Brain Derived Neurotrophic Factor (BDNF) mRNA Expression Levels in Mice Exposed to Learned Helplessness

Brain Derived Neurotrophic Factor (BDNF) is associated with changes in cellular structure that occur during the development of the nervous system, and in the adult brain contributes to neural plasticity. BDNF is found in high concentrations in both the frontal cortex and hippocampus where it has been proposed to play a role in cognition and learning respectively. Low serum BDNF levels can be measured in patients with major depressive disorder, and there is a correlation between decreased BDNF levels and the severity of depression. At this time, research is attempting to solve the question of whether depression results secondary to diminished BDNF levels, or a reduction in BDNF levels occurs as a result of individuals becoming depressed. Learned Helplessness (LH) is utilized as a model for depression and this is confirmed due to the fact that LH is blocked by antidepressant medications. An advantage of using LH to induce depressive behavior is the fact that the onset of depression in an animal is at a defined time point. The model of Learned Helplessness allows for analysis of depressed patients via LH mice which at this current time is the most accurate model for depression. In this study, our results were consistent with the hypothesis that since BDNF levels are significantly reduced in the medial frontal cortices and hippocampus of depressed patients, as well as in several studies looking at depression in rodents, then BDNF mRNA levels would also be reduced in the brain tissue of LH mice compared to controls after induction of Learned Helplessness. We also predicted that the decrease in the amount of BDNF transcripts would be greater in the medial frontal cortical region (MFC) compared with hippocampal tissue, since deficits in this region have been identified in depressed patients. This was also found to be true in this experiment. The hypothesis was tested by measuring the mRNA message for the five BDNF transcript variants in both the hippocampus and the medial frontal cortex in mice that had experienced inescapable unpredicted foot shocks during learned helplessness training. This data was compared to control mice that did not experience the Learned Helplessness training. Differences in BDNF mRNA levels were then determined thereafter. Levels of mRNA BDNF in the HPC and MFC of both experimental LH and control animals were quantified using RT-PCR technique

Using team based learning in resident board review, the perfect marriage

Discussion of How the Problem was Identified and Explored. Board review has long been a tradition of many internal medicine training programs. Large in part, programs understand the importance of sessions focused on the ABIM exam. However, the classic format for these types of sessions often pertains to a standard review of multiple choice questions. We sought to redesign the format of our board review sessions based on premises of adult learning. Team Based Learning is known for drawing out misconceptions and using peer-based discussion to enhance interactive learning and retention. Thus, a TBL-based format was used to redesign the multiple choice question (MCQ) sessions. Description of the Innovation. Our board review sessions originally included MCQ answer and review with a subspecialist in the specified field representative of each subject (e.g. GI fellow facilitating GI board review). On average, 12 PGY3 residents attend each board review session which occurs during academic half day. In the new format, residents are separated into 4 teams with 6 high difficulty MCQs representing the Individual Readiness Assurance Test (IRAT) and subsequently the same MCQs in a Group Readiness Assurance Test (GRAT) format. Teams are then responsible for revealing their answers and a discussion is facilitated by a general internist with knowledge in testing and medical education. Results to Date. Testing of the 4 resident teams from a randomly selected sample revealed improvement in scores from an average IRAT to GRAT for the following teams: team one 2.5/6 to 4/6, team two 2.3/6 to 4/6, team three 4.5/6 to 6/6, team four 3.3/6 to 5/6. Analysis of individual residents also indicated substantial rises in correct answers for the IRAT as compared to the GRAT (e.g. 1/6 to 5/6). Anonymous survey data indicates an overwhelmingly positive response to the TBL session, with an average 11.4/12 of the residents indicating both their enjoyment of the session (5/5 on a 5 point Likert scale) and increased perception of improved medical and testing knowledge 4.6/5). Discussion/Reflection/Lessons Learned. Incorporation of a TBL-based format for internal medicine board review enhances individual and group learning for resident physicians. Interestingly, resident physicians enjoyed these sessions facilitated by general internal medicine faculty with an expertise in medical education in lieu of a content expert

Overcoming Resistance in Learning: Bridging the Gap Between Educator and Learner, Phase 3

