NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice.

The interleukin-1 family members, IL-1ß and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1ß processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

Tissue-nonspecific alkaline phosphatase is an anti-inflammatory nucleotidase.

Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/- mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/- mice had significantly increased levels of Il-1ß and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 µM of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1ß, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.

Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND: The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA). METHODS: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR. RESULT: A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA. CONCLUSION: DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.

Planned ventral hernia following damage control laparotomy in trauma: an added year of recovery but equal long-term outcome.

PURPOSE: Significantly injured trauma patients commonly require damage control laparotomy (DCL). These patients undergo either primary fascial closure during the index hospitalization or are discharged with a planned ventral hernia. Hospital and long-term outcomes of these patients have not been extensively studied. METHODS: Patients who underwent DCL for trauma from 2003 to 2012 at a regional Level I trauma center were identified and a comparison was made between those who had primary fascial closure and planned ventral hernia. RESULTS: DCL was performed in 154 patients, 47% of whom sustained penetrating injuries. The mean age and injury severity score (ISS) were 40 and 25, respectively. Hospital mortality was 19%. Primary fascial closure was performed in 115 (75%) of those undergoing DCL during the index hospitalization. Of these, 11 (9%) had reopening of the fascia. Of the surviving patients, 22 (19%) never had primary fascial closure and were discharged with a planned ventral hernia. Patients with primary fascial closure and those with planned ventral hernia were similar in age, gender, ISS, and mechanism. Those with planned ventral hernias underwent more subsequent laparotomies (3.0 vs. 1.3, p < 0.001), and had more enteric fistulas (18.2 vs. 4.3%, p = 0.041) and intra-abdominal infections (46 vs. 15%, p = 0.007), and had a greater number of hospital days (38 vs. 25, p = 0.007) during the index hospitalization. Sixteen (73%) patients with a planned ventral hernia had definitive reconstruction (mean days = 266). Once definitive abdominal wall closure was achieved, the two groups achieved similar rates of return to work and usual activity (71 vs. 70%, p = NS). CONCLUSIONS: Following DCL for trauma, patients with a planned ventral hernia have definitive reconstruction nearly 9 months after the initial injury. Once definitive abdominal wall closure has been achieved; patients with primary fascial closure and those with planned ventral hernia have similar rates of return to usual activity.

Evaluation and management of blunt traumatic aortic injury: a practice management guideline from the Eastern Association for the Surgery of Trauma

BACKGROUND: Blunt traumatic aortic injury (BTAI) is the second most common cause of death in trauma patients. Eighty percent of patients with BTAI will die before reaching a trauma center. The issues of how to diagnose, treat, and manage BTAI were first addressed by the Eastern Association for the Surgery of Trauma (EAST) in the practice management guidelines on this topic published in 2000. Since that time, there have been advances in the management of BTAI. As a result, the EAST guidelines committee decided to develop updated guidelines for this topic using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework recently adopted by EAST. METHODS: A systematic review of the MEDLINE database using PubMed was performed. The search retrieved English language articles regarding BTAI from 1998 to 2013. Letters to the editor, case reports, book chapters, and review articles were excluded. Topics of investigation included imaging to diagnose BTAI, type of operative repair, and timing of operative repair. RESULTS: Sixty articles were identified. Of these, 51 articles were selected to construct the guidelines. CONCLUSION: There have been changes in practice since the publication of the previous guidelines in 2000. Computed tomography of the chest with intravenous contrast is strongly recommended to diagnose clinically significant BTAI. Endovascular repair is strongly recommended for patients without contraindications. Delayed repair of BTAI is suggested, with the stipulation that effective blood pressure control must be used in these patients.(AU)

Management of pituitary incidentalomas. A survey of British and American endocrinologists.

The results of a survey of endocrinologists concerning their approaches to the evaluation of a patient with an incidentally discovered pituitary mass are presented in this article. The practices of British and American endocrinologists are compared. The wide variation in diagnostic approaches to the practice of ordering tests in the United Kingdom and the United States highlights the need for research and debate regarding the most appropriate management of patients with such findings.

Attitudes of faculty, housestaff, and medical students toward clinical practice guidelines.

PURPOSE: To examine attitudes of faculty, housestaff, and medical students toward clinical practice guidelines. METHOD: In a 1997 cross-sectional survey, a two-part, 26-item, self-administered questionnaire was mailed to all faculty, housestaff, and medical students in the department of internal medicine at Case Western Reserve University School of Medicine. The questionnaire asked for demographic information and attitudes toward clinical guidelines. RESULTS: Of 379 persons surveyed, 254 (67%) returned usable questionnaires: 56% of the medical students, 70% of the housestaff, and 73% of the full-time faculty. Medical students reported learning about guidelines predominantly during clerkships in internal medicine (71%) and pediatrics (68%). Overall, the respondents agreed most strongly that guidelines are "useful for the care of common problems," and least strongly that guidelines are "difficult to apply to individual patients" and "reduce physician options in patient care." Faculty were more likely to consider guidelines a "good educational tool" and less likely than were medical students and housestaff to agree that they promote "cookbook medicine." Of 11 influences on clinical decision making, the three groups together rated practice guidelines eighth or ninth. The use of guidelines for academic investigations was rated most appropriate, overall. In terms of their appropriateness, faculty consistently rated the use of guidelines more favorably except for use in malpractice suits. CONCLUSION: Faculty, housestaff, and medical students have significantly different perceptions of and attitudes toward clinical practice guidelines. Further studies are needed to explain the reasons for these differences. Considerable education and involvement must occur at all levels for practice guidelines to be successfully implemented and understood.

