Online interactive medical neuroimaging exercise to identify human brain structures.

A persisting need remains for developing methods for inspiring and teaching undergraduate medical students to quickly learn to identify the hundreds of human brain structures, tracts and spaces that are clinically relevant (viewed as three-dimensional volumes or two-dimensional neuroimages), and to accomplish this with the option of virtual on-line methods. This notably includes teaching the essentials of recommended diagnostic radiology to allow students to be familiar with patient neuroimages routinely acquired using magnetic resonance imaging (MRI) and computed tomography (CT). The present article includes a brief example video plus details a clinically oriented interactive neuroimaging exercise for first year medical students (MS1s) in small groups, conducted with instructors either in-person or as an entirely online virtual event. This "find-the-brain-structure" (FBS) event included teaching students to identify brain structures and other regions of interest in the central nervous system (and potentially in head and neck gross anatomy), which are traditionally taught using brain anatomy atlases and anatomical specimens. The interactive, small group exercise can be conducted in person or virtually on-line in as little as 30 min depending on the scope of objectives being covered. The learning exercise involves coordinated interaction between MS1s with one or several non-clinical faculty and may include one or several physicians (clinical faculty and/or qualified residents). It further allows for varying degrees of instructor interaction online and is easy to convey to instructors who do not have expertise in neuroimaging. Anonymous pre-event survey (n = 113, 100% response rate) versus post-event surveys (n = 92, 81% response rate) were attained from a cohort of MS1s in a neurobiology course. Results showed multiple statistically significant group-level shifts in response to several of the questions, showing an increase in MS1 confidence with reading MRI images (12% increase shift in mean, p < 0.001), confidence in their approaching physicians for medical training (9%, p < 0.01), and comfort levels in working online with virtual team-based peers and with team-based faculty (6%, p < 0.05). Qualitative student feedback revealed highly positive comments regarding the experience overall, encouraging this virtual medium as a desirable educational approach.

[Sex-specific differences in gastroenterological diseases]. / Geschlechtsspezifische Unterschiede in gastroenterologischen Erkrankungen.

Diseases of the gastrointestinal tract present with substantial sex differences that have a potential impact on patient outcome. This fact is not sufficiently addressed either in basic research or in clinical studies. For example, most animal studies utilize male animals. Despite differences in incidence, sex may affect complication rates, prognosis, or therapeutic response. The incidence of gastrointestinal cancers is frequently higher in males, but this observation cannot solely rely on a distinct risk behaviour. Here, differences in immune response and p53 signalling may be factors responsible for this finding. Nevertheless, taking sex differences into account and improving our understanding of relevant mechanisms is crucial and will most likely have a substantial impact on disease outcome. This overview aims to highlight sex differences in the context of various gastroenterological diseases, primarily to enhance awareness. Attention to sex-specific differences is essential to improve individualized treatment.

Modeling Obesity-Driven Pancreatic Carcinogenesis-A Review of Current In Vivo and In Vitro Models of Obesity and Pancreatic Carcinogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a 5-year survival rate below 10%, thereby exhibiting the worst prognosis of all solid tumors. Increasing incidence together with a continued lack of targeted treatment options will cause PDAC to be the second leading cause of cancer-related deaths in the western world by 2030. Obesity belongs to the predominant risk factors for pancreatic cancer. To improve our understanding of the impact of obesity on pancreatic cancer development and progression, novel laboratory techniques have been developed. In this review, we summarize current in vitro and in vivo models of PDAC and obesity as well as an overview of a variety of models to investigate obesity-driven pancreatic carcinogenesis. We start by giving an overview on different methods to cultivate adipocytes in vitro as well as various in vivo mouse models of obesity. Moreover, established murine and human PDAC cell lines as well as organoids are summarized and the genetically engineered models of PCAC compared to xenograft models are introduced. Finally, we review published in vitro and in vivo models studying the impact of obesity on PDAC, enabling us to decipher the molecular basis of obesity-driven pancreatic carcinogenesis.

Self-transcendence and life stories of humanistic growth among late-midlife adults.

