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Abstract Glial cells have been proposed as a source of neural progenitors, but the mechanisms underpinning the neurogenic potential of adult glia are not known. Using single cell transcriptomic profiling, we show that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition along a linear differentiation trajectory that allows them to retain neurogenic potential while acquiring mature glial functions. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a cell culture model of enteric neurogenesis and a gut injury model demonstrate that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits.

IntroductionSutures are flexible linear elements that join tissue and maintain their hold with a surgeon-created knot. Tension at the suture/tissue interface can cut the very tissues that sutures are designed to hold, leading to dehiscence and incisional hernia formation. A new suture design (Duramesh, Mesh Suture Inc., Chicago, IL) was approved for marketing by the United States Food and Drug Administration in September 2022. The multiple filaments of the mesh suture are designed to diffuse tension at the suture/tissue interface thereby limiting pull-through. The macroporosity and hollow core of the mesh suture encourage fibrovascular incorporation for a durable repair. We created the first registry and clinical report of patients undergoing mesh suture implantation to assess its real-world effectiveness.MethodsA patient registry was created based on institutional implant logs from January to August 2023 at an integrated health-care system. Operative reports were reviewed by the study team to verify use of “Duramesh” by dictation. Retrospective chart review was conducted to evaluate patient and surgical characteristics, follow-up, and short-term outcomes of interest. Results were analyzed using descriptive statistics and Chi-squared analysis with Microsoft Excel and GraphPad Prism.ResultsThree hundred seventy-nine separate implantations by 56 surgeons across 12 (sub) specialties at a university hospital and two community hospitals were performed. Mesh suture was used for treatment of the abdominal wall in 314 cases. Follow-up averaged 80.8 ± 52.4 days. The most common abdominal wall indications were ventral hernia repair (N = 97), fascial closure (N = 93), abdominal donor site closure from autologous breast reconstruction (N = 51), and umbilical hernia repair (N = 41). Mesh suture was used in all Centers for Disease Control (CDC) wound classifications, including 92 CDC class 2 or 3 abdominal operations. There were 19 surgical site infections (6.1%) and 37 surgical site events (11.8%).ConclusionsShort-term registry data demonstrates the wide diversity of surgical disciplines and scenarios in which mesh suture has been used to date. The early adoption of mesh suture into practice highlights that consequences of suture pull-through influence operative decision making. As this is the first interim report of the Duramesh mesh suture registry, follow-up is too short for characterization of long-term durability of abdominal wall closures.

Objective Poor interdisciplinary care team communication has been associated with increased mortality. The study aimed to define conditions for effective interdisciplinary care team communication.Design An observational cross-sectional qualitative study.Setting A surgical intensive care unit in a large, urban, academic referral medical centre.Participants A total 6 interviews and 10 focus groups from February to June 2021 (N=33) were performed. Interdisciplinary clinicians who cared for critically ill patients were interviewed. Participants included intensivist, transplant, colorectal, vascular, surgical oncology, trauma faculty surgeons (n=10); emergency medicine, surgery, gynaecology, radiology physicians-in-training (n=6), advanced practice providers (n=5), nurses (n=7), fellows (n=1) and subspecialist clinicians such as respiratory therapists, pharmacists and dieticians (n=4). Audiorecorded content of interviews and focus groups were deidentified and transcribed verbatim. The study team iteratively generated the codebook. All transcripts were independently coded by two team members.Primary outcome Conditions for effective interdisciplinary care team communication.Results We identified five themes relating to conditions for effective interdisciplinary care team communication in our surgical intensive care unit setting: role definition, formal processes, informal communication pathways, hierarchical influences and psychological safety. Participants reported that clear role definition and standardised formal communication processes empowered clinicians to engage in discussions that mitigated hierarchy and facilitated psychological safety.Conclusions Standardising communication and creating defined roles in formal processes can promote effective interdisciplinary care team communication by fostering psychological safety.

