (IM) clerkship.
From July 2010 to February 2012, all students viewed 15 online tutorials covering MU competencies. The authors measured student MU documentation and performance in the chart of a virtual patient using a fully functional training EMR. Specific MU measurements included, adding: a new problem, a new medication, an advanced directive, smoking status, the results of screening tests; and performing a DDI (in which a major interaction was probable), and communicating a plan for this interaction.
A total of 130 MU errors were identified. Sixty-eight (30.6%) students had at least one error, and 30 (13.5%) had more than one (range 2–6). Of the 130 errors, 90 (69.2%) were errors in structured data entry. Errors occurred in medication dosing and instructions (18%), DDI identification (12%), documenting smoking status (15%), and colonoscopy results (23%). Students with MU errors demonstrated poorer performance on end-of-clerkship professionalism assessments (r =−0.112, p=0.048) and lower observed structured clinical examination (OSCE) history-taking skills (r =−0.165, p=0.008) and communication scores (r= − 0.173, p=0.006).
MU errors among medical students are common and correlate with subsequent poor performance in multiple educational domains. These results indicate that without assessment and feedback, a substantial minority of students may not be ready to progress to more advanced MU tasks.
documentation/methods; electronic health records; professional competence; students; medical; curriculum
The authors used results from a twenty-year, high-intensity follow-up to measure the influence of aging, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD).
Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD, or schizoaffective disorder other than mainly schizophrenic, (n = 220), were divided according to their ages at intake into youngest (18–29 years), middle (30–44 years), and oldest (≥45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizoaffective episodes. General linear models (GLM) then tested for effects of time and time-by-group interactions on these measures. Regression analyses compared the influence of age of onset and of current age.
Analyses revealed no significant time or group-by-time effects on the proportions of weeks in major depressive episodes in any of three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group.
These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.
major depression; age periods; age of onset; symptom persistence
In the past few years there has been an ongoing debate as to whether the proliferation of open access (OA) publishing would damage the peer review system and put the quality of scientific journal publishing at risk. Our aim was to inform this debate by comparing the scientific impact of OA journals with subscription journals, controlling for journal age, the country of the publisher, discipline and (for OA publishers) their business model.
The 2-year impact factors (the average number of citations to the articles in a journal) were used as a proxy for scientific impact. The Directory of Open Access Journals (DOAJ) was used to identify OA journals as well as their business model. Journal age and discipline were obtained from the Ulrich's periodicals directory. Comparisons were performed on the journal level as well as on the article level where the results were weighted by the number of articles published in a journal. A total of 610 OA journals were compared with 7,609 subscription journals using Web of Science citation data while an overlapping set of 1,327 OA journals were compared with 11,124 subscription journals using Scopus data.
Overall, average citation rates, both unweighted and weighted for the number of articles per journal, were about 30% higher for subscription journals. However, after controlling for discipline (medicine and health versus other), age of the journal (three time periods) and the location of the publisher (four largest publishing countries versus other countries) the differences largely disappeared in most subcategories except for journals that had been launched prior to 1996. OA journals that fund publishing with article processing charges (APCs) are on average cited more than other OA journals. In medicine and health, OA journals founded in the last 10 years are receiving about as many citations as subscription journals launched during the same period.
Our results indicate that OA journals indexed in Web of Science and/or Scopus are approaching the same scientific impact and quality as subscription journals, particularly in biomedicine and for journals funded by article processing charges.
impact; open access; peer review; scientific publishing
Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.
Prone breast positioning reduces skin reaction and heart and lung dose, but may also reduce radiation dose to axillary lymph nodes (ALNs).
Women with early stage breast cancer treated with whole breast irradiation (WBI) in the prone position were identified. Patients treated in the supine position were matched for treating physician, laterality, and fractionation. Ipsilateral breast, tumor bed, and Level I, II, and III ALNs were contoured according to the RTOG breast atlas. Clips marking surgically removed sentinel lymph nodes (SLN)s were contoured. Treatment plans developed for each patient were retrospectively analyzed. V90% and V95% was calculated for each axillary level. When present, dose to axillary surgical clips was calculated.
Treatment plans for 46 women (23 prone and 23 supine) were reviewed. The mean V90% and V95% of ALN Level I was significantly lower for patients treated in the prone position (21% and 14%, respectively) than in the supine position (50% and 37%, respectively) (p < 0.0001 and p < 0.0001, respectively). Generally, Level II & III ALNs received little dose in either position. Sentinel node biopsy clips were all contained within axillary Level I. The mean V95% of SLN clips was 47% for patients treated in the supine position and 0% for patients treated in the prone position (p < 0.0001). Mean V90% to SLN clips was 96% for women treated in the supine position but only 13% for women treated in the prone position.
Standard tangential breast irradiation in the prone position results in substantially reduced dose to the Level I axilla as compared with treatment in the supine position. For women in whom axillary coverage is indicated such as those with positive sentinel lymph node biopsy who do not undergo completion axillary dissection, treatment in the prone position may be inappropriate.
