Assessing medical students' knowledge in differentiating the diagnosis and treatment of unipolar vs bipolar depression.

BACKGROUND: Depression is one of the leading causes of premature death and disability. However, both unipolar and bipolar depression are underdiagnosed and undertreated. The aims of this study were to assess medical students' level of confidence in and knowledge of diagnosing and treating depression before and after completing a psychiatry clerkship, and their knowledge of differentiating unipolar vs bipolar depression. METHODS: Third-year medical students at Augusta University (Georgia, USA) completed an online questionnaire to assess confidence in and knowledge of diagnosing and treating unipolar and bipolar depression. RESULTS: Students who completed a psychiatry clerkship were statistically significantly more comfortable/confident with diagnosing (P < .0001) and treating (P < .0001) unipolar depression. Regarding bipolar depression, 73% of students who completed a psychiatry clerkship correctly diagnosed bipolar disorder, vs 59% of students who did not complete a psychiatry clerkship. This difference was not statistically significant (P = .181). CONCLUSIONS: Students who completed a psychiatry clerkship were more confident in diagnosing and treating unipolar depression compared with those who did not complete a psychiatry clerkship. However, there was no statistically significant difference between students who had completed a psychiatry clerkship and those who had not completed a psychiatry clerkship in making the correct diagnosis of bipolar depression. Neither group had a very high rate of correct diagnosis.

Moral injury, posttraumatic stress disorder, and religious involvement among U.S. veterans.

BACKGROUND: Traumatic experiences can cause ethical conflicts. "Moral injury" (MI) has been used to describe this emotional/cognitive state, and could contribute to the development of posttraumatic stress disorder (PTSD) or block its recovery. We examine the relationship between MI and PTSD, and the impact of religious involvement (RI) on that relationship. METHODS: We conducted a study of 120 veterans enrolled at the Charlie Norwood VA Medical Center in Augusta, Georgia. Standard measures of PTSD symptoms, MI, and RI were administered. Regression models were used to examine correlates of PTSD symptoms and the moderating or mediating effects of RI. RESULTS: A strong relationship was found between MI and PTSD symptoms (r = 0.54, P ≤ .0001), and between MI and RI (r = -.41, P ≤ .0001), but only a weak relationship was found between RI and PTSD symptoms (r = -.17, P = .058). RI did not mediate or moderate the relationship between MI and PTSD symptoms in the overall sample. However, among non-Middle Eastern war theater veterans, a significant buffering effect of religiosity was found. CONCLUSIONS: MI has a strong positive relationship with PTSD symptoms and an inverse relationship with RI. RI did not mediate or moderate the relationship between MI and PTSD in the overall sample, but it moderated this relationship in non-Middle Eastern war theater veterans.

Interpathologist Diagnostic Agreement for Non-Small Cell Lung Carcinomas Using Current and Recent Classifications.

CONTEXT.­: Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES.­: To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure. DESIGN.­: We used a Web-based survey to present core images of 54 NSCLC cases to 22 practicing pathologists for diagnosis, initially as H&E only, then as H&E plus mucin and 4 IHC stains. Each case was diagnosed according to published 2004, 2011, and 2015 NSCLC classifications. Cohen's kappa was calculated for the 231 pathologist pairs as a measure of IPDA. RESULTS.­: Twenty-two pathologists diagnosed 54 NSCLC cases by using 4 published classifications. IPDA is significantly higher for H&E/mucin/IHC diagnoses than for H&E-only diagnoses. IPDA for H&E/mucin/IHC diagnoses is highest with the 2015 classification. IPDA is estimated higher after collapse of stated diagnoses into subhead or dichotomized classes. IPDA for H&E/mucin/IHC diagnoses with the 2015 World Health Organization classification is similar for community and academic pathologists, and is higher when pathologists have pulmonary pathology expertise, have more than 6 years of practice experience, or diagnose more than 100 new lung carcinoma cases per year. CONCLUSIONS.­: Higher IPDA is associated with use of mucin and IHC stains, with the 2015 NSCLC classification, and with pathologists' pulmonary pathology expertise, practice duration, and frequency of lung carcinoma cases.

Racial/ethnic differences in the association of childhood adversities with depression and the role of resilience.

BACKGROUND: Adverse childhood experiences (ACE) including childhood abuse and trauma increase depressive symptoms. The role of resilience and how it interacts with both ACEs and the potential development of depressive symptoms, including how race and ethnicity moderate these effects, are much less studied. The aims of this study were to examine: 1) whether there is a dose-response relationship between trauma and depressive symptoms; 2) whether early trauma affected European Americans (EA) and African Americans (AA) in a similar fashion; and 3) whether resilience mitigates the effect of trauma. METHODS: The present study comprised a cross-sectional study of subjects from a longitudinal cohort. All subjects were 19 years or older with traumatic experiences prior to age 18. Subjects were assessed for depressive symptoms as well as resilience. RESULTS: In 413 subjects enrolled, ACEs were significantly associated with depression severity in a dose-response fashion (p<0.001). Notably, AAs had lower depression scores at low to moderate levels of ACEs than EAs, but reported comparable levels of depression with severe exposure to ACEs (pInteraction=0.05). In both EAs and AAs, young adults with high and medium levels of resilience showed less depressive symptoms compared to those with low resilience (p<0.05). LIMITATIONS: to consider are the cross-sectional design, possibility of other confounders, and potential for recall bias of this study. CONCLUSION: While ACEs were significantly associated with severity of depression in a dose-response fashion, higher resilience mitigated the impact of childhood adversities on depressive symptoms in young adults. The results are encouraging, and guides research for therapeutics to boost resilience.

Mismatch repair gone awry: Management of Lynch syndrome.

The hallmark of Lynch syndrome involves germline mutations of genes important in DNA mismatch repair. Affected family kindreds will have multiple associated malignancies, the most common of which is colorectal adenocarcinoma. Recently, evidence has shown that clinical diagnostic criteria provided by the Amsterdam Criteria and the Bethesda Guidelines must be linked with microsatellite instability testing to correctly diagnose Lynch syndrome. We present a case of metachronous colorectal adenocarcinomas in a patient less than 50 years of age, followed by a discussion of Lynch syndrome, with an emphasis on surveillance and prevention of malignancies.

Blastomycosis: a case study of a dimorphic fungal disease.

UNLABELLED: A 17-year-old male presented to a local hospital with symptoms of pneumonia and a hacking cough productive of yellow sputum. Direct examination of a bronchial lavage sample revealed organisms morphologically consistent with Blastomyces dermatitidis, which was confirmed by culture. The patient was placed on intravenous antifungal therapy and his condition improved dramatically. OBJECTIVES: to describe the gross and microscopic morphologies of both yeast and mold forms of B. dermatitidis; to identify B. dermatitidis given patient history, and microscopic and colony morphology; to describe the symptoms of primary pulmonary infections caused by B. dermatitidis, and to name additional tissues typically affected by the systemic pathogen.

Diagnostic and clinical considerations in concomitant bone marrow involvement by plasma cell myeloma and chronic lymphocytic leukemia/monoclonal B-cell lymphocytosis: a series of 15 cases and review of literature.

CONTEXT: Plasma cell myeloma and chronic lymphocytic leukemia are both common hematologic malignancies, sharing many epidemiologic features. Concomitant detection of the 2 conditions poses special diagnostic challenges for the pathologist. OBJECTIVE: To describe the pathologic findings in cases of concomitant bone marrow involvement by myeloma and CD5(+) monoclonal B cells and to outline the differential diagnostic possibilities, suggest a workup for correct diagnosis, and examine clinical outcome. DESIGN: Fifteen cases that met the diagnostic criteria were identified from pathology databases at 4 participating institutions. Morphologic findings were reviewed, additional immunohistochemical stains performed, and flow cytometric, cytogenetic, and relevant laboratory and clinical information was summarized. Previously published cases were searched from electronic databases and cross-references. RESULTS: Most patients (13 of 15) were older males. Often (11 of 15) they presented clinically with myeloma, yet had both monotypic plasma cells and B cells in the diagnostic marrow. In 4 patients, myeloma developed 24 months or later after chronic lymphocytic leukemia. In 7 patients, myeloma and CD5(+) B cells showed identical immunoglobulin light-chain restriction. Primary differential diagnoses include lymphoplasmacytic lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. CD56 and/or cyclin D1 expression by plasma cells was helpful for correct diagnosis. Most patients in our cohort and published reports were treated for plasma cell myeloma. CONCLUSIONS: Concomitant detection of myeloma and chronic lymphocytic leukemia in the bone marrow is a rare event, which must be carefully differentiated from lymphomas with lymphoplasmacytic differentiation for correct treatment.

Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Sudden death from diffuse leptomeningeal oligodendrogliomatosis.

In this paper the authors describe the rare disorder of diffuse leptomeningeal oligodendrogliomatosis in a patient with an oligodendroglioma of the cauda equina who died suddenly. Reviewing this uncommon pathological entity is important so that it can be recognized and treated appropriately. This young, otherwise healthy woman with initial symptoms of low-back pain had a mass lesion of the cauda equina. During a workup, profound refractory intracranial hypertension suddenly developed despite aggressive surgical and medical intervention. Autopsy revealed a spinal cord oligodendroglioma with diffuse leptomeningeal oligodendrogliomatosis of the brain and spinal cord. Given the unforeseen outcome in this patient, this entity, although rare, should be considered in patients with similar presentations and addressed early to prevent similar outcomes. A review of the details of this case as well as the literature is presented below.

Pseudo-Pelger-Huët anomaly induced by medications: a clinicopathologic study in comparison with myelodysplastic syndrome-related pseudo-Pelger-Huët anomaly.

Pseudo-Pelger-Huët anomaly (PPHA) has been documented in association with transplant medications and other drugs. This iatrogenic neutrophilic dysplasia is reversible with cessation or adjustment of medications but is frequently confused with myelodysplastic syndrome (MDS) based on the conventional concept that PPHA is a marker for dysplasia. We investigated the clinicopathologic features in iatrogenic PPHA and compared them with MDS-related PPHA. The 13 cases studied included 5 bone marrow/stem cell transplantations, 3 solid organ transplantations, 1 autoimmune disease, 3 chronic lymphocytic leukemias, and 1 breast carcinoma. For 12 cases, there was follow-up evaluation, and all demonstrated at least transient normalization of neutrophilic segmentation. All 9 cases of MDS demonstrated at least 2 of the following pathologic abnormalities on bone marrow biopsy: hypercellularity (8/9), morphologic dysplasia (8/9), clonal cytogenetic abnormality (7/9), and increased blasts (3/9), whereas these abnormalities were typically absent in iatrogenic PPHA. Iatrogenic PPHA displayed a higher proportion of circulating PPHA cells than in MDS (mean, 47.4%; SD, 31.6% vs mean, 12.3%; SD, 9.8; P < .01). A diagnostic algorithm is proposed in which isolated PPHA is indicative of transient or benign PPHA unless proven otherwise.

Identification of key amino acids responsible for the substantially higher affinities of human type 1 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD1) for substrates, coenzymes, and inhibitors relative to human 3beta-HSD2.

The human type 1 (placenta, breast tumors, and prostate tumors) and type 2 (adrenals and gonads) isoforms of 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD1 and 3beta-HSD2) are encoded by two distinct genes that are expressed in a tissue-specific pattern. Our recent studies have shown that His156 contributes to the 14-fold higher affinity that 3beta-HSD1 exhibits for substrate and inhibitor steroids compared with human 3beta-HSD2 containing Tyr156 in the otherwise identical catalytic domain. Our structural model of human 3beta-HSD localizes His156 or Tyr156 in the subunit interface of the enzyme homodimer. The model predicts that Gln105 on one enzyme subunit has a higher probability of interacting with His156 on the other subunit in 3beta-HSD1 than with Tyr156 in 3beta-HSD2. The Q105M mutant of 3beta-HSD1 (Q105M1) shifts the Michaelis-Menten constant (Km) for 3beta-HSD substrate and inhibition constants (Ki) for epostane and trilostane to the much lower affinity profiles measured for wild-type 3beta-HSD2 and H156Y1. However, the Q105M2 mutant retains substrate and inhibitor kinetic profiles similar to those of 3beta-HSD2. Our model also predicts that Gln240 in 3beta-HSD1 and Arg240 in 3beta-HSD2 may be responsible for the 3-fold higher affinity of the type 1 isomerase activity for substrate steroid and cofactors. The Q240R1 mutation increases the isomerase substrate Km by 2.2-fold to a value similar to that of 3beta-HSD2 isomerase and abolishes the allosteric activation of isomerase by NADH. The R240Q2 mutation converts the isomerase substrate, cofactor, and inhibitor kinetic profiles to the 4-14-fold higher affinity profiles of 3beta-HSD1. Thus, key structural reasons for the substantially higher affinities of 3beta-HSD1 for substrates, coenzymes, and inhibitors have been identified. These structure and function relationships can be used in future docking studies to design better inhibitors of the 3beta-HSD1 that may be useful in the treatment of hormone-sensitive cancers and preterm labor.

Adult-derived stem cells and their potential for use in tissue repair and molecular medicine.

This report reviews three categories of precursor cells present within adults. The first category of precursor cell, the epiblast-like stem cell, has the potential of forming cells from all three embryonic germ layer lineages, e.g., ectoderm, mesoderm, and endoderm. The second category of precursor cell, the germ layer lineage stem cell, consists of three separate cells. Each of the three cells is committed to form cells limited to a specific embryonic germ layer lineage. Thus the second category consists of germ layer lineage ectodermal stem cells, germ layer lineage mesodermal stem cells, and germ layer lineage endodermal stem cells. The third category of precursor cells, progenitor cells, contains a multitude of cells. These cells are committed to form specific cell and tissue types and are the immediate precursors to the differentiated cells and tissues of the adult. The three categories of precursor cells can be readily isolated from adult tissues. They can be distinguished from each other based on their size, growth in cell culture, expressed genes, cell surface markers, and potential for differentiation. This report also discusses new findings. These findings include the karyotypic analysis of germ layer lineage stem cells; the appearance of dopaminergic neurons after implantation of naive adult pluripotent stem cells into a 6-hydroxydopamine-lesioned Parkinson's model; and the use of adult stem cells as transport mechanisms for exogenous genetic material. We conclude by discussing the potential roles of adult-derived precursor cells as building blocks for tissue repair and as delivery vehicles for molecular medicine.

The higher affinity of human type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD1) for substrate and inhibitor steroids relative to human 3beta-HSD2 is validated in MCF-7 tumor cells and related to subunit interactions.

Two distinct genes encode the tissue-specific expression of the two isoforms of human 3beta-hydroxysteroid dehydrogenase: 3beta-HSD1 (placenta, mammary gland, breast tumors) and 3beta-HSD2 (gonads, adrenals). Purified 3beta-HSD1 utilizes DHEA as a substrate with 13-fold lower Km than 3beta-HSD2. Using homogenates of human MCF-7 Tet-off breast tumor cells stably transfected with human 3beta-HSD1 or 3beta-HSD2, DHEA is utilized as substrate by 3beta-HSD1 (Km = 4.8 microM) much more avidly than by 3beta-HSD2 (Km = 43 microM). In addition, the 3beta-HSD inhibitor, epostane, binds to purified 3beta-HSD1 with a 17-fold higher affinity compared to 3beta-HSD2. In the MCF-7 cells, two 3beta-HSD inhibitors block 3beta-HSD1 activity (Ki = 0.06 microM, epostane; 0.08 microM, trilostane) with 12- to 14-fold higher affinities compared to the inhibition of 3beta-HSD2 (Ki = 0.85 microM, epostane; 1.01 microM, trilostane). Thus, the substantially higher affinities of human 3beta-HSD1 for substrate and inhibitor steroids measured using the pure isoenzymes have been validated using microsome-bound 3beta-HSD1 and 3beta-HSD2 in the MCF-7 cells. Similar to our previously reported H156Y mutant of 3beta-HSD1, the Q105M mutant of 3beta-HSD1 shifts the substrate and inhibitor kinetic profiles to those of wild-type 3beta-HSD2. However, the Q105M mutant of 3beta-HSD2 retains the substrate and inhibitor kinetic profiles of wild-type 3beta-HSD2. Our structural homology model of human 3beta-HSD predicts that Gln105 on one enzyme subunit hydrogen-binds to His156 on the other subunit of the enzyme homodimer. The higher affinity of 3beta-HSD1 for the steroids may be related to different subunit interactions in the quaternary structures of the two isoenzymes. It may be possible to exploit these kinetic differences to selectively inhibit the conversion of DHEA ultimately to estradiol by 3beta-HSD1 and slow the growth of breast tumor cells.