Therapeutic Area: ASCVD/CVD in Special Populations Background: Association between socioeconomic status and cardiovascular diseases (CVD) is well-documented. Racial disparities in prevalence and outcomes of CVD have also been extensively studied. The intersection of income, race, and CVD is relatively underexplored. Hence, we aimed to study the prevalence of CVD and associated risk factors among different races/ethnicities across different income groups. Methods: This retrospective analysis included data from participants from the National Health and Nutrition Examination Survey from 2005-2018. Adults ≥20 years who identified as non-Hispanic (NH) White, NH Black, or Hispanic (Mexican-American and other Hispanics) were included. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The participants were divided into four quartiles based on PIR 3.9 (highest income). Weighted logistic regression was performed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to determine the association of race/ethnicity and CVD and associated risk factors in each quartile. Models were adjusted for age, sex, race, health insurance, marital status, citizenship status, and level of education and PIR. Results: We included 31,884 unweighted participants that corresponded to 191,307,167 weighted, nationally representative participants. Of these, 8,009 (weighted 16.3%), 7,967 (weighted 19.2%), 7,944 (weighted 26.9%), and 7,964 (weighted 37.5%) participants belonged to 1st, 2nd, 3rd, and 4th quartiles respectively. The proportion of NH-Whites increased with increasing PIR quartiles whereas the proportion of NH-Blacks and Hispanics decreased with increasing PIR quartiles. In adjusted analyses, the prevalence odds of diabetes mellitus (DM), hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke decreased in a step-wise manner from 1st to 4th PIR quartile. Overall, NH Blacks had higher prevalence odds of DM, hypertension, obesity, CHF, and stroke compared to NH Whites, whereas NH Whites had higher prevalence odds of CAD and dyslipidemia compared to NH Blacks (Figure 1). The model testing for PIR-race/ethnicity interaction revealed that PIR-race/ethnicity interaction was significant for obesity (P-interaction 0.002) and diabetes mellitus (P-interaction 0.027) (Figure 2). The difference in prevalence odds between NH White adults and NH Black adults was greater for obesity and diabetes mellitus in the highest PIR quartile compared to the lowest PIR quartile. PIR-race/ethnicity interaction for stroke was 0.053 with the difference in prevalence odds between NH White adults and NH Black adults being greater in the higher PIR quartiles compared to the lowest PIR quartile. Conclusions: The difference in prevalence between NH White and NH Black adults was greater for diabetes mellitus, obesity and stroke in the highest PIR quartile compared to the lowest PIR quartile. These data suggest a complex interplay between race/ethnicities and income inequalities resulting in disparities in CVD.

Therapeutic Area: ASCVD/CVD in Special Populations Background: Association between socioeconomic status and cardiovascular diseases (CVD) is well-documented. Racial disparities in prevalence and outcomes of CVD have also been extensively studied. The intersection of income, race, and CVD is relatively underexplored. Hence, we aimed to study the prevalence of CVD and associated risk factors among different races/ethnicities across different income groups. Methods: This retrospective analysis included data from participants from the National Health and Nutrition Examination Survey from 2005-2018. Adults ≥20 years who identified as non-Hispanic (NH) White, NH Black, or Hispanic (Mexican-American and other Hispanics) were included. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The participants were divided into four quartiles based on PIR 3.9 (highest income). Weighted logistic regression was performed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to determine the association of race/ethnicity and CVD and associated risk factors in each quartile. Models were adjusted for age, sex, race, health insurance, marital status, citizenship status, and level of education and PIR. Results: We included 31,884 unweighted participants that corresponded to 191,307,167 weighted, nationally representative participants. Of these, 8,009 (weighted 16.3%), 7,967 (weighted 19.2%), 7,944 (weighted 26.9%), and 7,964 (weighted 37.5%) participants belonged to 1st, 2nd, 3rd, and 4th quartiles respectively. The proportion of NH-Whites increased with increasing PIR quartiles whereas the proportion of NH-Blacks and Hispanics decreased with increasing PIR quartiles. In adjusted analyses, the prevalence odds of diabetes mellitus (DM), hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke decreased in a step-wise manner from 1st to 4th PIR quartile. Overall, NH Blacks had higher prevalence odds of DM, hypertension, obesity, CHF, and stroke compared to NH Whites, whereas NH Whites had higher prevalence odds of CAD and dyslipidemia compared to NH Blacks (Figure 1). The model testing for PIR-race/ethnicity interaction revealed that PIR-race/ethnicity interaction was significant for obesity (P-interaction 0.002) and diabetes mellitus (P-interaction 0.027) (Figure 2). The difference in prevalence odds between NH White adults and NH Black adults was greater for obesity and diabetes mellitus in the highest PIR quartile compared to the lowest PIR quartile. PIR-race/ethnicity interaction for stroke was 0.053 with the difference in prevalence odds between NH White adults and NH Black adults being greater in the higher PIR quartiles compared to the lowest PIR quartile. Conclusions: The difference in prevalence between NH White and NH Black adults was greater for diabetes mellitus, obesity and stroke in the highest PIR quartile compared to the lowest PIR quartile. These data suggest a complex interplay between race/ethnicities and income inequalities resulting in disparities in CVD.

