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The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system. [ABSTRACT FROM AUTHOR]

Background: In vitro studies indicate that the Fy blood group system antigens serve as receptors for chemokines such as monocyte chemotactic protein-1 (MCP-1) and RANTES. However, it is unclear whether subjects with the Fy(a-b-) phenotype exhibit altered clearance and hence altered plasma levels of chemo-kines, because they still express Fy on endothelial cells.Study Design and Methods: To clarify a possible in vivo role of Fy on RBCs in the regulation of chemo-kine levels, healthy young volunteers of common Fy phenotypes were compared in a cross-sectional study.Results: More than 90 percent of the 34 subjects of African origin were Fy(a-b-), one black volunteer was Fy(a+b-), and two were Fy(a-b+). As expected, all 65 white volunteers were positive for either Fy(a) and/or Fy(b). Unexpectedly, persons expressing either Fy(a) and/or Fy(b) had significantly higher plasma levels of MCP-1 than Fy(a-b-) volunteers (women: 154 vs. 110 ng/L, p<0.01; men: 179 vs. 169 ng/L, p = 0.03). Surprisingly, plasma levels of MCP-1 were found to be sex-dependent: median MCP-1 levels averaged 180 ng per L in men but only 139 ng per L in women (p<0.001). Further, MCP-1 levels decreased significantly throughout the menstrual cycle of 18 women studied longitudinally.Conclusion: MCP-1 levels are about 30 percent higher in men than in premenopausal women, and MCP-1 levels are also higher in persons with RBCs expressing Fy antigens than in Fy(a-b-) persons. These findings have direct implications for the concept and interpretation of clinical studies measuring MCP-1 levels; the role of the observed differences in MCP-1 levels for the pathogenesis of MCP-1-dependent diseases, such as atherosclerosis, merits further investigation. [ABSTRACT FROM AUTHOR]

Surgical management of carotid stenosis has evolved from open carotid endarterectomy (CEA) to include multiple alternative procedures including transfemoral carotid artery stenting (tfCAS) and transcarotid artery stenting. In recent years, Transcarotid Artery Revascularization (TCAR) has emerged as a third option, combining open cut down to the common carotid artery (CCA) with endovascular stenting and neuroprotection via reversal of cerebral blood flow. In this case series, a modified TCAR procedure using a prosthetic conduit was successfully performed exclusively under local anesthesia in a total of 10 patients with carotid artery stenosis, high cardiac risk, and anatomical contraindications to a traditional TCAR., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients., Objectives: The aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers., Methods: Eight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry., Results: Bolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants., Conclusion: In conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity., (© 2024 The Author(s).)

Introduction: Management of pediatric cancer patients involves invasive procedures such as punctures, injections, catheter placements, and chemotherapy which can generate fatigue, nausea, vomiting, anxiety, and pain. Virtual Reality (VR) is a nonpharmacological intervention classified as a cognitive-behavioral method to relieve symptoms., Methods: We designed a crossover protocol and included 20 patients between 9 and 12 years old; ten were male. All patients had acute lymphoblastic leukemia diagnosis and were treatedwith St. Jude's XV protocol in the maintenance phase. Pain and anxiety were measured with validated scales in the pediatric population., Results: Although we used a small group of patients, we found statistical difference in the reduction of anxiety and perception of time., Discussion: These results open a window to non-pharmacological treatments and show a strategy to improve quality of life in children inside the hospital., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Velasco-Hidalgo, González-Garay, Segura-Pacheco, Esparza-Silva, Cuéllar Mendoza, Ochoa-Drucker, Campos-Ugalde, Bernabé-Gaspar and Zapata-Tarrés.)