OBJECTIVE: Self-transcendence is the experience of feeling connected to something greater than oneself. Previous studies have shown high scores on self-transcendence are associated with well-being and other psychological benefits, but have rarely examined the lived experiences of highly self-transcendent people. METHOD: Black and White men and women in late-midlife completed Life Story Interviews and self-report measures of self-transcendence. In Study 1 (N = 144, Mage  = 56.4), we used grounded theory methodology to differentiate the stories told by participants scoring either extremely high or extremely low on self-transcendence. In Study 2 (N = 125; Mage  = 60.4), we created a quantitative coding scheme and scored 1,375 new life story scenes. RESULTS: In Study 1, six narrative themes were identified (closure, interconnectedness, lifelong learning, secure attachment, self-actualization, and spiritual pluralism) as part of a "humanistic growth story." In Study 2, four of the narrative themes were found to predict self-transcendence scores with significant effect sizes of ß = .26 to .47. CONCLUSIONS: In our sample, highly self-transcendent individuals tended to narrate their lived experiences as spiritual journeys of humanistic growth. This study adds to our understanding of one path of personality growth in late-midlife, that toward self-transcendence.

Molecular determinants of Yellow Fever Virus pathogenicity in Syrian Golden Hamsters: one mutation away from virulence.

Yellow fever virus (Flavivirus genus) is an arthropod-borne pathogen, which can infect humans, causing a severe viscerotropic disease with a high mortality rate. Adapted viral strains allow the reproduction of yellow fever disease in hamsters with features similar to the human disease. Here, we used the Infectious Subgenomic Amplicons reverse genetics method to produce an equivalent to the hamster-virulent strain, Yellow Fever Ap7, by introducing a set of four synonymous and six nonsynonymous mutations into a single subgenomic amplicon, derived from the sequence of the Asibi strain. The resulting strain, Yellow Fever Ap7M, induced a disease similar to that described for Ap7 in terms of symptoms, weight evolution, viral loads in the liver and lethality. Using the same methodology, we produced mutant strains derived from either Ap7M or Asibi viruses and investigated the role of each of Ap7M nonsynonymous mutations in its in vivo phenotype. This allowed identifying key components of the virulence mechanism in hamsters. In Ap7M virus, the reversion of either E/Q27H or E/D155A mutations led to an important reduction of both virulence and in vivo replicative fitness. In addition, the introduction of the single D155A Ap7M mutation within the E protein of the Asibi virus was sufficient to drastically modify its phenotype in hamsters toward both a greater replication efficiency and virulence. Finally, inspection of the Asibi strain E protein structure combined to in vivo testing revealed the importance of an exposed α-helix in domain I, containing residues 154 and 155, for Ap7M virulence in hamsters.

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma.

Microarray analysis revealed genes of the posterior HOXD locus normally involved in bone formation to be over-expressed in primary Ewing sarcoma (ES). The expression of posterior HOXD genes was not influenced via ES pathognomonic EWS/ETS translocations. However, knock down of the dickkopf WNT signaling pathway inhibitor 2 (DKK2) resulted in a significant suppression of HOXD10, HOXD11 and HOXD13 while over-expression of DKK2 and stimulation with factors of the WNT signaling pathway such as WNT3a, WNT5a or WNT11 increased their expression. RNA interference demonstrated that individual HOXD genes promoted chondrogenic differentiation potential, and enhanced expression of the bone-associated gene RUNX2. Furthermore, HOXD genes increased the level of the osteoblast- and osteoclast-specific genes, osteocalcin (BGLAP) and platelet-derived growth factor beta polypeptide (PDGFB), and may further regulate endochondral bone development via induction of parathyroid hormone-like hormone (PTHLH). Additionally, HOXD11 and HOXD13 promoted contact independent growth of ES, while in vitro invasiveness of ES lines was enhanced by all 3 HOXD genes investigated and seemed mediated via matrix metallopeptidase 1 (MMP1). Consequently, knock down of HOXD11 or HOXD13 significantly suppressed lung metastasis in a xeno-transplant model in immune deficient mice, providing overall evidence that posterior HOXD genes promote clonogenicity and metastatic potential of ES.

Are telehealth technologies for hypertension care and self-management effective or simply risky and costly?