The effect of prophylactic nifedipine on renal function in patients administered contrast media.

STUDY OBJECTIVE: To determine if prophylaxis with nifedipine could decrease the frequency of contrast medium-induced renal impairment. DESIGN: Prospective, randomized clinical trial. SETTING: A university-affiliated hospital. PATIENTS: Patients undergoing scheduled radiologic examinations involving infusion of contrast media. INTERVENTIONS: Forty-two patients were randomized to receive nifedipine 10 mg orally 1 hour before the imaging procedure, and 43 to receive no treatment. MEASUREMENTS AND MAIN RESULTS: Baseline serum creatinine levels were compared with maximum levels 24 and 48 hours after administration of contrast medium. No statistically significant difference was seen in either the mean change or mean percentage change in serum creatinine between the control and nifedipine groups. The mean changes in serum creatinine were +7.4 mumol/L in the control group and +2.7 mumol/L in the nifedipine group (p = 0.33); the mean percentage changes were +10.2% and +4.8%, respectively (p = 0.54). CONCLUSION: Regardless of statistical analysis, it is unlikely that elevations in serum creatinine of this magnitude (< 0.1 mg/dl) are of clinical significance. We therefore conclude that prophylactic nifedipine is not clinically beneficial in preserving renal function in patients receiving contrast medium and that the agent should not be routinely administered for this purpose.

Sclerotherapy for malignant pleural effusions: alternatives to tetracycline.

Malignant pleural effusion (MPE) causes significant morbidity in cancer patients. Management is often challenging because of the recurrent nature of MPE and the inconsistent response rates of various treatments. In patients whose underlying malignancy is unresponsive to systemic chemotherapy or radiation, MPE is usually managed by tube thoracostomy with subsequent sclerotherapy. Selection of a sclerosing agent should be based on several factors, including efficacy, toxicity, cost, and convenience. Of the numerous agents available for managing MPE, doxycycline, bleomycin, and talc have emerged as the most promising. Even these agents have disadvantages, such as the high cost of bleomycin and the possible need for multiple dosing of doxycycline. Talc is clearly the most controversial of the three. Although its efficacy is well documented, its role remains unclear because of its unattractive side effect profile and inconvenient preparation and administration. Results of controlled comparative trials are needed to identify the optimal sclerosing agent.

Oral azole drugs as systemic antifungal therapy.

The oral azole drugs--ketoconazole, fluconazole, and itraconazole--represent a major advance in systemic antifungal therapy. Among the three, fluconazole has the most attractive pharmacologic profile, including the capacity to produce high concentrations of active drug in cerebrospinal fluid and urine. Ketoconazole, the first oral azole to be introduced, is less well tolerated than either fluconazole or itraconazole and is associated with more clinically important toxic effects, including hepatitis and inhibition of steroid hormone synthesis. However, ketoconazole is less expensive than fluconazole and itraconazole--an especially important consideration for patients receiving long-term therapy. All three drugs are effective alternatives to amphotericin B and flucytosine as therapy for selected systemic mycoses. Ketoconazole and itraconazole are effective in patients with the chronic, indolent forms of the endemic mycoses, including blastomycosis, coccidioidomycosis, and histoplasmosis; itraconazole is also effective in patients with sporotrichosis. Fluconazole is useful in the common forms of fungal meningitis--namely, coccidioidal and cryptococcal meningitis. In addition, fluconazole is effective for selected patients with serious candida syndromes such as candidemia, and itraconazole is the most effective of the azoles for the treatment of aspergillosis.

Secondary dyslipidemia. Inadvertent effects of drugs in clinical practice.

OBJECTIVE: To examine the available literature on commonly prescribed drugs and their effects on blood lipid and lipoprotein levels. DATA SOURCES: The review was based on searches of English-language articles from 1975 to 1990 by Medlars II and MEDLINE programs, the Index Medicus for 1980 to 1990, and references from identified articles. Relevant journals published within the last 6 months were also examined. STUDY SELECTION: More than 500 articles were identified for inclusion. Articles were selected on the basis of appropriateness of design to demonstrate significant results, determined by consensus when necessary. DATA EXTRACTION: Studies were classified according to type (observational or interventional), length of follow-up, and type of controls. Quanitative analysis of lipid, lipoprotein, and apoprotein changes induced by drugs was computed as the percentage of change observed during the course of the study (interventional) or compared with the controls at a given time (observational). DATA SYNTHESIS: Steroid hormones that have strong progestogenic and androgenic properties, retinoids, cyclosporine A, and phenothiazines are potentially atherogenic. Steroid hormones with dominant estrogenic properties, several anticonvulsants, biguanides, high-dose ketoconazole, and aminosalicylic acid are potentially antiatherogenic. Corticosteroids appear to elevate all the lipoprotein cholesterol levels. Oral estrogens, retinoids, and corticosteroids also can elevate triglyceride levels. Other drugs with questionable effects on lipoprotein metabolism are reviewed. CONCLUSION: Although the long-term implications of drug-induced lipoprotein changes are still undefined, physicians need to consider these effects in clinical practice.