1983 Clinic Yearbook

The Clinic is the yearbook of the Sidney Kimmel Medical College (formerly Jefferson Medical College) at Thomas Jefferson University

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated

Physician empathy: definition, components, measurement, and relationship to gender and specialty

OBJECTIVE: There is a dearth of empirical research on physician empathy despite its mediating role in patient-physician relationships and clinical outcomes. This study was designed to investigate the components of physician empathy, its measurement properties, and group differences in empathy scores. METHOD: A revised version of the Jefferson Scale of Physician Empathy (with 20 Likert-type items) was mailed to 1,007 physicians affiliated with the Jefferson Health System in the greater Philadelphia region; 704 (70%) responded. Construct validity, reliability of the empathy scale, and the differences on mean empathy scores by physicians’ gender and specialty were examined. RESULTS: Three meaningful factors emerged (perspective taking, compassionate care, and standing in the patient’s shoes) to provide support for the construct validity of the empathy scale that was also found to be internally consistent with relatively stable scores over time. Women scored higher than men to a degree that was nearly significant. With control for gender, psychiatrists scored a mean empathy rating that was significantly higher than that of physicians specializing in anesthesiology, orthopedic surgery, neurosurgery, radiology, cardiovascular surgery, obstetrics and gynecology, and general surgery. No significant difference was observed on empathy scores among physicians specializing in psychiatry, internal medicine, pediatrics, emergency medicine, and family medicine. CONCLUSIONS: Empathy is a multidimensional concept that varies among physicians and can be measured with a psychometrically sound tool. Implications for specialty selection and career counseling are discussed

An operational measure of physician lifelong learning: its development, components and preliminary psychometric data

Despite the emphasis placed on physicians’ lifelong learning, no psychometrically sound instrument has been developed to provide an operational measure of the concept and its components among physicians. The authors designed this study to develop a tool for measuring physician lifelong learning, to identify its underlying components and to assess its psychometric properties. A 37-item questionnaire was developed, based on a review of literature and the results of two pilot studies. Psychometric analyses of the responses of 160 physicians identified 19 items that were included in the Jefferson Scale of Physician Lifelong Learning. Factor analysis of the 19 items showed five meaningful factors that were consistent with the definition and major features of lifelong learning. They were ‘need recognition’, ‘research endeavor’, ‘self-initiation’, ‘technical skills’ and ‘personal motivation’. The method of contrasted groups provided evidence in support of the validity of the five factors. The factors’ reliability was assessed by coefficient alpha. It is concluded that lifelong learning is a multifaceted concept, and its operational measure is feasible for evaluating different educational programs and for studying group differences among physicians

Development of an Instrument to Measure Lifelong Learning Among Physicians

No abstract available

Comparisons of American, Israeli, Italian and Mexican physicians and nurses on the total and factor scores of the Jefferson scale of attitudes toward physician-nurse collaborative relationships

This cross-cultural study was designed to compare the attitudes of physicians and nurses toward physician–nurse collaboration in the United States, Israel, Italy and Mexico. Total participants were 2522 physicians and nurses who completed the Jefferson Scale of Attitudes Toward Physician–Nurse Collaboration (15 Likert-type items, (Hojat et al., Evaluation and the Health Professions 22 (1999a) 208; Nursing Research 50 (2001) 123). They were compared on the total scores and four factors of the Jefferson Scale (shared education and team work, caring as opposed to curing, nurses, autonomy, physicians’ dominance). Results showed inter- and intra-cultural similarities and differences among the study groups providing support for the social role theory (Hardy and Conway, Role Theory: Perspectives for Health Professionals, Appleton-Century-Crofts, New York, 1978) and the principle of least interest (Waller and Hill, The Family: A Dynamic Interpretation, Dryden, New York, 1951) in inter-professional relationships. Implications for promoting physician–nurse education and inter-professional collaboration are discussed

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect

Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy we identified 5 de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020