Hypertension is a prevalent chronic disease that requires ongoing management and self-care. The disease affects 31% of American adults and contributed to or caused the deaths of 348,000 Americans in 2008, fewer than 50% of whom effectively self-managed the disease. However, self-management is complex, with patients requiring ongoing support and easy access to care. Telehealth may help foster the knowledge and skills necessary for those with hypertension to engage in successful self-management. This paper considers the applicability, efficacy, associated risks, and cost-effectiveness of telehealth for individuals and populations with hypertension. Telehealth is a broad term, encompassing telemedicine and mobile health that is used for physician-patient interactions, diagnostics, care delivery, education, information sharing, monitoring, and reminders. Telemedicine may have considerable utility for people diagnosed with hypertension who have poor access or social barriers that constrain access, but potential risks exist. Telehealth technology is evolving rapidly, even in the absence of fully proven cost-effectiveness and efficacy. Considering the cost of inpatient and emergency department care for patients with hypertension, telehealth is a highly attractive alternative, but there are risks to consider. Incorporating telehealth, which is increasingly characterized by mobile health, can increase both the capacity of health care providers and the reach of patient support, clinical management, and self-care. Telehealth studies need improvement; long-term outcome data on cardiovascular events must be obtained, and robust risk analyses and economic studies are needed to prospectively evaluate the safety and cost savings for hypertension self-management.

High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias.

To understand the genetic mechanisms driving variant and IGHV4-34-expressing hairy-cell leukemias, we performed whole-exome sequencing of leukemia samples from ten affected individuals, including six with matched normal samples. We identified activating mutations in the MAP2K1 gene (encoding MEK1) in 5 of these 10 samples and in 10 of 21 samples in a validation set (overall frequency of 15/31), suggesting potential new strategies for treating individuals with these diseases.

Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia.

PURPOSE: In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission (CR) rate even in small series, and of 39 reported cases from six studies, overall response rate after cladribine was 44% with 8% CRs. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, patients with HCLv were treated with simultaneous cladribine and rituximab. EXPERIMENTAL DESIGN: Patients with HCLv with 0 to 1 prior courses of cladribine received cladribine 0.15 mg/kg for days 1 to 5, with eight weekly doses of rituximab 375 mg/m(2) beginning day 1. Restaging was performed, and minimal residual disease (MRD) in blood and marrow was quantified using PCR, immunohistochemistry, and flow cytometry. RESULTS: By 6 months, 9 (90%) of 10 patients achieved CR, compared with 3 (8%) of 39 reported cases treated with cladribine alone (P < 0.0001). Of the 9 CRs, 8 remain free of MRD at 12 to 48 (median 27) months of follow-up. No dose-limiting toxicities were observed when beginning cladribine and rituximab on the same day, although most patients required short-term steroids to prevent and treat rituximab infusion reactions. Cytopenias in CRs resolved in 7 to 211 (median 34) days without major infections. CONCLUSION: Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves CRs without MRD and is feasible to administer.

Evidence of canonical somatic hypermutation in hairy cell leukemia.

To compare hairy cell leukemia (HCL) with chronic lymphocytic leukemia (CLL) and normal B cells with respect to their B-cell receptors, somatic hypermutation (SHM) features in HCL were examined in a series of 130 immunoglobulin gene heavy chain rearrangements, including 102 from 100 classic (HCLc) and 28 from 26 variant (HCLv) patients. The frequency of unmutated rearrangements in HCLc was much lower than that in HCLv (17% vs 54%, P < .001) or historically in CLL (17% vs 46%, P < .001), but HCLv and CLL were similar (P = .45). As previously reported for CLL, evidence of canonical SHM was observed in HCLc rearrangements, including: (1) a higher ratio of replacement to silent mutations in the complementarity determining regions than in the framework regions (2.83 vs 1.41, P < .001), (2) higher transition to transversion ratio than would be expected if mutations were random (1.49 vs 0.5, P < .001), and (3) higher than expected concentration of mutations within RGYW hot spots (13.92% vs 3.33%, P < .001). HCLv met these 3 criteria of canonical SHM to a lesser extent. These data suggest that, whereas HCLc cells may recognize antigen-like CLL and normal B cells before malignant transformation, HCLv cells from some patients may originate differently, possibly without undergoing antigen recognition.

Assessment of the northern distribution range of selected Perkinsus species in eastern oysters (Crassostrea virginica) and hard clams (Mercenaria mercenaria) with the use of PCR-based detection assays.

Perkinsus species are protistan parasites of molluscs. In Chesapeake Bay, Perkinsus marinus, Perkinsus chesapeaki, and Perkinsus andrewsi are sympatric, infecting oysters and clams. Although P. marinus is a pathogen for Crassostrea virginica, it remains unknown whether P. andrewsi and P. chesapeaki are equally pathogenic. Perkinsus species have been reported in C. virginica as far north as Maine, sometimes associated with high prevalence, but low mortality. Thus, we hypothesized that, in addition to P. marinus, Perkinsus species with little or no pathogenicity for C. virginica may be present. Accordingly, we investigated the distribution of Perkinsus species in C. virginica and Mercenaria mercenaria, collected from Maine to Virginia, by applying PCR-based assays specific for P. marinus, P. andrewsi, and a Perkinsus sp. isolated from M. mercenaria. DNA samples of M. mercenaria possessed potent PCR inhibitory activity, which was overcome by the addition of 1 mg/ml BSA and 5% (v/v) DMSO to the PCR reaction mixture. All 3 Perkinsus species were found in both host species throughout the study area. Interestingly, the prevalence of P. marinus in M. mercenaria was significantly lower than in C. virginica, suggesting that M. mercenaria is not an optimal host for P. marinus.

