Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1-3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK'547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

Significance of Postprocedural Contrast Medium Injection after CT-Guided Abscess Drainage.

The aim was to evaluate the additive clinical value of an additional post-procedural control-scan after CT-guided percutaneous abscess drainage (PAD) placement with contrast medium (CM) via the newly placed drain. All CT-guided PADs during a 33-month period were retrospectively analyzed. We analyzed two subgroups, containing patients with and without surgery before intervention. Additionally, radiological records were reevaluated, concerning severe inflammatory response syndrome (SIRS) during the intervention. A total of 499 drainages were placed under CT-guidance in 352 patients. A total of 197 drainages were flushed with CM directly after the intervention, and 51 (26%) showed an additional significant finding. An immediate change of therapy was found in 19 cases (9%). The subgroup that underwent surgery (120 CM-drainages; 32 (27%) additional findings; 13 (11%) immediate changes of therapy) showed no statistically significant difference compared to the subgroup without surgery (77 CM-drainages; 19 (25%) additional findings; 5 (6%) immediate changes of therapy). SIRS occurred in 2 of the 197 flushed drainages (1%) after CM application. An additional scan with CM injection via the newly placed drain revealed clinically significant additional information in almost 26% of the drainages reviewed in this study. In 9% of the cases this information led to an immediate change of therapy. Risks for SIRS are low.

Longitudinally extensive transverse myelitis as a sign of multisystem inflammatory syndrome following COVID-19 infection: A pediatric case report.

COVID-19 infection can cause inflammatory reactions that could involve several organs. In the pediatric population, Multi-System Inflammatory Syndrome in Children (MIS-C) has been reported as one of the consequences of COVID-19. We report a unique pediatric COVID-19 patient with MIS-C, associated with paralysis of the extremities. MRI showed abnormal signal in the cervical spinal cord compatible with transverse myelitis. Methylprednisolone and IVIG were administered, without significant symptom improvement. As a next step, Infliximab was tried for her, and she responded remarkably well to this treatment. Infliximab may be considered as a treatment option in COVID-19 patients with transverse myelitis.

Cryptococcal Meningitis and Post-Infectious Inflammatory Response Syndrome in a Patient With X-Linked Hyper IgM Syndrome: A Case Report and Review of the Literature.

The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of Cryptococcus neoformans in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.

Neuroimaging findings associated with the fetal inflammatory response syndrome.

The fetal inflammatory response syndrome (FIRS) is a condition whereby the fetus mounts an inflammatory response to intrauterine infection/inflammation. Clinical consequences include preterm premature rupture of membranes (PPROM), spontaneous preterm delivery, neonatal sepsis, bronchopulmonary dysplasia, and brain and other organ injury. Mechanisms leading to brain injury in FIRS have been investigated in animal and human studies. We review the neuroimaging findings of brain injury in FIRS, which overlap those of hypoxic-ischemic injury, and clinical correlation is necessary for a correct diagnosis. FIRS should be considered the primary diagnosis when neuroimaging findings such as periventricular leukomalacia are identified in preterm children born as a consequence of PPROM and spontaneous preterm labor. Additionally, FIRS should be considered in term infants who do not have the most common features of HIE (e.g. a sentinel event). Systematic histopathologic examination of the placenta and umbilical cord and/or detection of characteristic inflammatory markers in such cases are needed to establish the correct diagnosis.

The effect of systemic inflammation indexes and 18FDG PET metabolic parameters on survival in advanced lung adenocarcinoma.

OBJECTIVE: To determine the effect of systemic inflammation indexes and fluorine-18 fluorodeoxyglucose (18FDG) positron emission tomography (PET) metabolic parameters on survival in advanced lung adenocarcinoma. METHODS: A total of 133 patients who underwent 18FDG PET for initial staging were investigated retrospectively. Baseline patient characteristics, routine blood test results, 18FDG PET metabolic parameters, and treatment history were examined. Overall survival (OS) was demonstrated by Kaplan-Meier analysis, and the curves were compared by the log-rank test. Systemic inflammation response index (SIRI) was defined as neutrophil x monocyte/lymphocyte count. RESULTS: Lymphocyte/monocyte ratio (LMR) and SIRI were found to be significant for OS. The cutoff point was 2.25 for LMR. Median OS was 8 months for ⩽2.25 and 14 months for >2.25 (p = 0.005). For SIRI, the cutoff point was 2. SIRI ⩽2 was associated with a median OS of 16 months compared to 10 months for patients with SIRI >2 (p = 0.043). Maximum of standardized uptake value, total lesion glycolysis, and metabolic tumor volume were not found to be significant for OS (p = 0.225, p = 0.061, p = 0.355, respectively). No correlation was found between inflammatory indexes and PET metabolic parameters. CONCLUSION: Age and LMR parameters were prognostic for survival in Cox regression analysis. There was no correlation between 18FDG PET parameters and inflammatory indexes.

The Relationship Between 18F-FDG Uptake on PET/CT and Markers of Systemic Inflammatory Response in Patients Undergoing Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND/AIM: This study evaluated the prognostic relationship between tumor 18F-fluorodeoxyglucose (FDG) uptake on positron-emission tomography (PET)/computed tomography (CT) imaging and markers of systemic inflammatory response (SIR) in patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Between 2002 and 2016, 94 patients with ICC who underwent 18F-FDG-PET scans before surgery were analyzed. 18F-FDG uptake was quantified as a maximum standardized uptake value (SUVmax). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) were selected as SIR markers. RESULTS: There was no strong correlation between SUVmax and, NLR, PLR and CRP (all Pearson's |r| <0.40). Multivariate Cox regression analyses identified high tumor SUVmax (≥8) and high NLR (≥5) as independent predictors of poor overall survival (p=0.013 and p=0.002) and disease-free survival (p<0.001 and p=0.004). CONCLUSION: Prognostic information provided by tumor SUVmax and SIR markers may be independent prognostic factors in patients undergoing surgery for ICC.

Noninvasive Whole-Body Imaging of Phosphatidylethanolamine as a Cell Death Marker Using 99mTc-Duramycin During TNF-Induced SIRS.

Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body. It is associated with the presence of pro- and antiinflammatory cytokines in serum, including tumor necrosis factor (TNF). TNF has multiple effects and leads to cytokine production, leukocyte infiltration, and blood pressure reduction and coagulation, thereby contributing to tissue damage and organ failure. A sterile mouse model of sepsis, TNF-induced SIRS, was used to visualize the temporal and spatial distribution of damage in susceptible tissues during SIRS. For this, a radiopharmaceutical agent, 99mTc-duramycin, that binds to exposed phosphatidylethanolamine on dying cells was longitudinally visualized using SPECT/CT imaging. Methods: C57BL/6J mice were challenged with intravenous injections of murine TNF or vehicle, and necrostatin-1 was used to interfere with cell death. Two hours after vehicle or TNF treatment, mice received 99mTc-duramycin intravenously (35.44 ± 3.80 MBq). Static whole-body 99mTc-duramycin SPECT/CT imaging was performed 2, 4, and 6 h after tracer injection. Tracer uptake in different organs was quantified by volume-of-interest analysis using PMOD software and expressed as SUVmean After the last scan, ex vivo biodistribution was performed to validate the SPECT imaging data. Lastly, terminal deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed to correlate the obtained results to cell death. Results: An increased 99mTc-duramycin uptake was detected in mice injected with TNF, when compared with control mice, in lungs (0.55 ± 0.1 vs. 0.34 ± 0.05), intestine (0.75 ± 0.13 vs. 0.56 ± 0.1), and liver (1.03 ± 0.14 vs. 0.64 ± 0.04) 4 h after TNF and remained significantly elevated until 8 h after TNF. The imaging results were consistent with ex vivo γ-counting results. Significantly increased levels of tissue damage were detected via TUNEL staining in the lungs and intestine of mice injected with TNF. Interestingly, necrostatin-1 pretreatment conferred protection against lethal SIRS and reduced the 99mTc-duramycin uptake in the lungs 8 h after TNF (SUV, 0.32 ± 0.1 vs. 0.51 ± 0.15). Conclusion: This study demonstrated that noninvasive 99mTc-duramycin SPECT imaging can be used to characterize temporal and spatial kinetics of injury and cell death in susceptible tissues during TNF-induced SIRS, making it useful for global, whole-body assessment of tissue damage during diseases associated with inflammation and injury.

Integrating MRI and Chemokine Receptor CXCR4-Targeted PET for Detection of Leukocyte Infiltration in Complicated Urinary Tract Infections After Kidney Transplantation.