Background: Resistance in learning (RIL) defines a set of attitudes or behaviors demonstrated by learners in an educational setting that result in decreased learning. Literature describes the etiology as multifactorial, including learning environment, characteristics of the learner, and teaching style. In conjunction with a team of academic hospitalists, we are using quality improvement methodology to address an educational problem within Phase I of medical school- resistance in learning. We are conducting a series of PDSA cycles to identify types of RIL during the Phase I pre-clinical years of medical school with the goal of implementing and evaluating an informed intervention within the curriculum to maximize both student academic success and the future benefit of patients. We hypothesize that an overall reduction in RIL will contribute to higher USMLE Step 1 scores, higher satisfaction with the Phase 1 curriculum, and a decreased number of students who repeat courses. Methods: A total of three PDSA cycles have been implemented. In Cycle 1 we conducted a student-faculty focus group using semi-structured questions. Focus group themes informed cycle 2 in which a survey was administered to 140 students. In Cycle 3 we implemented the “WISE” curriculum, designed to focus on Wellness, Integration, Step 1 preparation, and Education about learning. Baseline motivation for learning and self-efficacy has been surveyed. Results: Focus groups revealed the following themes: “Relevance,” “Motivation,” and “Alignment of curriculum with USMLE Step 1. Students surveyed on potential interventions asked for better alignment between the curriculum and USMLE Step 1, more consistency across the curriculum, and the opportunity to integrate concepts across systems early on and continuously throughout the curriculum. 90% of newly matriculated students cited an intrinsic motivation to enter medical school while 53% of second year students reported “finding relevance to USMLE Step 1” as their top reason for increased motivation to learn. 78% of students reported feeling highly capable of learning the content for USMLE Step 1 and 56% felt confident in their ability to achieve their academic goals. 93% of students prioritized “mastery goals”, yet 85% also endorsed “performance goals”. Conclusions and Next Steps: Motivation to learn is increased by finding “relevance” in topics as they pertain to USMLE Step 1. Cycle 3 revealed newly matriculated students maintain a strong sense of self efficacy in academic achievement. Students prioritize wanting to master content, although simultaneously have a desire to perform well. Students are intrinsically motivated at the start of medical school, citing making an impact and curiosity as their top motivations. However, as the curriculum progresses, motivation to learn is increased by making content more relevant to USMLE Step 1. Motivation for learning will continue to be surveyed throughout the new curriculum to evaluate change over time. Pre and post-curriculum USMLE Step 1 scores will be compared

Overcoming Resistance in Learning: Bridging the Gap Between Educator and Learner

Block chair faculty organized a book club to gain insight into how to best help students at UNM SOM. “Why Students Resist Learning,” by authors Anton O. Tolman and Janine Kremling became a central resource for faculty. The phenomenon of resistance in learning is a set of attitudes or behaviors that can be overtly or covertly demonstrated by learners in an educational setting and ultimately result in decreased learning and performance. Resistance is a fluid and multifactorial state. Factors include learning environment, individual characteristics of the learner, and teaching style. In order to maximize student learning and success at UNM SOM, we must first identify the types of resistance being demonstrated. In an effort to begin to understand resistance in learning at UNM SOM, we first focused on the student perspective

Clinical vignette: VIPoma as a cause of persistent diarrhea

A 48-year-old man originally presented with a 5-day history of watery, nonbloody diarrhea without recent travel or contact with ill people. His medical history was significant for a prolonged course of Clostridium difficile diarrhea 1 year earlier. On physical exam, he had orthostatic hypotension, dry mucous membranes, mild right lower quadrant tenderness to palpation, and hyperactive bowel sounds. Laboratory testing revealed a sodium level of 130 mEq/L, a potassium level of 1.7 mEq/L, a chloride level of 102 mEq/L, a bicarbonate level of 13 mEq/L, a blood urea nitrogen level of 43 mg/dL, a creatinine level of 1.6 mg/dL, and a calcium level of 11.4 mg/dL. Despite several liters of IV hydration and aggressive potassium repletion, he remained severely hypokalemic with a potassium level of 1.5 mEq/L. He was admitted to the medical ICU for further resuscitation. Stool testing was negative for C. difficile and other infectious organisms. The patient\u27s symptoms resolved before additional evaluation, and he was discharged with a presumed diagnosis of severe viral gastroenteritis. The patient returned 1 week later with recurrence of profuse diarrhea. His physical examination was notable for a blood pressure of 104/59 mm Hg (nonorthostatic) and a pulse of 106 beats/min, again with dry mucous membranes and mild tenderness to palpation of the right lower quadrant. Serum chemistry panel revealed a sodium level of 137 mEq/L, a potassium level of 2.3 mEq/L, a chloride level of 111 mEq/L, a bicarbonate level of 10 mEq/L, a blood urea nitrogen level of 38 mg/dL, a creatinine level of 2.3 mg/dL, and a calcium level of 10.4 mg/dL. Testing was again negative for an infectious source of diarrhea, and colonoscopy was not suggestive of inflammatory bowel disease. An abdominal CT revealed a 5-cm pancreatic tail mass. The patient was later found to have an elevated vasoactive intestinal peptide (VIP) level of 1,765 pg/mL (reference range, 0 to 60 pg/mL). Fecal osmolality was not obtained. The tumor was resected, and histology confirmed a neuroendocrine tumor