Breast cancer; Prone; Axillary lymph nodes; Radiation; ACOSOG Z0011
Following DNA damage, human cells undergo arrests in the G1 and G2 phases of the cell cycle and a simultaneous arrest in cell size. We previously demonstrated that the cell size arrest can be uncoupled from the cell cycle arrest by mutational inactivation of the PTEN tumor suppressor gene. Here we show that the cell size checkpoint is inducible by DNA-damaging chemotherapeutic agents as well as by ionizing radiation and is effectively regulated by PTEN but not by its oncogenic counterpart, PIK3CA. Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control. To discover putative PTEN regulators and/or effectors involved in size checkpoint control, we employed a novel endogenous epitope tagging (EET) approach, which revealed that endogenous PTEN interacts at the membrane with an actin-remodeling complex that includes actin, gelsolin, and EPLIN. Pharmacological inhibition of actin remodeling in PTEN+/+ cells recapitulated the lack of size checkpoint control seen in PTEN−/− cells. Taken together, these results provide further support for the existence of a DNA damage-inducible size checkpoint that is regulated by a major tumor suppressor, and they provide a novel Akt-independent mechanism by which PTEN controls cell size.
Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1R132 or the homologous IDH2R172. Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. 78 human melanoma samples were analyzed for IDH1R132 and IDH2R172 mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1R132 and IDH2R172 mutation status 53 metastatic brain tumors, including 9 melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1R132 or IDH2R172 may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors.
isocitrate dehydrogenase 1; isocitrate dehydrogenase 2; melanoma; brain tumors metastases
To examine the efficacy of a cognitive-behavioral intervention (CBT) to prevent depression among methadone maintenance patients undergoing antiviral treatment for hepatitis C (HCV), 29 patients beginning HCV treatment were randomized to CBT or standard care (SC). Study participants did not meet criteria for major depressive disorder at the time of study recruitment. CBT did not result in less depression-related antiviral treatment failure, better adherence to antiviral treatment, or better HCV RNA outcomes. There were no significant treatment group differences on depressive symptoms over time. The CBT group did display a greater and more consistent decline in both BDI-II and HAM-D scores over time (d=.85 on the BDI-II; d=.72 on the HAM-D).
Hepatitis C; Antiviral treatment; Depressive symptoms; Cognitive-behavioral treatment; Beck depression inventory; Hamilton rating scale for depression
Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6 specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 Rb-proficient cell lines regardless of other genetic lesions, whereas each of 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. shRNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 had significant disease progression or died while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly-diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy.
glioblastoma; cyclin-dependent kinase; Rb; p16INK4a; PD-0332991; bioluminescence
We determined if subthreshold hypomanic symptoms predicted new onset mania or hypomania.
We identified 550 individuals followed for at least one year in the National Institute of Mental Health Collaborative Depression Study with a diagnosis of major depression at intake. All participants were screened at baseline for a total of five manic symptoms: elevated mood, decreased need for sleep, high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 and up to 31 years. Longitudinal Interval Follow-up Examinations monitored course of illness and identified any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox Proportional-Hazards Regression.
With a cumulative probability of one-in-four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II and 7.5% to bipolar I disorder. The number of subthreshold hypomanic symptoms, psychosis, and age of onset predicted progression to bipolar disorder. Less need for sleep, unusual energy, and increased goal-directed activities were specifically implicated.
Symptoms of hypomania, even when of low intensity, were very frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. Therefore, continued monitoring for the possibility of progression to bipolar disorder over the long-term course of major depressive disorder is necessary.
Age of Onset; Bipolar disorder; Depressive disorder; Delusions; Prospective studies
Much remains unknown about the phenomenology of bipolar I disorder.
To determine the type of bipolar I mood episodes that occur over time, and their relative frequency.
A total of 219 individuals with Research Diagnostic Criteria bipolar I disorder were prospectively followed for up to 25 years (median 20 years). Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation.
Overall, 1208 mood episodes were prospectively observed. The episodes were empirically classified as follows: major depression, 30.9% (n = 373); minor depression, 13.0% (n = 157); mania, 20.4% (n = 246); hypomania, 10.4% (n = 126); cycling, 17.3% (n = 210); cycling plus mixed state, 7.8% (n = 94); and mixed, 0.2% (n = 2).
Cycling episodes constituted 25% of all episodes. Work groups revising ICD–10 and DSM–IV should add a category for bipolar I cycling episode.
The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.
glioblastoma; genomics; copy number; 1p36; 4p16; ERRFI1; TACC3
Saccadic eye movements rapidly orient the line of sight towards the object of interest. Pre-motor burst neurons (BNs) controlling saccades receive excitation from superior colliculus and cerebellum, but inhibition by omnipause neurons (OPNs) prevents saccades. When the OPNs pause, BNs begin to fire. It has been presumed that part of the BN burst comes from post-inhibitory rebound (PIR). We hypothesized that in the absence of prior inhibition from OPNs there would be no PIR, and thus the increase in initial firing rate of BNs would be reduced. Consequently, saccade acceleration would be reduced. We measured eye movements and showed that sustained eye closure, which inhibits the activity of OPNs and thus hypothetically should weaken PIR, reduced the peak velocity, acceleration, and deceleration of saccades in healthy human subjects. Saccades under closed eyelids also had irregular trajectories; the frequency of the oscillations underlying this irregularity was similar to that of high-frequency ocular flutter (back-to-back saccades) often seen in normal subjects during attempted fixation at straight ahead while eyes are closed. Saccades and quick phases of nystagmus are generated by the same pre-motor neurons, and we found that the quick-phase velocity of nystagmus was also reduced by lid closure. These changes were not due to a mechanical hindrance to the eyes, because lid closure did not affect the peak velocities or accelerations of the eyes in the “slow-phase” response to rapid head movements of comparable speeds to those of saccades. These results indicate a role for OPNs in generating the abrupt onset and high velocities of saccades. We hypothesize that the mechanism involved is PIR in pre-motor burst neurons.
Omnipause neurons; Burst neurons; Oscillations; Ballistic movement; Post-inhibitory rebound