Rapid intestinal regeneration after injury is critical to maintain barrier integrity and homeostasis, but must be tightly controlled to prevent tumorigenesis. Here they show that the aryl hydrocarbon receptor is required to terminate the regenerative response after wound healing.

Abstract Background Telemedicine has become an integral part of health care delivery in recent years. One of the leading applications for this use is WhatsApp — a free smartphone application that allows instant messaging with pictures and videos. This study analyzed the emerging role of WhatsApp on reducing the need for referrals to medical specialists and to compare the views of physicians regarding WhatsApp consultations. Methods A cross-sectional study based on an anonymous web-survey was conducted among PCPs and medical specialists working in the Israel Defense Forces Medical-Corps during September and October, 2019. Results Of 201 participants, 153 were PCPs and 48 were medical specialists. 86.9 % of PCPs and 86.5 % of specialists used WhatsApp every day in professional settings. Added workload, potential breaching of patient confidentiality and lack of full documentation of consultations were the main concerns among physicians using the application. 60.7 % of PCPs and 95.7 % of specialists stated that these consultations have reduced the need for in-person appointments at least once a week. Conclusions In times of COVID-19 that require social distancing, WhatsApp provides a simple, readily available platform for consultations between healthcare providers, even to the extent of rendering some in-person appointments unnecessary. Healthcare organizations should address the matters troubling healthcare providers, mainly patient confidentiality and lack of documentation in patients’ medical records, while providing adequate compensation for those providing the service during and after work hours.

Central nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function. Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear. Here, we used high resolution NG Capture-C to map the cis-regulatory interaction landscape of the key neuro-developmental Paupar-Pax6 lncRNA-mRNA locus. The results define chromatin architecture changes associated with high Paupar-Pax6 expression in neurons and identify both promoter selective as well as shared cis-regulatory-promoter interactions involved in regulating Paupar-Pax6 co-expression. We discovered that the TCF7L2 transcription factor, a regulator of chromatin architecture and major effector of the Wnt signalling pathway, binds to a subset of these candidate cis-regulatory elements to coordinate Paupar and Pax6 co-expression. We describe distinct roles for Paupar in Pax6 expression control and show that the Paupar DNA locus contains a TCF7L2 bound transcriptional silencer whilst the Paupar transcript can act as an activator of Pax6. Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.

BackgroundThe COVID-19 outbreak required prompt action by health authorities around the world in response to a novel threat. With enormous amounts of information originating in sources with uncertain degree of validation and accuracy, it is essential to provide executive-level decision-makers with the most actionable, pertinent, and updated data analysis to enable them to adapt their strategy swiftly and competently. ObjectiveWe report here the origination of a COVID-19 dedicated response in the Israel Defense Forces with the assembly of an operational Data Center for the Campaign against Coronavirus. MethodsSpearheaded by directors with clinical, operational, and data analytics orientation, a multidisciplinary team utilized existing and newly developed platforms to collect and analyze large amounts of information on an individual level in the context of SARS-CoV-2 contraction and infection. ResultsNearly 300,000 responses to daily questionnaires were recorded and were merged with other data sets to form a unified data lake. By using basic as well as advanced analytic tools ranging from simple aggregation and display of trends to data science application, we provided commanders and clinicians with access to trusted, accurate, and personalized information and tools that were designed to foster operational changes and mitigate the propagation of the pandemic. The developed tools aided in the in the identification of high-risk individuals for severe disease and resulted in a 30% decline in their attendance to their units. Moreover, the queue for laboratory examination for COVID-19 was optimized using a predictive model and resulted in a high true-positive rate of 20%, which is more than twice as high as the baseline rate (2.28%, 95% CI 1.63%-3.19%). ConclusionsIn times of ambiguity and uncertainty, along with an unprecedented flux of information, health organizations may find multidisciplinary teams working to provide intelligence from diverse and rich data a key factor in providing executives relevant and actionable support for decision-making.