Background: Telecommunicator CPR (T-CPR), whereby emergency dispatch facilitates cardiac arrest recognition and coaches CPR over the telephone, is an important strategy to increase early recognition and bystander CPR in adult out-of-hospital cardiac arrest (OHCA). Little is known about this treatment strategy in the pediatric population. We investigated the role of T-CPR and related performance among pediatric OHCA., Methods and Results: This study was a retrospective cohort investigation of OHCA among individuals <18 years in King County, Washington, from April 1, 2013, to December 31, 2019. We reviewed the 911 audio recordings to determine if and how bystander CPR was delivered (unassisted or T-CPR), key time intervals in recognition of arrest, and key components of T-CPR delivery. Of the 185 eligible pediatric OHCAs, 23% (n=43) had bystander CPR initiated unassisted, 59% (n=109) required T-CPR, and 18% (n=33) did not receive CPR before emergency medical services arrival. Among all cases, cardiac arrest was recognized by the telecommunicator in 89% (n=165). Among those receiving T-CPR, the median (interquartile range) interval from start of call to OHCA recognition was 59 seconds (38-87) and first CPR intervention was 115 seconds (94-162). When stratified by age (≤8 versus >8), the older age group was less likely to receive CPR before emergency medical services arrival (88% versus 69%, P =0.002). For those receiving T-CPR, bystanders spent a median of 207 seconds (133-270) performing CPR. The median compression rate was 93 per minute (82-107) among those receiving T-CPR., Conclusions: T-CPR is an important strategy to increase early recognition and early CPR among pediatric OHCA.

Background: Despite advances in techniques and care, major amputation bears a high risk for mortality. Previously identified factors associated with increased risk of mortality include amputation level, renal function, and pre-operative white cell count., Methods: A single center retrospective chart review was conducted identifying patients who had undergone a major amputation. Chi-squared, t-testing, and Cox proportional hazard modeling were performed examining death at 6 months and 12 months., Results: Factors associated with an increased risk of six-month mortality include age (OR 1.01-1.05, P < .001), sex (OR 1.08-3.24, P < .01), minority race (OR 1.18-18.19, P < .01), chronic kidney disease (OR 1.40-6.06, P < .001), and use of pressors at the induction of anesthesia for index amputation (OR 2.09-7.85, P < .000). Factors associated with increased risk of 12 month mortality were similar., Discussion: Patients undergoing major amputation continue to suffer high mortality. Those patients who received their amputation under physiologically stressful conditions were more likely to die within 6 months. Reliably predicting six-month mortality can assist surgeons and patients in making appropriate care decisions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Drug overdose (OD) is a public health challenge and an important cause of out-of-hospital cardiac arrest (OHCA). Existing studies evaluating OD-related OHCA (OD-OHCA) either aggregate all drugs or focus on opioids. The epidemiology, presentation, and outcomes of drug-specific OHCA are largely unknown., Objective: To evaluate the temporal pattern, clinical presentation, care, and outcomes of adult patients with OHCA overall and according to the drug-specific profile., Design, Setting, and Participants: This cohort study of adults with OHCA in King County Washington was conducted between January 1, 2015, and December 31, 2021. Etiology of OHCA was determined using emergency medical service, hospital, and medical examiner records. Etiology was classified as non-OD OHCA or OD-OHCA, with drug-specific profiles categorized as (1) opioid without stimulant, (2) stimulant without opioid, (3) opioid and stimulant, or (4) all other nonstimulant, nonopioid drugs. Statistical analysis was performed on July 1, 2023., Exposure: Out-of-hospital cardiac arrest., Main Outcomes and Measures: The primary outcome was survival to hospital discharge. The secondary outcome was survival with favorable functional status defined by Cerebral Performance Category 1 or 2 based on review of the hospital record., Results: In this cohort study, there were 6790 adult patients with