Baylor Research Institute

Wexler, O., M. S. Gough, M. A. Morgan, C. M. Mack, M. J. Apostolakos, K. P. Doolin, R. A. Mooney, E. Arning, T. Bottiglieri and A. P. Pietropaoli (2016). “Methionine metabolites in patients with sepsis.” J Intensive Care Med: 2016 Sep [Epub ahead of print].

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OBJECTIVE: Sepsis is characterized by microvascular dysfunction and thrombophilia. Several methionine metabolites may be relevant to this sepsis pathophysiology. S-adenosylmethionine (SAM) serves as the methyl donor for trans-methylation reactions. S-adenosylhomocysteine (SAH) is the by-product of these reactions and serves as the precursor to homocysteine. Relationships between plasma total homocysteine concentrations (tHcy) and vascular disease and thrombosis are firmly established. We hypothesized that SAM, SAH, and tHcy levels are elevated in patients with sepsis and associated with mortality. METHODS: This was a combined case-control and prospective cohort study consisting of 109 patients with sepsis and 50 control participants without acute illness. The study was conducted in the medical and surgical intensive care units of the University of Rochester Medical Center. Methionine, SAM, SAH, and tHcy concentrations were compared in patients with sepsis versus control participants and in sepsis survivors versus nonsurvivors. RESULTS: Patients with sepsis had significantly higher plasma SAM and SAH concentrations than control participants (SAM: 164 [107-227] vs73 [59-87 nM], P < .001; SAH: 99 [60-165] vs 35 [28-45] nM, P < .001). In contrast, plasma tHcy concentrations were lower in sepsis patients compared to healthy control participants (4 [2-6]) vs 7 [5-9] muM; P = .04). In multivariable analysis, quartiles of SAM, SAH, and tHcy were independently associated with sepsis (P = .006, P = .05, and P < .001, respectively). Sepsis nonsurvivors had significantly higher plasma SAM and SAH concentrations than survivors (SAM: 223 [125-260] vs 136 [96-187] nM; P = .01; SAH: 139 [81-197] vs 86 [55-130] nM, P = .006). Plasma tHcy levels were similar in survivors vs nonsurvivors. The associations between SAM or SAH and hospital mortality were no longer significant after adjusting for renal dysfunction. CONCLUSIONS: Methionine metabolite concentrations are abnormal in sepsis and linked with clinical outcomes. Further study is required to determine whether these abnormalities have pathophysiologic significance.

Tominaga, G. T., K. L. Staudenmayer, S. Shafi, K. M. Schuster, S. A. Savage, S. Ross, P. Muskat, N. T. Mowery, P. Miller, K. Inaba, M. J. Cohen, D. Ciesla, C. V. Brown, S. Agarwal, M. B. Aboutanos, G. H. Utter and M. Crandall (2016). “The american association for the surgery of trauma grading scale for 16 emergency general surgery conditions: Disease-specific criteria characterizing anatomic severity grading.” J Trauma Acute Care Surg 81(3): 593-602.

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The concepts for the EGS grading scales were modeled loosely from cancer staging criteria and trauma organ injury scales. For each of EGS diseases, the descriptions and grade were specifically defined using findings derived from four distinct categories: (1) clinical, (2) imaging, (3) operative, and (4) pathologic. These categories were selected to create the most holistic picture of the disease process. Furthermore, it was recognized that not all EGS conditions would require operative intervention, so the grading system could not rely solely on operative or pathologic findings. In cases where the grade differed between the four categories, the highest grade of EGS disease would apply. For example, if the computed tomography (CT) scan shows evidence of acute gangrenous appendicitis without perforation (Grade 2) but the pathologic findings are transmural necrosis with perforation (Grade 3), then the patient would be classified as Grade 3. Definitions were derived after examination of existing grading systems, review of the literature, and expert opinion. Previously reported scoring systems for these 16 EGS diseases were reviewed. No anatomic disease grading scales were found for breast abscess, intestinal obstruction, infectious colitis, pelvic inflammatory disease, and pleural space infections. Diagnostic imaging (CT, magnetic resonance imaging [MRI], ultrasound, endoscopic, nuclear medicine scan) descriptions based on disease severity have been published for acute cholecystitis,18–20 acute diverticulitis,9,10,21,22 esophageal perforation,23 acute pancreatitis,24–26 pelvic inflammatory disease,27 perforated peptic ulcer,28 and perirectal abscess.29 These were reviewed and incorporated into our data dictionary for these disease processes where applicable. Proposed EGS disease data dictionaries for each grade of disease were then carefully reviewed and revised until a consensus was achieved.

Jenkinson, E. M., M. P. Rodero, P. R. Kasher, C. Uggenti, A. Oojageer, L. C. Goosey, Y. Rose, C. J. Kershaw, J. E. Urquhart, S. G. Williams, S. S. Bhaskar, J. O’Sullivan, G. M. Baerlocher, M. Haubitz, G. Aubert, K. W. Baranano, A. J. Barnicoat, R. Battini, A. Berger, E. M. Blair, J. E. Brunstrom-Hernandez, J. A. Buckard, D. M. Cassiman, R. Caumes, D. M. Cordelli, L. M. De Waele, A. J. Fay, P. Ferreira, N. A. Fletcher, A. E. Fryer, H. Goel, C. A. Hemingway, M. Henneke, I. Hughes, R. J. Jefferson, R. Kumar, L. Lagae, P. G. Landrieu, C. M. Lourenco, T. J. Malpas, S. G. Mehta, I. Metz, S. Naidu, K. Ounap, A. Panzer, P. Prabhakar, G. Quaghebeur, R. Schiffmann, E. H. Sherr, K. R. Sinnathuray, C. Soh, H. S. Stewart, J. Stone, H. Van Esch, C. E. Van Mol, A. Vanderver, E. L. Wakeling, A. Whitney, G. D. Pavitt, S. Griffiths-Jones, G. I. Rice, P. Revy, M. S. van der Knaap, J. H. Livingston, R. T. O’Keefe and Y. J. Crow (2016). “Mutations in snord118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.” Nat Genet: 2016 Aug [Epub ahead of print].

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Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Agtarap, S., W. Scott, A. M. Warren and Z. Trost (2016). “Validation of the injustice experiences questionnaire in a heterogeneous trauma sample.” Rehabil Psychol: 2016 Jul [Epub ahead of print].

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PURPOSE/OBJECTIVE: A recent study by Trost et al. (2015) investigated the influence of perceived injustice-reflecting appraisals of the severity and irreparability of loss following injury, blame, and unfairness-on physical and psychological outcomes in a sample of patients 12 months after sustaining a traumatic injury. This brief report examines the psychometric properties of the Injustice Experiences Questionnaire (IEQ) using the previous sample from Trost et al. (2015) with added trauma patients (total N = 206). RESEARCH METHOD/DESIGN: Primary analyses included confirmatory and exploratory factor analyses to validate the measurement model of the IEQ in patients 12 months after traumatic injury. Reliability analyses were conducted and construct validity was assessed by examining associations between the IEQ and other pain-related, psychological, and health-related outcome variables of interest. RESULTS: Results replicated both one- and two-factor structures from past research, with a high factor correlation in confirmatory factor analyses and cross-loadings in exploratory factor analysis. Item characteristics analysis demonstrated overall strong internal consistency (alpha = .95). In addition, significant associations with psychosocial variables provide additional construct validity in regards to related outcomes. CONCLUSION/IMPLICATIONS: The IEQ shows strong psychometric properties and is suitable for use in a sample of diverse traumatic injury. However, results suggest the use of a one-factor model for the IEQ in this sample. Future trauma and rehabilitation research can use the IEQ to explore how injustice perceptions related to traumatic injury can prospectively influence physical and psychological outcomes.

Kathania, M., P. Khare, M. Zeng, B. Cantarel, H. Zhang, H. Ueno and K. Venuprasad (2016). “Itch inhibits il-17-mediated colon inflammation and tumorigenesis by ror-gammat ubiquitination.” Nat Immunol 17(8): 997-1004.

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Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and gammadelta T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-gammat and targeted ROR-gammat for ubiquitination. Inhibition or genetic inactivation of ROR-gammat attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch(-/-) mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.