Integrating SNOMED CT into the UMLS: an exploration of different views of synonymy and quality of editing.

OBJECTIVE: The integration of SNOMED CT into the Unified Medical Language System (UMLS) involved the alignment of two views of synonymy that were different because the two vocabulary systems have different intended purposes and editing principles. The UMLS is organized according to one view of synonymy, but its structure also represents all the individual views of synonymy present in its source vocabularies. Despite progress in knowledge-based automation of development and maintenance of vocabularies, manual curation is still the main method of determining synonymy. The aim of this study was to investigate the quality of human judgment of synonymy. DESIGN: Sixty pairs of potentially controversial SNOMED CT synonyms were reviewed by 11 domain vocabulary experts (six UMLS editors and five noneditors), and scores were assigned according to the degree of synonymy. MEASUREMENTS: The synonymy scores of each subject were compared to the gold standard (the overall mean synonymy score of all subjects) to assess accuracy. Agreement between UMLS editors and noneditors was measured by comparing the mean synonymy scores of editors to noneditors. RESULTS: Average accuracy was 71% for UMLS editors and 75% for noneditors (difference not statistically significant). Mean scores of editors and noneditors showed significant positive correlation (Spearman's rank correlation coefficient 0.654, two-tailed p < 0.01) with a concurrence rate of 75% and an interrater agreement kappa of 0.43. CONCLUSION: The accuracy in the judgment of synonymy was comparable for UMLS editors and nonediting domain experts. There was reasonable agreement between the two groups.

Identifying consumer-friendly display (CFD) names for health concepts.

We have developed a systematic methodology using corpus-based text analysis followed by human review to assign "consumer-friendly display (CFD) names" to medical concepts from the National Library of Medicine (NLM) Unified Medical Language System (UMLS) Metathesaurus. Using NLM MedlinePlus queries as a corpus of consumer expressions and a collaborative Web-based tool to facilitate review, we analyzed 425 frequently occurring concepts. As a preliminary test of our method, we evaluated 34 ana-lyzed concepts and their CFD names, using a questionnaire modeled on standard reading assessments. The initial results that consumers (n=10) are more likely to understand and recognize CFD names than alternate labels suggest that the approach is useful in the development of consumer health vocabularies for displaying understandable health information.

Failure analysis of MetaMap Transfer (MMTx).

A pilot study was conducted to evaluate the performance of the MetaMap Transfer (MMTx), a tool that extracts terms from free text and suggests matches to concepts in the Unified Medical Language System' (UMLS'). Five participants, including a content domain expert and a UMLS Expert, manually extracted and mapped terms to UMLS concepts for two disease summary documents from NLM's consumer health site, Genetic Home Reference. The resulting adjudicated annotations were used as a gold standard. Differences in auto-mated term extraction and mapping between MMTx and MetaMap were noted. A failure analysis was conducted to categorize the types of terms not correctly mapped by MMTx. The most frequent type of failure (30%) resulted from missing inferential or world knowledge. Characteristics of each category are discussed. We distinguish between classes of failures that may be easily rectified, such as alternative retrieval strategies to extract exact matches, and ones that require additional research, such as coordinating conjunctions, co-reference resolution, and word sense disambiguation

Tracking meaning over time in the UMLS Metathesaurus.

The Unified Medical Language System(R) (UMLS) Metathesaurus contains records arranged by concept or meaning. Each concept contains a unique identifier (CUI) that can be used to track the concept over time. Since the January 2001 release, the Metathesaurus has included the file MRCUI that contains mappings for CUIs that disappear. This paper describes the processes that facilitated this effort and the ongoing effort to find suitable mappings for concepts whose meanings no longer exist in the Metathesaurus. This study highlights the need to identify missed synonymy prior to a release. It also shows a need to work more closely with source providers to identify the closest match in the Metathesaurus when they eliminate terms from their vocabularies.