Complicated urinary tract infections (UTIs) are frequent in immunosuppressed patients after kidney transplantation and may lead to allograft failure or urosepsis. Noninvasive detection of allograft involvement as well as localization of the primary site of infection are challenging. Therefore, we sought to determine whether molecularly targeted PET, combined with diffusion-weighted MRI, enables detection of leukocytes in renal allografts. Methods: Thirteen kidney transplant recipients with complicated UTIs underwent both PET with a specific CXCR4 ligand, 68Ga-pentixafor, and diffusion-weighted MRI. The spatial distribution and intensity of CXCR4 upregulation in renal allografts as determined by SUVs on PET and diffusion restriction as determined by apparent diffusion coefficients (ADCs) on MRI were analyzed and compared with urinalysis, clinical chemistry and bacteriology, and biopsy, if available. Results: Combined PET/MRI detected acute allograft infection in 9 patients and lower UTI/nonurologic infections in the remaining 4 patients. Leukocyte infiltration was identified by areas of CXCR4 upregulation compared with unaffected parenchyma in PET (SUVmean, 4.6 vs. 3.7; P < 0.01), corresponding to areas with increased cell density in MRI (ADCmin, 0.89 vs. 1.59 × 10-3 mm2/s, P < 0.01). Allograft CXCR4 signal was paralleled by CXCR4 upregulation in lymphoid organs. Histopathologic evaluation supported a correlation between CXCR4 signal and presence of leukocytes. Conclusion: Combined CXCR4-targeted PET/MRI with 68Ga-pentixafor may enable the noninvasive detection of leukocytes in renal allografts. This novel methodology may refine the characterization of infectious and inflammatory kidney diseases and may serve as a platform for future clinical studies targeting allograft infection.

Routine surveillance cholangiography after percutaneous cholecystostomy delays drain removal and cholecystectomy.

INTRODUCTION: Percutaneous cholecystostomy (PC) is often performed for patients with acute cholecystitis who are at high risk for operative morbidity and mortality. However, the necessity for routine cholangiography after PC remains unclear. We hypothesized that routine surveillance cholangiography (RSC) after PC would provide no benefit compared to on-demand cholangiography (ODC) triggered by signs or symptoms of biliary pathology. METHODS: We performed a 3-year retrospective cohort analysis of patients managed with PC for acute cholecystitis at two tertiary care hospitals. Patients who had routine surveillance cholangiography (RSC, n = 43) were compared to patients who had on-demand cholangiography (ODC, n = 41) triggered by recurrent biliary disease. RESULTS: RSC and ODC groups were similar by severity of acute cholecystitis, presence of gallstones, systemic inflammatory response syndrome (SIRS) criteria at the time of PC, SIRS criteria 72 hours after PC, and hospital length of stay. Two patients in the ODC group developed clinical indications for cholangiography. All 44 RSC patients had cholangiography, and 67 total cholangiograms were performed in this group. Surveillance cholangiography identified six patients (14%) with cystic duct filling defect and seven patients (16%) with a common bile duct filling defect, all of whom were asymptomatic. Fifteen patients (35%) in the RSC group had 32 ERCP procedures; five patients (12%) in the ODC group had 7 ERCPs (p = 0.021). The ODC group had fewer days to drain removal (35 vs. 61, p < 0.001) and days to cholecystectomy (39 vs. 81, p = 0.005). Rates of recurrent cholecystitis, cholangitis, gallstone pancreatitis, drain removal, and cholecystectomy were similar between groups. CONCLUSION: RSC after PC for acute cholecystitis identified biliary pathology in asymptomatic patients and propagated further testing, but did not provide clinical benefit. ODC was associated with earlier drain removal, earlier cholecystectomy, and decreased resource utilization. LEVEL OF EVIDENCE: Prognostic study, level III; therapeutic study, level IV.

[Assessment of oxygen status in critical patients with systemic inflammatory reaction].

Diagnostic ability of alveolar-arterial oxygen gradient (A-aDO2 and respiratory index (RI) for acute respiratory distress syndrome was underestimated before recent time. 68 patients with severe inhomogeneous lung injure (severe concomitant trauma, pneumonia, and pancreonecrosis) were involved in the study. Patients were divided into two groups (basic group--34 patients and control group--34 patients). There were no differences in data of severity-of-disease by APACHE II and SOFA scales and J.F. Murrey lung injury score in both groups. Conventional volume controlled and pressure control respiratory techniques were used in patients of control group. Multi-level ventilation with three levels was used in patients of basic group. Blood gas containing, A-aDO2 and RI were studied. Gas status data improved both to gas exchange efficacy in patients of basic group. The data were significant different in the control group. Thus multilevel ventilation improves alveolar ventilation and arterial oxygenation, decreases pulmonary shunt and lung injury and improves respiratory lung functions.

Diagnostic coronary angiography is related to decreased TNF-alpha production after ex-vivo whole blood stimulation with LPS.

BACKGROUND: Several studies showed serum markers elevation as a result to coronary angiography. We investigated the effect of diagnostic coronary angiography (DCA) on the development of systemic inflammatory response syndrome (SIRS) and on whole blood cytokine production capacity after ex-vivo LPS stimulation. METHODS: In this observational study, clinical characteristics and serum cytokines of the patients were recorded at baseline and at 2, 6, 12, and 24h after DCA. Peripheral blood was collected at baseline and at 2, and 24h for complete blood count, coagulation profile and ex-vivo (100 microl) stimulation with LPS (500 pg) for subsequent cytokine measurement. Values are expressed as median+/-IQR and were compared using Wilcoxon's signed rank test with Bonferroni adjustment. RESULTS: We included 23 male patients (mean age 52.0+/-18.0 years) undergoing DCA. None of the patients developed clinical or laboratory signs of SIRS. Serum IL-6 significantly increased at 12h. There was a significant decrease in TNF-alpha production after ex-vivo LPS stimulation of whole blood at 2 and 24h compared to baseline (median+/-IQR; 716.0+/-319.0; 576.0+/-715.0 vs. 1154+/-844.0 pg/ml; respectively) suggesting that DCA may cause transient endotoxin tolerance. CONCLUSIONS: DCA is related to increased serum IL-6 levels but does not cause clinical SIRS. Development of SIRS after DCA is indicative of other in origin complication. DCA is associated with immune cells hyporesponsiveness, possibly through monocyte depression, expressed as decreased TNF-alpha production after whole blood stimulation with LPS ex vivo.

Echocardiography in the critically ill: current and potential roles.

BACKGROUND: The use of echocardiography in the critically ill presents specific challenges. However, information of direct relevance to clinical management can be obtained relating to abnormalities of structure and function and can be used to estimate pulmonary arterial and venous pressures. DISCUSSION: Investigation of the consequences of myocardial ischaemia, valvular dysfunction and pericardial disease can be facilitated, and changes characteristic of specific conditions (e.g. sepsis, pulmonary thromboembolism) detected. Echocardiography can also be used to monitor the effects of therapeutic interventions. CONCLUSIONS: The applications of echocardiography in the critical care setting (excluding standard peri-operative echocardiography for cardiac surgery) are reviewed, with particular emphasis on the assessment of cardiac physiology.

How safe is the port access technique in minimally invasive coronary artery bypass grafting?

BACKGROUND: This study compares conventional coronary artery bypass grafting (CABG) with port access CABG via a left anterior small thoracotomy in patients requiring surgical multivessel revascularization. Clinical, neuropsychological, and angiographic outcomes were studied, as well as parameters of myocardial and cerebral protection. Pathogenicity of cardiopulmonary bypass (CPB) was further evaluated by measuring parameters of peripheral limb ischemia and inflammatory whole-body response. METHODS: In a prospective randomized study, 40 patients who required multivessel CABG were assigned to either conventional CABG via complete median sternotomy (group A) or port access CABG via minithoracotomy (group B). Control angiograms were performed in group B only. In addition, patients underwent neuropsychological testing after the operation. CK, CK-MB, and Troponin T levels were documented. S-100B protein and neuron-specific enolase (NSE) served to quantify cerebral injury. The terminal complement complex (C5b-9) and myeloperoxidase concentrations were determined to analyze inflammatory whole-body response after CPB. RESULTS: There was no mortality. One patient suffered a retrograde aortic dissection immediately after onset of CPB, but had an uneventful postoperative course after surgical repair. Troponin T and CK-MB showed no difference between groups. CK and myoglobin were significantly higher in the minimally invasive cohort. Changes in complement activation (C5b-9) and myeloperoxidase during CPB markers of the whole-body inflammatory response were similar in both groups. S-100B concentrations in the port access group were significantly higher, whereas NSE levels were similar in both groups. Both groups did not display any significant difference in neuropsychological testing. CONCLUSIONS: Minimally invasive multivessel CABG via minithoracotomy using port access technology is feasible and safe. Though prolonged operating and CPB times with significantly higher S-100B concentrations were observed in group B, equivalent myocardial and cerebral protection and similar whole-body inflammatory response were documented.

Evaluation of transesophageal echocardiography as a diagnostic and therapeutic aid in a critical care setting.

OBJECTIVES: To assess the impact of transesophageal echocardiography (TEE) on therapeutic management in relation to pulmonary artery catheterization (PAC) in the ICU. DESIGN: Retrospective analysis of 108 consecutive TEE video and related patient files during a 7-month period. SETTING: A 33-bed medical and surgical ICU. METHODS: All critically ill patients with or without PAC in whom a TEE was performed, excluding postoperative cardiac surgical patients. Patients were divided in a cardiac and a septic group depending on the primary disease on admission to the ICU. The impact of TEE in relation to PAC on ICU management was evaluated in whether therapy changes were performed strictly on the basis of the TEE findings. MAIN RESULTS: Of 64% of patients with a PAC, 44% underwent therapy changes after TEE: 41% in the cardiac and 54% in the septic subgroup. In 41% of patients without a PAC, TEE led to a change in therapy. CONCLUSIONS: TEE results in altered therapeutic management in at least one third of our (noncardiac surgery) ICU patient population independent of the presence of a PAC.