Is prostacyclin responsible for producing the hyperdynamic response during early sepsis?

OBJECTIVE: Although polymicrobial sepsis is characterized by an early hyperdynamic phase (2-10 hrs after cecal ligation and puncture [CLP]), followed by a late hypodynamic phase (20 hrs after CLP), it remains unknown whether prostacyclin or prostaglandin I2 (PGI2) plays a significant role in modulating the hyperdynamic state during early sepsis. The aim of this study was to determine whether inhibition of PGI2 synthesis prevents the occurrence of the hyperdynamic response during early sepsis. DESIGN: Prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: Adult male Sprague-Dawley rats were subjected to sepsis by CLP. INTERVENTIONS AND MEASUREMENTS: Blood samples were collected at 2, 5, 10, or 20 hrs after CLP, and plasma concentrations of PGI2, in the form of its stable product 6-keto-PGF1alpha, were measured by radioimmunoassay. In additional studies, a PGI2 synthase inhibitor, tranylcypromine, was administered subcutaneously at the time of CLP and again at 3 hrs after CLP. At 5 hrs after the onset of sepsis, the maximal rates of the left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax) were determined by an in vivo heart performance analyzer. Microvascular blood flow in the liver, small intestine, and spleen was assessed by laser Doppler flowmetry. MAIN RESULTS: Plasma concentrations of 6-keto-PGF1alpha increased significantly at 2-20 hrs after CLP. At 5 hrs after the onset of sepsis, +/-dP/dt(max) and microvascular blood flow in the tested tissues increased significantly. Inhibition of PGI2 synthase activity did not prevent the occurrence of hypercardiovascular responses under such conditions. Moreover, the administration of tranylcypromine significantly reduced circulating concentrations of 6-keto-PGF1alpha at 5 hrs after CLP. CONCLUSIONS: Because inhibition of PGI2 production did not prevent the occurrence of the hyperdynamic and hypercardiovascular response during the early stage of sepsis, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions.     

Differential fluid regulation during and after soft tissue trauma and hemorrhagic shock in males and proestrus females

Gender differences in immune and organ functions have been described in different rodent models of trauma- and pressure-controlled hemorrhagic shock. We hypothesized that gender influences the regulation of plasma and tissue fluids in rats under such conditions. To study this we used male and weight matched proestrus female Sprague-Dawley rats, which were assigned to three groups (n = 7/group): sham, maximal bleedout (trauma and 45 min of blood pressure at 35 mmHg without resuscitation), or 5 h after completion of trauma-hemorrhage and resuscitation. Trauma-hemorrhage involved midline laparotomy and approx. 90 min of hemorrhagic shock (35 mmHg), followed by fluid resuscitation (4x the shed blood volume with Ringers lactate). (51)Cr-EDTA, (125)I-albumin distribution, and wet weight/dry weight were used to calculate plasma volume and extracellular fluid volume and cellular water content. Proestrus female rats showed significantly higher plasma volumes compared with weight-matched males. The volume of blood withdrawn in the first 15 min of hemorrhagic shock was significantly less in proestrus females compared with males; however, there was no significant difference in the total shed blood volume. Moreover, proestrus females showed less interstitial edema formation compared with male rats at 5 h after resuscitation. We conclude that differences in the regulation of plasma and tissue volumes exist between males and proestrus females during and after trauma-hemorrhage. The increased circulating blood volume could contribute the improved immune and organ functions in proestrus females under those conditions.     

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Purpose

Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May, 2017. The conference goal was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” (MQTiPSS), to enhance translational value of these models.

Methods

31 experts from 13 countries participated and were divided into 6 thematic Working Groups (WG): (1) Study Design, (2) Humane modeling, (3) Infection types, (4) Organ failure/dysfunction, (5) Fluid resuscitation and (6) Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002–2013).

Results

Overall, the participants reached consensus on 29 points; 20 at “recommendation” (R) and 9 at “consideration” (C) strength. This Executive Summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2 and 3).

Conclusions

We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as “best practices” that should be implemented for animal sepsis models. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.