Sepsis is one of the leading causes of hospitalization and death among hemodialysis patients. Infections due to multidrug-resistant organisms (MDROs) are common among these patients, but empiric broad-spectrum coverage for every septic patient is associated with unfavorable outcomes. A retrospective case–control study was conducted at Shamir Medical Center, Israel (July 2016–April 2020), to determine predictors of MDRO infections among septic (per SEPSIS-3) ambulatory adult hemodialysis patients with permanent dialysis access (i.e., fistula, graft, or tunneled Perm-A-Cath). MDROs were determined according to established definitions. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to construct a prediction score and determine its performance. Of 509 patients, 225 (44%) had microbiologically confirmed infection, and 79 patients (35% of 225) had MDROs. The eventual independent predictors of MDRO infections were Perm-A-Cath access (vs. fistula or graft, aOR = 3, CI-95% = 2.1–4.2) and recent hospitalization in the previous three months (aOR = 2.3, CI-95% = 1.6–3.3). The score to predict MDRO sepsis with the highest performances contained seven parameters and displayed an area under the receiver operating characteristic curve (ROC AUC) of 0.74. This study could aid in defining a group of hemodialysis patients for which empiric broad-spectrum agents could be safely avoided.

Antibiotic resistance is a global problem affecting both human and animal health. Ensuring the strategic and effective use of antibiotics is paramount to combatting the emergence and spread of resistance. This study explored New York State (NYS) dairy farmers' perceptions regarding antibiotic use in dairy farming and antibiotic resistance. Dairy farmers' perceptions were assessed through semi-structured, in-person interviews. Twenty interviews with farm owners and/or managers of 15 conventional and five USDA certified organic dairy farms with 40 to 2,300 lactating cows were conducted. Thematic analysis was used to assess, compare and contrast transcripts for farmers' characterization of their beliefs, values, and concerns. Conventional dairy farmers had a low level of concern about the possible impacts of on-farm antibiotic resistance on human health and believed their antibiotic use was already judicious. Generally, they believed their cattle's health would suffer if antibiotic use were further curtailed. Conventional farmers expressed frustration over the possibility of more stringent governmental, milk cooperative, buyer, or marketer requirements for antibiotic use and associated animal welfare in the future. They attributed expanding regulations in part to misinformed consumer preferences, that farmers felt were influenced by the marketing of organic dairy products. Organic dairy farmers were generally more concerned about issues related to antibiotic resistance than conventional farmers. Both conventional and organic farmers placed emphasis on disease prevention through herd health management rather than treatment. In conclusion, the conventional NYS dairy farmers in this study were skeptical of the need for and benefits of reduced antibiotic use on their dairy farms. Interventions for farmers, delivered by a trusted source such as a veterinarian, that provide training about proper antibiotic use practices and information of possible financial benefits of refining antibiotic use may hold promise.

The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. Our work suggests that one of these, Disrupted In Renal Carcinoma 3 (DIRC3), may be a clinically important MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that activates expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in cancer associated processes and is needed for DIRC3 control of anchorage-independent growth. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets that can act not only as downstream mediators of MITF-SOX10 function but as feedback regulators of MITF-SOX10 activity.

PURPOSE: The purpose of this study was to report the rate of reactivation and structural outcome, after the laser or bevacizumab treatment for aggressive posterior retinopathy of prematurity (APROP). METHODS: Retrospective chart review was conducted on consecutive infants with APROP treated with (1) laser or (2) bevacizumab, followed by fluorescein angiography and prophylactic laser to the persistent avascular retina. RESULTS: Thirty-six eyes of 19 patients were included in this study. The mean gestational age was 24.5 weeks with a mean birth weight of 632 g in the bevacizumab group and 24.7 weeks and 777 g in the laser group. Unfavorable outcome occurred in 1 of 22 eyes treated with bevacizumab and in 5 of 14 eyes in the laser group (P = 0.002). Reactivation requiring treatment was common in both groups, 9/22 after bevacizumab and 6/14 after laser (ns). CONCLUSION: Regardless of the initial treatment reactivation requiring retreatment is common in eyes with APROP. The unfavorable structural outcome was significantly more common after initial laser treatment than after initial bevacizumab treatment.

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The possibility of using computer simulation and mathematical modeling to gain insight into biological and other complex systems is receiving increased attention. However, it is as yet unclear to what extent these techniques will provide useful biological insights or even what the best approach is. Epstein-Barr virus (EBV) provides a good candidate to address these issues. It persistently infects most humans and is associated with several important diseases. In addition, a detailed biological model has been developed that provides an intricate understanding of EBV infection in the naturally infected human host and accounts for most of the virus' diverse and peculiar properties. We have developed an agent-based computer model/simulation (PathSim, Pathogen Simulation) of this biological model. The simulation is performed on a virtual grid that represents the anatomy of the tonsils of the nasopharyngeal cavity (Waldeyer ring) and the peripheral circulation--the sites of EBV infection and persistence. The simulation is presented via a user friendly visual interface and reproduces quantitative and qualitative aspects of acute and persistent EBV infection. The simulation also had predictive power in validation experiments involving certain aspects of viral infection dynamics. Moreover, it allows us to identify switch points in the infection process that direct the disease course towards the end points of persistence, clearance, or death. Lastly, we were able to identify parameter sets that reproduced aspects of EBV-associated diseases. These investigations indicate that such simulations, combined with laboratory and clinical studies and animal models, will provide a powerful approach to investigating and controlling EBV infection, including the design of targeted anti-viral therapies.

Background: The mechanisms underlying the initiation of sustained ventricular tachycardia (VT) have not been fully elucidated. The extent to which reentry, abnormal automaticity, and triggered activity play a role in VT differs depending on the etiology of left ventricular dysfunction. By analyzing electrograms from implantable cardioverter defibrillator (ICD), we sought to determine whether there were differences in VT initiation patterns between patients with ischemic and nonischemic cardiomyopathy. Methods: We analyzed ICD electrograms in patients with ejection fractions < 40% who had sustained VT over a 27‐month period. The trigger for VT onset was classified as a ventricular premature beat (VPB), supraventricular tachycardia, or of “sudden onset.” The baseline cycle length, VT cycle length, coupling interval, and prematurity ratio were recorded for each event. The prematurity ratio was calculated as the coupling interval of the VT initiator divided by the baseline cycle length. Results: Sixty‐three VT events in 14 patients met the inclusion criteria. A VPB initiated the VT in 58 episodes (92%), 1 episode (2%) was initiated by a supraventricular tachycardia, and 4 episodes (6%) were sudden onset. The prematurity ratio was significantly higher (P < 0.05) in patients with ischemic cardiomyopathy (0.751 ± 0.068) as compared to patients with nonischemic cardiomyopathy (0.604 ± 0.139). Conclusion: VPBs initiated most sustained VT episodes. A significantly higher prematurity ratio was observed in the ischemic heart disease group. This may represent different mechanisms of VT initiation in patients with ischemic versus nonischemic heart disease.

This article describes an interesting case of automated implantable cardioverter defibrillator (AICD) extrusion fifteen months after implantation. The case report is followed by a discussion of the causes and treatment of skin erosion following pacemaker/AICD insertion.

Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T-cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them.

The following article presents an unusual case of atrial tachycardia, initially misdiagnosed due to a lack of clear P waves. The diagnosis was eventually confirmed using the atrial electrogram from the patients pacemaker.

We have performed the first extensive profiling of Epstein-Barr virus (EBV) miRNAs on in vivo derived normal and neoplastic infected tissues. We describe a unique pattern of viral miRNA expression by normal infected cells in vivo expressing restricted viral latency programs (germinal center: Latency II and memory B: Latency I/0). This includes the complete absence of 15 of the 34 miRNAs profiled. These consist of 12 BART miRNAs (including approximately half of Cluster 2) and 3 of the 4 BHRF1 miRNAs. All but 2 of these absent miRNAs become expressed during EBV driven growth (Latency III). Furthermore, EBV driven growth is accompanied by a 5-10 fold down regulation in the level of the BART miRNAs expressed in germinal center and memory B cells. Therefore, Latency III also expresses a unique pattern of viral miRNAs. We refer to the miRNAs that are specifically expressed in EBV driven growth as the Latency III associated miRNAs. In EBV associated tumors that employ Latency I or II (Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric carcinoma), the Latency III associated BART but not BHRF1 miRNAs are up regulated. Thus BART miRNA expression is deregulated in the EBV associated tumors. This is the first demonstration that Latency III specific genes (the Latency III associated BARTs) can be expressed in these tumors. The EBV associated tumors demonstrate very similar patterns of miRNA expression yet were readily distinguished when the expression data were analyzed either by heat-map/clustering or principal component analysis. Systematic analysis revealed that the information distinguishing the tumor types was redundant and distributed across all the miRNAs. This resembles "secret sharing" algorithms where information can be distributed among a large number of recipients in such a way that any combination of a small number of recipients is able to understand the message. Biologically, this may be a consequence of functional redundancy between the miRNAs.

To develop more detailed models of EBV persistence we have studied the dynamics of virus shedding in healthy carriers. We demonstrate that EBV shedding into saliva is continuous and rapid such that the virus level is replaced in < or =2 minutes, the average time that a normal individual swallows. Thus, the mouth is not a reservoir of virus but a conduit through which a continuous flow stream of virus passes in saliva. Consequently, virus is being shed at a much higher rate than previously thought, a level too high to be accounted for by replication in B cells in Waldeyer's ring alone. Virus shedding is relatively stable over short periods (hours-days) but varies through 3.5 to 5.5 logs over longer periods, a degree of variation that also cannot be accounted for solely by replication in B cells. This variation means, contrary to what is generally believed, that the definition of high and low shedder is not so much a function of variation between individuals but within individuals over time. The dynamics of shedding describe a process governing virus production that is occurring independently < or =3 times at any moment. This process grows exponentially and is then randomly terminated. We propose that these dynamics are best explained by a model where single B cells sporadically release virus that infects anywhere from 1 to 5 epithelial cells. This infection spreads at a constant exponential rate and is terminated randomly, resulting in infected plaques of epithelial cells ranging in size from 1 to 10(5) cells. At any one time there are a very small number (< or =3) of plaques. We suggest that the final size of these plaques is a function of the rate of infectious spread within the lymphoepithelium which may be governed by the structural complexity of the tissue but is ultimately limited by the immune response.

Lymphocytic gastritis (LG) is associated with helicobacter pylori (Hp) and celiac disease (CD). We aimed to clarify the relationship between Hp infection and CD by defining a unique histopathology profile of LG in these two diseases. Forty patients who underwent upper endoscopy were divided into four groups: eight controls, ten active CD patients without Hp, twelve CD negative with Hp, and ten active CD with Hp infection. Antral samples were assessed by immunohistochemical staining for CD20, CD3, CD4, CD8, CD57, CNA42, and Ki67 for lymphoid aggregates, intraepithelial lymphocytes (IELs) number, density of lamina propria (LP) lymphocytes, and inflammatory glandular involvement. Only IELs positive for CD3 and CD8 were increased significantly in CD patients with or without Hp infection. Hp did not contribute to the number of CD8 IELs. In complicated cases with Hp and suspicious for CD, the number of CD8+ IELs hints toward a CD rather than Hp infection.