Ward redesign project: Improving admission processes and flow

Background: With changing ACGME work-hour restrictions, residency programs across the country have continued to work on optimizing admission and workflow processes. Prior to our institutions new inpatient service structure, nighttime medicine admissions were handled by one upper-level resident (post-graduate year 2 or 3) on a night-float rotation, and one intern who was from one of the inpatient ward teams. Day call responsibilities in the old structure included performing daytime admissions as well as medical intensive care unit (MICU) transfers. To improve workflow, our residency program instituted two major ward structure modifications. The first change involved the creation of a two-resident night-float team, with the rotating intern returning to daytime coverage only. The second change was the uncoupling of daytime admissions and MICU transfers into two separate call days. Purpose: The major goals in modifying our inpatient ward structure were to improve throughput from the Emergency Department (ED) to inpatient wards services, decrease the number of hand-offs of patients between admitting teams, and create a more even distribution of patients on inpatient ward teams. Description: Data was collected before and after implementation of the above interventions. When compared to the previous system, the new system was associated with decreased numbers of daily patient hand-offs between admitting teams (5.60 vs. 3.07 patients, p = 0.021) and decreased ED-to-admission times (historical average 5.5 hours vs. new system average 2.9 hours). There was a moderate increase in number of daily admission evaluations (15.50 vs. 16.56 patients, p = 0.56) and number of daily admissions performed (10.75 vs. 12.62 patients, p = 0.18). There was a minimal change in the daily distribution of patients on medicine ward team censuses over the two study periods (11.23 +/- 2.29 vs. 10.21 +/- 3.11 patients). Average inpatient ward censuses were not different over the two study periods (old system 81.46 patients vs. new system 81.7 patients, p = 0.917). Conclusions: Creation of a two-resident night-float team and separating daytime admission and MICU-transfer responsibilities over two teams was associated with improved overall workflow in our resident medicine ward system.\u2

Clinical vignette: Zero in 60 in 48 hours

Cirrhosis is a known cause of thrombocytopenia but it is important to consider other etiologies when the degree of thrombocytopenia is severe, especially in light of impending life-threatening bleeding. One must always maintain a low threshold for additional diagnostic entities when patients present acutely and confirmatory testing reveals profound thrombocytopenia. A 34-year-old man with cirrhosis secondary to Hepatitis C and alcohol abuse presented with persistent bleeding from preexisting oral ulcers and hematuria. Patient denied melena, hematemesis or hematochezia. His past medical history was significant for pancytopenia secondary to cirrhosis, active hepatitis C infection and hypersplenism. He denied any recent change in his medications nor taking any herbal medications or supplements. Vital signs were normal on admission. Physical examination was positive for dried blood on the lips and hepatosplenomegaly. Lab work revealed a platelet count of 0 with chronic leukopenia and anemia. His baseline platelet count is approximately 35,000. Urine analysis indicated gross blood. Coagulation workup was not suggestive of Disseminated Intravascular Coagulation (DIC). Peripheral smear was significant for complete lack of platelets without schistocytes. He was started on daily platelet transfusions with minimal change in his platelet count. A diagnosis of secondary Immune Thrombocytopenic Purpura (ITP) was made and therapy was initiated with intravenous immunoglobulin (IVIG) and dexamethasone. His platelet count failed to improve with worsening hematuria. He also received Rituximab, Romiplostim infusions and high dose methylprednisolone. The patient underwent splenic artery embolization three times. In spite of all efforts he continued to have hematuria and bleeding from intravenous lines with only transient rise in counts. He was taken for laparoscopic splenectomy with a platelet count of 35,000; following which the bleeding subsided and his platelet count improved to 100,000. Patient had a complicated hospital course but was eventually discharged home and currently his platelet counts are within normal limits. This patient appeared to have developed secondary ITP from his active Hepatitis C. Though he had chronic thrombocytopenia from cirrhosis and splenomegaly, it would be unusual to see this degree of platelet drop from these causes alone. ITP is a diagnosis of exclusion and bleeding is usually not proportionate to level of thrombocytopenia as in this patient. This case illustrates the fact that a clinician must have a low threshold for expanding the differential diagnosis of thrombocytopenia, especially diagnoses that are likely to harm the patient such as Thrombotic Thrombocytopenic Purpura, Disseminated Intravascular Coagulation and ITP. This case also demonstrates the challenging nature of managing severe refractory ITP. Splenectomy is the preferred therapy for patients with ITP who are refractory to first-line therapy with glucocorticoids or IVIG and is shown to cause sustained remission in two-thirds of patients

A soft selective sweep during rapid evolution of gentle behaviour in an Africanized honeybee

Africanized honey bees (AHB) are notoriously aggressive, but in Puerto Rico they have a ‘gentle’ phenotype. Here, Avalos et al. show that there has been a soft selective sweep at several loci in the Puerto Rican AHB population and suggest a role in the rapid evolution of gentle behaviour

Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

BACKGROUND: Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders. METHODS: We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013-17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result. FINDINGS: The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2-99·0) and 99·6% specificity (99·1-99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate). INTERPRETATION: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. FUNDING: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina

Integrating Genome-Wide Genetic Variations and Monocyte Expression Data Reveals Trans-Regulated Gene Modules in Humans

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns—independent component analysis—to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease