Methicillin-Resistant Staphylococcus aureus Cellulitis Causing Meningitis From Hematogenous Dissemination: A Case Report.

Methicillin-resistant Staphylococcus aureus meningitis is commonly associated with surgical procedures that closely interact with the central nervous system; however, hematogenous spread via bacteremia is rarely reported. Here, we present a case of methicillin-resistant Staphylococcus aureus meningitis as a complication of a diabetic foot infection that disseminated into a bloodstream infection causing infective endocarditis, discitis, vertebral osteomyelitis, and meningitis that was successfully treated with intravenous daptomycin and rifampin.

Characterization of monoclonal gammopathy of undetermined significance progression to multiple myeloma through meta-analysis of GEO data.

The etiology of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is still obscure as are the processes that enable the progression of MGUS to MM. Understanding the unique vs. shared transcriptomes can potentially elucidate why individuals develop one or the other. Furthermore, highlighting key pathways and genes involved in the pathogenesis of MM or the development of MGUS to MM may allow the discovery of novel drug targets and therapies. We employed STARGEO platform to perform three separate meta-analysis to compare MGUS and MM transcriptomes. For these analyses we tagged (1) 101 MGUS patient plasma cells from bone marrow samples and 64 plasma cells from healthy controls (2) 383 MM patient CD138+ cells from bone marrow and the 101 MGUS samples in the first analysis as controls (3) 517 MM patient peripheral blood samples and 97 peripheral blood samples from healthy controls. We then utilized Ingenuity Pathway Analysis (IPA) to analyze the unique genomic signatures within and across these samples. Our study identified genes that may have unique roles in MGUS (GADD45RA and COMMD3), but also newly identified signaling pathways (EIF2, JAK/STAT, and MYC) and gene activity (NRG3, RBFOX2, and PARP15) in MGUS that have previously been shown to be involved in MM suggesting a spectrum of molecular overlap. On the other hand, genes such as DUSP4, RN14, LAMP5, differentially upregulated in MM, may be seen as tipping the scales from benignity to malignancy and could serve as drug targets or novel biomarkers for risk of progression. Furthermore, our analysis of MM identified newly associated gene/pathway activity such as inhibition of Wnt-signaling and defective B cell development. Finally, IPA analysis, suggests the multifactorial, oncogenic qualities of IFNγ signaling in MM may be a unifying pathway for these diverse mechanisms and prompts the need for further studies.

Evaluation of a single-use disk stack centrifuge for improved efficiency and sustainability at 1000 L GMP manufacturing scale.

Direct depth filtration is an established technology for single-use harvest operation. Advantages of direct depth filtration include familiarity with depth filtration in downstream processes and simplicity of the operation. Drawbacks include low capacity, large footprint, labor-intensive set-up, high water use, and high waste in the form of discarded filters. Single-use centrifugation is emerging as an alternative to depth filtration for the single-use harvest step. Within the single-use centrifugation space, disc stack centrifugation represents the newest entrant. In this study, we evaluated the performance of the GEA kytero single-use disc stack centrifuge to clarify two monoclonal antibody-producing cell culture fluids. The separation performance of the GEA kytero centrifuge varied between the two cell culture fluids, with differences in centrate turbidity and centrate filterability measured. A comparison was then performed to determine resource savings, compared to direct two-stage depth filtration, when using a GEA kytero centrifuge to harvest a 1000 L bioreactor. The analysis concluded that replacement of the first stage of depth filters with a GEA kytero centrifuge has the potential to decrease the required second stage depth filtration area by up to 80%. The decrease in depth filter area resulting from the use of the GEA kytero would result in a decrease in the harvest step footprint, a decrease in buffer volume required to prime and rinse depth filters, and a decrease in the volume of plastic waste. An economic comparison of the GEA kytero single-use centrifuge against a direct depth filtration step found that for a 1000 L harvest step, the GEA kytero centrifuge may reduce costs by up to 20% compared with two-stage direct depth filtration.

Probing predilection to Crohn's disease and Crohn's disease flares: A crowd-sourced bioinformatics approach.

Background: Crohn's Disease (CD) is an inflammatory disease of the gastrointestinal tract that affects millions of patients. While great strides have been made in treatment, namely in biologic therapy such as anti-TNF drugs, CD remains a significant health burden. Method: We conducted two meta-analyses using our STARGEO platform to tag samples from Gene Expression Omnibus. One analysis compares inactive colonic biopsies from CD patients to colonic biopsies from healthy patients as a control and the other compares colonic biopsies from active CD lesions to inactive lesions. Separate tags were created to tag colonic samples from inflamed biopsies (total of 65 samples) and quiescent tissue in CD patients (total of 39 samples), and healthy tissue from non-CD patients (total of 30 samples). Results from the two meta-analyses were analyzed using Ingenuity Pathway Analysis. Results: For the inactive CD vs healthy tissue analysis, we noted FXR/RXR and LXR/RXR activation, superpathway of citrulline metabolism, and atherosclerosis signaling as top canonical pathways. The top upstream regulators include genes implicated in innate immunity, such as TLR3 and HNRNPA2B1, and sterol regulation through SREBF2. In addition, the sterol regulator SREBF2, lipid metabolism was the top disease network identified in IPA (Fig. 1). Top upregulated genes hold implications in innate immunity (DUOX2, REG1A/1B/3A) and cellular transport and absorption (ABCG5, NPC1L1, FOLH1, and SLC6A14). Top downregulated genes largely held roles in cell adhesion and integrity, including claudin 8, PAQR5, and PRKACB.For the active vs inactive CD analysis, we found immune cell adhesion and diapedesis, hepatic fibrosis/hepatic stellate cell activation, LPS/IL-1 inhibition of RXR function, and atherosclerosis as top canonical pathways. Top upstream regulators included inflammatory mediators LPS, TNF, IL1B, and TGFB1. Top upregulated genes function in the immune response such as IL6, CXCL1, CXCR2, MMP1/7/12, and PTGS2. Downregulated genes dealt with cellular metabolism and transport such as CPO, RBP2, G6PC, PCK1, GSTA1, and MEP1B. Conclusion: Our results build off established and recently described research in the field of CD. We demonstrate the use of our user-friendly platform, STARGEO, in investigating disease and finding therapeutic avenues.

Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data.

BACKGROUND: Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment. AIM: To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets. METHODS: We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis. RESULTS: Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms. CONCLUSION: This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.

Transcriptome changes in stages of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a 'multiple hit' hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM: To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS: We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS: Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION: In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a cancer of epithelial origin with a high incidence in certain populations. While NPC has a high remission rate with concomitant chemoradiation, recurrences are frequent, and the downstream morbidity of treatment is significant. Thus, it is imperative to find alternative therapies. METHODS: We employed a Search Tag Analyze Resource (STARGEO) platform to conduct a meta-analysis using the National Center for Biotechnology's (NCBI) Gene Expression Omnibus (GEO) to define NPC pathogenesis. We identified 111 tumor samples and 43 healthy nasopharyngeal epithelium samples from NPC public patient data. We analyzed associated signatures in Ingenuity Pathway Analysis (IPA), restricting genes that showed statistical significance (p<0.05) and an absolute experimental log ratio greater than 0.15 between disease and control samples. RESULTS: Our meta-analysis identified activation of lipopolysaccharide (LPS)-induced tissue injury in NPC tissue. Additionally, interleukin-1 (IL-1) and SB203580 were the top upstream regulators. Tumorigenesis-related genes such as homeobox A10 (HOXA10) and prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) as well as those associated with extracellular matrix degradation, such as matrix metalloproteinases 1 and 3 (MMP-1, MMP-3) were also upregulated. Decreased expression of genes that encode proteins associated with maintaining healthy nasal respiratory epithelium structural integrity, including sentan-cilia apical structure protein (SNTN) and lactotransferrin (LTF) was documented. Importantly, we found that etanercept inhibits targets upregulated in NPC and LPS induction, such as MMP-1, PTGS2, and possibly MMP-3. CONCLUSIONS: Our analysis illustrates that nasal epithelial barrier dysregulation and maladaptive immune responses are key components of NPC pathogenesis along with LPS-induced tissue damage.

A merged microarray meta-dataset for transcriptionally profiling colorectal neoplasm formation and progression.

Transcriptional profiling of pre- and post-malignant colorectal cancer (CRC) lesions enable temporal monitoring of molecular events underlying neoplastic progression. However, the most widely used transcriptomic dataset for CRC, TCGA-COAD, is devoid of adenoma samples, which increases reliance on an assortment of disparate microarray studies and hinders consensus building. To address this, we developed a microarray meta-dataset comprising 231 healthy, 132 adenoma, and 342 CRC tissue samples from twelve independent studies. Utilizing a stringent analytic framework, select datasets were downloaded from the Gene Expression Omnibus, normalized by frozen robust multiarray averaging and subsequently merged. Batch effects were then identified and removed by empirical Bayes estimation (ComBat). Finally, the meta-dataset was filtered for low variant probes, enabling downstream differential expression as well as quantitative and functional validation through cross-platform correlation and enrichment analyses, respectively. Overall, our meta-dataset provides a robust tool for investigating colorectal adenoma formation and malignant transformation at the transcriptional level with a pipeline that is modular and readily adaptable for similar analyses in other cancer types.

Meta-Analysis Reveals the Prognostic Relevance of Nuclear and Membrane-Associated Bile Acid Receptors in Gastric Cancer.

INTRODUCTION: Bile acids (BAs) arising from duodenogastric reflux are known to facilitate gastric cancer (GC) development. Although BAs traditionally contribute to carcinogenesis through direct cellular cytotoxicity, increasing evidence implicates nuclear and membrane BA receptors (BARs) as additional factors influencing cancer risk. Indeed, some BARs are already linked with GC, but conflicting evidence and lack of information regarding other endogenous BARs warrant further investigation. In this study, we meta-analyzed multiple data sets to identify clinically relevant relationships between BAR expression and prognosis, clinicopathology, and activity in GC. METHODS: We collected transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas to analyze associations between BAR expression and GC prognosis, subtype, and clinicopathology. We also used Ingenuity Pathway Analysis to assess and predict functions, upstream regulators, and downstream mediators of membrane and nuclear BARs in GC. RESULTS: BARs showed differential distribution in GC; membrane BARs (G protein-coupled BAR 1, sphingosine-1-phosphate receptor 2, and cholinergic receptor muscarinic 2) were enriched in diffuse-, genome-stable, and mesenchymal-type tumors, whereas nuclear BARs (pregnane-X-receptor, constitutive androstane receptor, and farnesoid-X-receptor) were enriched in chromosome instability and metabolic subtypes. High expression of all membrane but not nuclear BARs was associated with poor prognosis and unfavorable GC clinicopathologic features. Similarly, expression patterns of membrane but not nuclear BARs varied geographically, aligning with Helicobacter pylori infection and GC mortality rates. Finally, GC-related oncogenes, namely transforming growth factor ß1, were associated with membrane BARs, whereas many metabolic-associated genes were associated with nuclear BARs. DISCUSSION: Through transcriptomic meta-analysis, we identified distinct expression profiles between nuclear and membrane BARs that demonstrate prognostic relevance and warrant further investigation.

Metaanalysis Reveals Genetic Correlates of Osteoporosis Pathogenesis.

OBJECTIVE: Osteoporosis is a growing healthcare burden. By identifying osteoporosis-promoting genetic variations, we can spotlight targets for new pharmacologic therapies that will improve patient outcomes. In this metaanalysis, we analyzed mesenchymal stem cell (MSC) biomarkers in patients with osteoporosis. METHODS: We employed our Search Tag Analyze Resource for the Gene Expression Omnibus (STARGEO) platform to conduct a metaanalysis to define osteoporosis pathogenesis. We compared 15 osteoporotic and 14 healthy control MSC samples. We then analyzed the genetic signature in Ingenuity Pathway Analysis. RESULTS: The top canonical pathways identified that were statistically significant included the serine peptidase inhibitor kazal type 1 pancreatic cancer pathway, calcium signaling, pancreatic adenocarcinoma signaling, axonal guidance signaling, and glutamate receptor signaling. Upstream regulators involved in this disease process included ESR1, dexamethasone, CTNNß1, CREB1, and ERBB2. CONCLUSION: Although there has been extensive research looking at the genetic basis for inflammatory arthritis, very little literature currently exists that has identified genetic pathways contributing to osteoporosis. Our study has identified several important genes involved in osteoporosis pathogenesis including ESR1, CTNNß1, CREB1, and ERBB2. ESR1 has been shown to have numerous polymorphisms, which may play a prominent role in osteoporosis. The Wnt pathway, which includes the CTNNß1 gene identified in our study, plays a prominent role in bone mass regulation. Wnt pathway polymorphisms can increase susceptibility to osteoporosis. Our analysis also suggests a potential mechanism for ERBB2 in osteoporosis through Semaphorin 4D (SEMA4D). Our metaanalysis identifies several genes and pathways that can be targeted to develop new anabolic drugs for osteoporosis treatment.

Investigating genetic drivers of dermatomyositis pathogenesis using meta-analysis.

AIMS: Dermatomyositis (DM) is a progressive, idiopathic inflammatory myopathy with poorly understood pathogenesis. A hallmark of DM is an increased risk for developing breast, ovarian, and lung cancer. Since autoantibodies against anti-TIF-1-γ, a member of the tripartite motif (TRIM) proteins, has a strong association with malignancy, we examined expression of the TRIM gene family to identify pathways that may be contributing to DM pathogenesis. MATERIALS AND METHODS: We employed the Search Tag Analyze Resource for GEO platform to search the NCBI Gene Expression Omnibus to elucidate TRIM family gene expression as well as oncogenic drivers in DM pathology. We conducted meta-analysis of the data from human skin (60 DM vs 34 healthy) and muscle (71 DM vs 22 healthy). KEY FINDINGS: We identified genes involved in innate immunity, antigen presentation, metabolism, and other cellular processes as facilitators of DM disease activity and confirmed previous observations regarding the presence of a robust interferon signature. Moreover, analysis of DM muscle samples revealed upregulation of TRIM14, TRIM22, TRIM25, TRIM27, and TRIM38. Likewise, analysis of DM skin samples showed upregulation of TRIM5, TRIM6, TRIM 14, TRIM21, TRIM34, and TRIM38 and downregulation of TRIM73. Additionally, we noted upregulation of oncogenes IGLC1, IFI44, POSTN, MYC, NPM1, and IDO1 and related this change to interferon signaling. While the clinical data associated with genetic data that was analyzed did not contain clinical data regarding malignancy in these cohorts, the observed genetic changes may be associated with homeostatic and signaling changes that relate to the increased risk in malignancy in DM. SIGNIFICANCE: Our results implicate previously unknown genes as potential drivers of DM pathology and suggest certain TRIM family members may have disease-specific roles with potential diagnostic and therapeutic implications.

The dietary peroxidized lipid, 13-HPODE, promotes intestinal inflammation by mediating granzyme B secretion from natural killer cells.

It is well known that consumption of a high-fat diet (HFD) promotes intestinal inflammation despite little being known about causative factors. Recent evidence implicates dietary peroxidized lipids (POLs), which are typically formed from the oxidation of polyunsaturated fatty acid double bonds, as potential contributors due to their enrichment in HFDs, ability to be formed during gastrointestinal transit, and immunogenic and cytotoxic properties. 13-HPODE, the most common dietary POL, demonstrates pro-inflammatory activity in a variety of immune cells, especially Natural Killer (NK) cells whose role in mediating intestinal inflammation remains unclear. Therefore, we set out to investigate how 13-HPODE and other POLs modulate NK-cell activity in the context of intestinal inflammation. We not only found that NK cells fully decompose exogenous 13-HPODE, but that direct treatment stimulates TNF-α and MCP1 expression as well as Granzyme B (GZMB) secretion in a dose-dependent manner. Similar results were observed upon incubation of NK cells with oxidized, but not-unoxidized, low-density lipoproteins. Secretory products from 13-HPODE-treated NK cells were able to induce Caco2 intestinal cell inflammation in the same way as exogenous GZMB with greater sensitivity in undifferentiated compared to differentiated cells. Results were recapitulated in 13-HPODE-fed mice, demonstrating both spatial and temporal patterns of elevated GZMB expression that favored acute treatments in the distal intestinal epithelium. Collectively, our results suggest that that HFD-derived POLs, like 13-HPODE, potentially contribute to intestinal inflammation by stimulating the secretion of pro-inflammatory granzymes by resident NK cells, ultimately revealing a more direct role for diet in modulating gut homeostasis and the immune environment.

Are Fried Foods Unhealthy? The Dietary Peroxidized Fatty Acid, 13-HPODE, Induces Intestinal Inflammation In Vitro and In Vivo.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder characterized by progressive inflammation and the erosion of the gut mucosa. Although the exact cause of IBD is unknown, multiple factors contribute to its complex pathogenesis. Diet is one such factor and a strong correlation exists between the western-style, high fat diets (HFDs) and IBD incidence rates. In this study, we propose that the peroxidized fatty acid components of HFDs could contribute to inflammation of the gut. The inflammatory nature of peroxidized linoleic acid (13-HPODE), was confirmed in vitro by analyzing pro-inflammatory gene expression in Caco-2 cells via RT-PCR and ELISA. Additionally, peroxide induced apoptosis was tested by Annexin-V fluorescent staining, while permeability was tested by FITC-dextran flux and TEER. The 13-HPODE-induced inflammation of intestinal epithelium was evaluated in vivo by analyzing pro-inflammatory cytokines under acute and chronic conditions after feeding 13-HPODE to C57BL/6J mice. Our data show that 13-HPODE significantly induced pro-inflammatory gene expression of TNF-α and MCP-1 in vitro, most notably in differentiated Caco-2 cells. Further, acute and chronic 13-HPODE treatments of mice similarly induced pro-inflammatory cytokine expression in the epithelium of both the proximal and distal small intestines, resident immune cells in Peyer's patches and peritoneal macrophages. The results of this study not only confirm the pro-inflammatory properties of peroxidized fats on the gut mucosa, but for the first time demonstrate their ability to differentially induce pro-inflammatory gene expression and influence permeability in the intestinal epithelium and mucosal cells. Collectively, our results suggest that the immunogenic properties of HFD's in the gut may be partly caused by peroxide derivatives, providing potential insight into how these diets contribute to exacerbations of IBD.

Negative Effects of a High-Fat Diet on Intestinal Permeability: A Review.

The intestinal tract is the largest barrier between a person and the environment. In this role, the intestinal tract is responsible not only for absorbing essential dietary nutrients, but also for protecting the host from a variety of ingested toxins and microbes. The intestinal barrier system is composed of a mucus layer, intestinal epithelial cells (IECs), tight junctions (TJs), immune cells, and a gut microbiota, which are all susceptible to external factors such as dietary fats. When components of this barrier system are disrupted, intestinal permeability to luminal contents increases, which is implicated in intestinal pathologies such as inflammatory bowel disease, necrotizing enterocolitis, and celiac disease. Currently, there is mounting evidence that consumption of excess dietary fats can enhance intestinal permeability differentially. For example, dietary fat modulates the expression and distribution of TJs, stimulates a shift to barrier-disrupting hydrophobic bile acids, and even induces IEC oxidative stress and apoptosis. In addition, a high-fat diet (HFD) enhances intestinal permeability directly by stimulating proinflammatory signaling cascades and indirectly via increasing barrier-disrupting cytokines [TNFα, interleukin (IL) 1B, IL6, and interferon γ (IFNγ)] and decreasing barrier-forming cytokines (IL10, IL17, and IL22). Finally, an HFD negatively modulates the intestinal mucus composition and enriches the gut microflora with barrier-disrupting species. Although further research is necessary to understand the precise role HFDs play in intestinal permeability, current data suggest a stronger link between diet and intestinal disease than was first thought to exist. Therefore, this review seeks to highlight the various ways an HFD disrupts the gut barrier system and its many implications in human health.

Proinflammatory Properties of Peroxidized Fat May Contribute to the Etiology of Crohn's Disease.

Crohn's disease (CD) is a well-known subset of inflammatory bowel disease (IBD) that results in patchy inflammation through the entire thickness of the bowel wall, with the ability to target virtually any part of the gastrointestinal tract, but most commonly affecting the area between the ileum and the cecum. While a bacterial origin of Crohn's is well speculated, it is difficult to pinpoint what drives inflammation in these subjects, particularly the flare-ups or the sudden symptomatic intensification or recurrence. This review aims at tracing the etiology of CD back to diet, particularly fried foods, a known aggravator of symptoms. Based on the reactions that frying entails, the chemical composition of the food is altered in ways that can lead to maldigestion and inflammation. Current evidence suggests a direct dietary role in the inflammation underlying CD or the flare-ups. The presented review focuses on an underresearched, yet, very applicable topic. We suggest that emphasis should be put on dietary alteration as a means of treatment for patients with CD to supplement current therapy for optimal results. With the widespread popularity of fried foods, it is important to raise awareness about the potential negative outcomes that are prevalent worldwide.

Inflammatory Diseases of the Gut.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract whose prevalence has been dramatically increasing over the past decade. New studies have shown that IBD is the second most common chronic inflammatory disease worldwide after rheumatoid arthritis, affecting millions of people mainly in industrialized countries. Symptoms of IBD include frequent bloody diarrhea, abdominal cramping, anorexia, abdominal distension, and emesis. Although the exact etiology is unknown, it has been postulated that immunological, microbial, environmental, nutritional, and genetic factors contribute to the pathogenesis and severity of IBD. Today, no treatment has consistently been shown to be successful in treating IBD. This review summarizes current research on the epidemiology, etiology, pathophysiology, and existing treatment approaches, including pharmaceutical and nutritional options for IBD.

Dual kidney transplantation: a case-control comparison with single kidney transplantation from standard and expanded criteria donors.

BACKGROUND: The purpose of this study was to perform a case-matched cohort analysis of dual kidney transplantation (DKT) from expanded criteria donors (ECDs) compared to single kidney transplantation (SKT) from concurrent ECDs and standard criteria donors (SCDs, defined as non-ECD). METHODS: Deceased donor (DD) kidney transplants (KTs) performed at a single center between October 2001 and February 2006 were reviewed retrospectively. If the calculated DD creatinine clearance (CrCl) was <65 mL/min, then the kidneys were transplanted dually into a single patient. In the case of DKT and SKT from ECDs, low risk patients were chosen and informed consent was obtained. Patients in each group were matched for age, gender, race, transplant number, and time of transplant. RESULTS: Of 294 adult DD KTs performed, 16 (5%) were DKTs, which were matched with 16 concurrent SCD and 16 ECD SKT patients. Mean donor age in years (65 DKT vs. 33 SCD vs. 61 ECD; P<0.0001) and mean donor CrCl in ml/min (54 DKT vs. 91 SCD vs. 76 ECD; P=0.002) were different between groups. Patient survival was 100% in the DKT and SCD SKT groups and 94% in the ECD SKT group (mean follow up 23-28 months); graft survival rates in the DKT, SCD, and ECD groups were 81%, 81%, and 94%, respectively (P=NS). Graft function, rejection, and morbidity were similar between groups. CONCLUSIONS: DKT using kidneys from marginal ECDs is a viable option to counteract the growing shortage of available organs. Excellent short-term results and renal function can be achieved with older, low nephron mass donors provided that both kidneys are transplanted into a single recipient.

Experience with dual kidney transplants from donors at the extremes of age.

BACKGROUND: Dual kidney transplantation (DKT) from donors at the extremes of age represents one approach to expanding the organ donor pool. The purpose of this study was to review our experience with DKT from older donors and en bloc KT (EBKT) from small pediatric donors. METHODS: Deceased donor KTs performed at our center between October 2001 and November 2005, were reviewed retrospectively. If the calculated creatinine clearance in an expanded criteria donor was <65 mL/min, then the kidneys were transplanted dually into a single adult recipient. If a pediatric donor weighed <15 kg, then the kidneys were transplanted en bloc. In both instances, low-risk recipients were chosen (primary transplant, low sensitization, body mass index <25 kg/m(2), human leukocyte antigen matching). Donor, recipient, and transplant characteristics, waiting time, and outcomes were examined. RESULTS: Of a total of 279 deceased donor KTs during the 49-month study period, 15 (5%) recipients underwent DKT and 5 (2%) underwent EBKT. Mean donor age was 65.4 years and 21.4 months in the DKT and EBKT groups, respectively. Patient survival rates in both groups were 100% with a mean follow-up of 22 months (minimum, 6 months). Kidney graft survival rates were 80% (12/15) and 60% (3/5) in the DKT and EBKT groups, respectively. The combined incidence of delayed graft function was 10%. Mean 12-month glomerular filtration rates were 46 mL/min and 66 mL/min in the DKT and EBKT groups, respectively. CONCLUSIONS: DKT using kidneys from marginal elderly donors and EBKT from small pediatric donors appear to offer a viable option to counteract the shortage of acceptable kidney donors.

Intermediate-term outcomes with expanded criteria deceased donors in kidney transplantation: a spectrum or specter of quality?

OBJECTIVE: To compare intermediate-term outcomes in adult recipients of expanded criteria (ECD) versus concurrent standard criteria (SCD) deceased donor kidney transplants at a single center using a standardized approach. SUMMARY BACKGROUND DATA: Expanded criteria donors (ECDs) are a source of kidneys that increase the donor organ pool, but the value of transplanting these kidneys has been questioned because of concerns regarding diminished survival and predicted poorer intermediate-term outcomes. METHODS: Over a 47-month period, we performed 244 deceased donor kidney transplants into adult recipients, including 143 from SCDs and 101 from ECDs. Management algorithms were implemented to preserve nephron function, and recipient selection for an ECD kidney transplant was based on low immunologic risk. All patients received depleting antibody induction in combination with tacrolimus and mycophenolate mofetil. A total of 188 patients (77%) had at least a 1-year follow-up. RESULTS: ECDs were older, had a higher BMI, had an increased incidence of cerebrovascular brain death and preexisting donor hypertension, and had a lower estimated creatinine clearance (CrCl, all P < 0.01) compared with SCDs. Cold ischemic times were similar between groups, but more ECD kidneys were preserved with pulsatile perfusion (P < 0.01). ECD kidney recipients were older, less sensitized, had a lower BMI, had fewer 0-antigen mismatches, and had a shorter waiting time (all P < 0.01) compared with SCD kidney recipients. Actual patient (93%) and kidney graft (83%) survival rates were similar between groups with a mean follow-up of 24 months. The rates of delayed graft function (DGF), acute rejection, readmissions, operative complications, major infections, and resource utilization were comparable between groups. Renal function followed longitudinally was consistently better in SCD patients (P < 0.05). Black recipients had higher rates of DGF, acute rejection, and graft loss (P < 0.05), but the effects were less pronounced in the ECD group. CONCLUSIONS: By appropriate donor and recipient profiling and the use of management algorithms to project and protect renal function, excellent intermediate-term outcomes can be achieved with ECD kidney transplants that are comparable to SCD kidney transplants.