     

Benign nerve sheath tumor of stomach

Gastrointestinal mesenchymal tumors are a group of tumors, which originate from the mesenchymal stem cells of the gastrointestinal tract. Gastric schwannoma is a very rare gastrointestinal mesenchymal tumor, which represents only 0.2% of all gastric tumors and 4% of all benign gastric neoplasms. We report a 55 years old lady who suffered from pain epigastrium, vomiting, occasionally with blood, loss of appetite and weight loss. Endoscopic examination showed a round submucosal tumor with a central ulceration along the greater curvature of the stomach. The pathological examination revealed a picture of spindle cell tumor. Immunohistochemical stain was strongly positive for S-100 protein stain, and non-reactive for CD34, CD117, consistent with benign nerve sheath tumor of stomach i.e. gastric schwannoma.     

Flutamide attenuates pro-inflammatory cytokine production and hepatic injury following trauma-hemorrhage via estrogen receptor-related pathway

OBJECTIVE: To determine the mechanism by which flutamide administration following trauma-hemorrhage (T-H) decreases cytokine production and hepatic injury under those conditions. SUMMARY BACKGROUND DATA: Although studies have demonstrated that flutamide administration following T-H improves hepatic and immune functions, the mechanism by which flutamide produces the salutary effects remains unknown. METHODS: Male Sprague-Dawley rats underwent a 5-cm laparotomy and hemorrhagic shock (40 mm Hg for approximately 90 minutes), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Flutamide (25 mg/kg body weight, sc) was administered at the middle of resuscitation and animals were killed 2 hours thereafter. To block estrogen receptor (ER), ER antagonist ICI 182,780 was administrated with flutamide. RESULTS: Hepatic injury, myeloperoxidase activity, nuclear factor-kappaB (NF-kappaB) DNA binding activity and protein expression of intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant (CINC-1 and CINC-3) markedly increased following T-H. Hepatic mRNA and plasma IL-6 levels were also elevated following T-H. The alterations in these parameters induced by T-H were significantly attenuated by flutamide administration. The decreased plasma estradiol levels following T-H were restored to sham levels in the flutamide-treated T-H animals. Coadministration of ICI 182,780 prevented those salutary effects of flutamide administration on pro-inflammatory responses and hepatic injury following T-H. CONCLUSION: These findings suggest that the reduction in the production of pro-inflammatory mediators and hepatic injury produced by flutamide administration following T-H is likely due to the down-regulation in hepatic NF-kappaB DNA binding activity. Moreover, the salutary effects of flutamide administration appear to be mediated at least in part via ER-related pathway.     

EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges

Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.     

Cystatin C and carotid intima-media thickness in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA)

BACKGROUND: Persons with early kidney disease have an increased risk of cardiovascular events and mortality, but the importance of accelerated atherosclerosis in promoting these outcomes is unclear. We therefore explored whether serum cystatin C level is associated with carotid intima-media thickness (IMT) in ambulatory adults without clinical heart disease. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: We evaluated 6,557 ethnically diverse persons free of clinical cardiovascular disease aged 45 to 84 years at the baseline visit of the Multi-Ethnic Study of Atherosclerosis. PREDICTORS: Kidney function was estimated by using 2 methods: serum cystatin C level and estimated glomerular filtration rate, based on creatinine and cystatin C levels. OUTCOMES & MEASUREMENTS: Study outcomes were internal and common carotid IMT, measured by using high-resolution B-mode ultrasound. Multivariate linear and logistic regressions were used to evaluate the independent association of kidney function with carotid IMT. RESULTS: In unadjusted linear analysis, each SD (0.23 mg/L) greater cystatin C level was associated with 0.091-mm greater internal carotid IMT (P < 0.001), but this association was diminished by 70% after adjustment for age, sex, and race/ethnicity (0.027 mm; P < 0.001) and was no longer significant after adjustment for cardiovascular risk factors (0.005 mm; P = 0.5). Similarly, the strong unadjusted associations of cystatin C level with common carotid IMT disappeared after adjustment. Chronic kidney disease, defined by using either creatinine level or cystatin C-based estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), had no independent association with internal and common carotid IMT. LIMITATIONS: There were few participants with severe kidney disease. CONCLUSIONS: Cystatin C level had no independent association with carotid IMT in a population free of clinical heart disease. This observation suggests that accelerated atherosclerosis is unlikely to be the primary mechanism explaining the independent association of cystatin C level with cardiovascular risk.