emergency medical services-treated OHCA from a US metropolitan system. During the 7-year study period, there were 702 patients with OD-OHCA (median age, 41 years [IQR, 29-53 years]; 64% male [n = 450] and 36% female [n = 252]) and 6088 patients with non-OD OHCA (median age, 66 years [IQR, 56-77 years]; 65% male [n = 3944] and 35% female [n = 2144]). The incidence of OD-OHCA increased from 5.2 (95% CI, 3.8-6.6) per 100 000 person-years in 2015 to 13.0 (95% CI, 10.9-15.1) per 100 000 person-years in 2021 (P < .001 for trend), whereas there was no significant temporal change in the incidence of non-OD OHCA (P = .30). OD-OHCA were more likely to be unwitnessed (66% [460 of 702] vs 41% [2515 of 6088]) and less likely to be shockable (8% [56 of 702] vs 25% [1529 of 6088]) compared with non-OD OHCA. Unadjusted survival was not different (20% [138 of 702] for OD vs 18% [1095 of 6088] for non-OD). When stratified by drug profile, combined opioid-stimulant OHCA demonstrated the greatest relative increase in incidence. Presentation and outcomes differed by drug profile. Patients with stimulant-only OHCA were more likely to have a shockable rhythm (24% [31 of 129]) compared with patients with opioid-only OHCA (4% [11 of 295]) or patients with combined stimulant-opioid OHCA 5% [10 of 205]), and they were more likely to have a witnessed arrest (50% [64 of 129]) compared with patients with OHCA due to other drugs (19% [14 of 73]) or patients with combined stimulant-opioid OHCA (23% [48 of 205]). Patients with a combined opioid-stimulant OHCA had the lowest survival to hospital discharge (10% [21 of 205]) compared with patients with stimulant-only OHCA (22% [29 of 129]) or patients with OHCA due to other drugs (26% [19 of 73]), a difference that persisted after multivariable adjustment., Conclusions and Relevance: In a population-based cohort study, the incidence of OD-OHCA increased significantly from 2015 to 2021, with the greatest increase observed among patients with a combined stimulant-opioid OHCA. Presentation and outcome differed according to the drug-specific profile. The combination of increasing incidence and lower survival among among patients with a opioid-stimulant OHCA supports prevention and treatment initiatives that consider the drug-specific profile.

Introduction: Targeted false lumen management has been described for complex presentations of aortic dissection. The "Knickerbocker" technique is often referenced and includes dilating a focal portion of an oversized endograft in the true lumen to purposefully rupture the false lumen septum, but at the expense of increased risk for visceral propagation and malperfusion. This case series describes a novel modification of the Knickerbocker technique by caging the distal end of the endograft prior to focal dilation., Methods: A retrospective chart review was conducted at a tertiary academic center from 2018-2020. Patients were included if they had a history or current presentation of aortic dissection and underwent a Caged Knickerbocker (CKB) repair. Data were collected to include demographics, indications for repair, technical success, perioperative outcomes, hospital course, mortality, and further aortic interventions., Results: Five patients were included in our evaluation. Four patients (80%) presented with chronic Type B aortic dissection (cTBAD) and concomitant aneurysmal degeneration of the thoracic aorta; 1 patient (20%) presented with an acute rupture secondary to cTBAD. Three patients (60%) had previous aortic repairs, 2 of which were for Type A Aortic Dissection that additionally required redo sternotomy and total arch replacement prior to CKB. CKB was technically successful in all cases with no peri-operative complications. Two (40%) patients required further aortic intervention due to aneurysmal degeneration., Conclusion: Achieving complete false lumen thrombosis is a considerable challenge when managing complex aortic dissections. Our data demonstrate the technical feasibly and early successful outcomes with the CKB approach. Importantly, CKB facilitates future distal extension into the para-visceral aorta in cases of complex thoracoabdominal aortic aneurysms. Further research should focus on discerning individual patients who will benefit from targeted false lumen management and compare outcomes between different approaches.

Importance: Epinephrine improves return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA). These beneficial cardiac effects do not directly translate to better neurologic outcomes, possibly because of epinephrine-induced microvascular effects that produce critical brain ischemia., Objective: To examine whether targeted temperature management (TTM) modifies the adverse association between increasing prehospital epinephrine dose and neurologically favorable survival., Design, Setting, and Participants: This retrospective cohort study assessed 14 612 adults from Seattle and King County, Washington, with nontraumatic OHCA between January 1, 2008, and December 31, 2018, and included those who achieved return of spontaneous circulation and were unconscious at hospital admission. Data analysis was performed from April 2021 to May 2022., Exposures: Epinephrine dose and TTM during prehospital resuscitation., Main Outcomes and Measures: Favorable neurologic survival (Cerebral Performance Category [CPC] 1 or 2) and survival to hospital discharge., Results: Of the 14 612 assessed adults, 5253 (median age, 63 years; IQR, 51-74 years; 3460 [65.8%] male) were eligible for the study. The median epinephrine dose was 2.0 mg (IQR, 1.0-3.0 mg); 3052 patients (58.1%) received TTM. In all, 1889 patients (36.0%) survived with CPC 1 to 2, and 2177 (41.4%) survived to discharge. Increasing doses of epinephrine were associated with a decreasing likelihood of CPC 1 to 2 (odds ratio [OR], 0.46; 95% CI 0.42-0.50 for each additional milligram of epinephrine) and survival (OR, 0.47; 95% CI, 0.43-0.51). The dose-dependent epinephrine association was modified by TTM. After adjusting for Utstein covariates, TTM was associated with a relative stepwise improvement in odds of CPC 1 to 2 (interaction OR, 1.36; 95% CI, 1.22-1.51) and survival (interaction OR, 1.37; 95% CI, 1.24-1.51). A significant interaction was also observed when the analysis was stratified according to initial rhythm among shockable OHCA and nonshockable OHCA (shockable interaction OR, 1.20; 95% CI, 1.04-1.39; and nonshockable interaction OR, 1.24, 95% CI, 1.07-1.45)., Conclusions and Relevance: This cohort study found an interaction between TTM and epinephrine dose such that the beneficial association of TTM increased with increasing epinephrine dose, suggesting that TTM may attenuate the adverse effects of higher-dose epinephrine.

Background Air travel affords an opportunity to evaluate resuscitation performance and outcome in a setting where automated external defibrillators (AEDs) are readily available. Methods and Results The study cohort included people aged ≥18 years with out of hospital cardiac arrest (OHCA) traveling through Seattle-Tacoma International Airport between January 1, 2004 and December 31, 2019 treated by emergency medical services (EMS). The primary outcomes were pre-EMS therapies (cardiopulmonary resuscitation, application of AED), return of spontaneous circulation, and survival to hospital discharge. Over the 16-year study period, there were 143 OHCA occurring before EMS arrival, 34 (24%) on-plane and 109 (76%) off-plane. Cardiac etiology (81%) was the most common mechanism of arrest. The majority of arrests were bystander-witnessed and presented with a shockable rhythm; these characteristics were more common in off-plane OHCA compared with on-plane (witnessed: 89% versus 74% and shockable: 72% versus 50%). Pre-EMS therapies including cardiopulmonary resuscitation and AED application were common regardless of arrest location. Compared with on-plane OHCA, off-plane OHCA was associated with greater rates of return of spontaneous circulation (68% versus 44%) and 3-fold higher rate of survival to hospital discharge (44% versus 15%). All survivors of on-plane OHCA had AED application with defibrillation before EMS arrival. Conclusions When applied to air travel volumes, we estimate 350 air travel-associated OHCA occur in the United States and 2000 OHCA worldwide each year, nearly a quarter of which happen on-plane. These events are survivable when early arrest interventions including rapid arrest recognition, AED application, and CPR are deployed.

We investigated the risk of coronavirus disease (COVID-19)- patients transmitting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to emergency medical service (EMS) providers, stratified by aerosol-generating procedures (AGP), in King County, Washington, USA, during February 16-July 31, 2020. We conducted a retrospective cohort investigation using a statewide COVID-19 registry and identified 1,115 encounters, 182 with ≥1 AGP. Overall, COVID-19 incidence among EMS personnel was 0.57 infections/10,000 person-days. Incidence per 10,000 person-days did not differ whether or not infection was attributed to a COVID-19 patient encounter (0.28 vs. 0.59; p>0.05). The 1 case attributed to a COVID-19 patient encounter occurred within an at-risk period and involved an AGP. We observed a very low risk for COVID-19 infection attributable to patient encounters among EMS first responders, supporting clinical strategies that maintain established practices for treating patients in emergency conditions.

Background: Out-of-hospital cardiac arrest (OHCA) causes brain injury. Functional status of survivors at hospital discharge is a core resuscitation measure, frequently using the Cerebral Performance Category (CPC) or modified Rankin Scale (mRS). Which scale better predicts long-term survival following OHCA is not known., Methods: We evaluated long-term survival after hospital discharge in a retrospective cohort of persons resuscitated from OHCA in King County, WA from 2007 to 2015. Patients were independently assessed at discharge using both scales, leveraging the regional quality improvement registry, which records the 5-level CPC, and concurrent research studies involving the Resuscitation Outcomes Consortium, which used the 7-level mRS, taken from information in the hospital record. The risk of mortality associated with CPC and mRS categories was estimated using Kaplan-Meier survival analysis and Cox proportional hazards regression., Results: Among 878 eligible patients discharged alive, there were 358 deaths during 9118.5 person-years of follow-up. Overall 1, 5 and 10-year survival was 84.4%, 68.5%, and 53.7% and varied according to CPC and mRS (p < 0.01 per Kaplan-Meier). Compared to CPC-1, hazard ratio (HR) increased incrementally for CPC-2 = 1.33 (1.03-1.73), CPC-3 = 1.90 (1.37-2.65), and CPC-4 = 8.25 (5.63-12.10). Compared to mRS = 0, HR for mRS-1 = 1.02 (0.66-1.58), mRS-2 = 1.52 (1.00-2.32), mRS-3 = 1.41 (0.92-2.14), mRS-4 = 2.00 (1.37-2.97), and mRS-5 = 4.90 (3.23-7.44)., Conclusion: In OHCA survivors, CPC and mRS scales both predicted long-term survival. However mRS 0-1 and 2-3 groups did not have distinct prognoses, suggesting that a consolidated mRS score may simplify capture of relevant prognostic information for survival predictions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Fasciotomy with resection of nonviable muscle is often necessary when there is a delay in compartment syndrome (CS) diagnosis after revascularization. The reported rate of major amputation following missed CS or delayed fasciotomy ranges from 12% to 35%. Herein, the authors present a series of critically ill patients who experienced delayed CS diagnosis and required complete resection of the anterior and/or lateral compartments but still achieved limb salvage and function., Methods: A retrospective chart review identified five patients from April 2018 to April 2019 within a single institution who met the inclusion criteria. Patient charts were reviewed for demographic data, risk factors, time to diagnosis following revascularization, muscle compartments resected, operative and wound care details, and functional outcome at follow-up., Results: All of the patients developed CS of the lower extremity following revascularization secondary to acute limb ischemia and required two-incision, four-compartment fasciotomies. Further, they all required serial operative debridements to achieve limb salvage; however, there were no major amputations, and all of the patients were walking at follow-up., Conclusions: Delay in CS diagnosis can have devastating consequences, resulting in major amputation. In cases where myonecrosis is isolated to two or fewer compartments, complete compartment muscle resection can be safely performed, and limb preservation and function can be maintained with aggressive wound management and physical therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Emergency Medical Services (EMS) are often involved in end-of-life circumstances, yet little is known about how EMS interfaces with advance directives to forego unwanted resuscitation (Do Not Attempt Resuscitation (DNAR)). We evaluated the frequency of these directives involved in out-of-hospital cardiac arrest (OHCA) and how they impact care., Methods: We conducted a cohort investigation of adult, EMS-attended OHCA from January 1 to December 31, 2018 in King County, WA. DNAR status was ascertained from dispatch, EMS, and hospital records. Resuscitation was classified according to DNAR status: not initiated, initiated but ceased due to the DNAR, or full efforts., Results: Of 3152 EMS-attended OHCA, 314 (9.9%) had a DNAR directive. DNAR was present more often among those for whom EMS did not attempt resuscitation compared to when EMS provided some resuscitation (13.2% [212/1611] vs 6.6% [101/1541], (p < 0.05). Of those receiving resuscitation with a DNAR directive (n = 101), the DNAR was presented on average 6 min following EMS arrival. A total of 82% (n = 83) had EMS efforts ceased as a consequence of the DNAR while 18% (n = 18) received full efforts. Full-efforts compared to ceased-efforts were more likely to have a witnessed arrest (67% vs 36%), present with shockable rhythm (22% vs 6%), achieve spontaneous circulation by time of DNAR presentation (50% vs 4%), and have family contradict the DNAR (33% vs 0%) (p < 0.05 for each comparison)., Conclusions: Approximately 10% of EMS-attended OHCA involved DNAR. EMS typically fulfilled this end-of-life preference, though wishes were challenged by delayed directive presentation or contradictory family wishes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Early recognition of out-of-hospital cardiac arrest (OHCA) by 9-1-1 dispatchers is a critical first step along the resuscitation pathway. Barriers to recognition may lead to adverse outcomes among patients. This study aims to determine the impact of seizure-like activity among OHCA patients during 9-1-1 calls., Methods: We evaluated a retrospective cohort study of all adult, non-traumatic OHCAs that occurred prior to emergency medical services (EMS) arrival on scene in a major metropolitan area from 2014-2018. Dispatch recordings were reviewed to determine if seizure-like activity was reported by the caller using key descriptor phrases such as "seizing," "shaking," or "convulsing." We compared patient demographics, arrest factors, and hospital outcomes using a regional OHCA quality improvement database., Results: Among 3502 OHCAs meeting our inclusion criteria, 149 (4.3%) contained seizure-like activity. When compared to patients without seizure-like activity (3353; 95.7%), patients presenting with seizure-like activity were younger (54 vs. 66 years old; p < 0.05), had a witnessed arrest (88% vs 45%; p < 0.05), presented with an initial shockable rhythm (52% vs. 24%; p < 0.05), and survived to hospital discharge (44% vs. 16%; p < 0.05). The seizure-like activity group also had a longer median time to dispatcher identification of the cardiac arrest [130 s (72,193) vs 62 s (43,102); p < 0.05]., Conclusions: Reported seizure-like activity among patients in cardiac arrest poses a barrier to recognition of cardiac arrests by dispatchers leading to delays in resuscitation instructions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: The ability to identify patients with coronavirus disease 2019 (COVID-19) in the prehospital emergency setting could inform strategies for infection control and use of personal protective equipment. However, little is known about the presentation of patients with COVID-19 requiring emergency care, particularly those who used 911 emergency medical services (EMS)., Objective: To describe patient characteristics and prehospital presentation of patients with COVID-19 cared for by EMS., Design, Setting, and Participants: This retrospective cohort study included 124 patients who required 911 EMS care for COVID-19 in King County, Washington, a large metropolitan region covering 2300 square miles with 2.2 million residents in urban, suburban, and rural areas, between February 1, 2020, and March 18, 2020., Exposures: COVID-19 was diagnosed by reverse transcription-polymerase chain reaction detection of severe acute respiratory syndrome coronavirus 2 from nasopharyngeal swabs. Test results were available a median (interquartile range) of 5 (3-9) days after the EMS encounter., Main Outcomes and Measures: Prevalence of clinical characteristics, symptoms, examination signs, and EMS impression and care., Results: Of the 775 confirmed COVID-19 cases in King County, EMS responded to 124 (16.0%), with a total of 147 unique 911 encounters. The mean (SD) age was 75.7 (13.2) years, 66 patients (53.2%) were women, 47 patients (37.9%) had 3 or more chronic health conditions, and 57 patients (46.0%) resided in a long-term care facility. Based on EMS evaluation, 43 of 147 encounters (29.3%) had no symptoms of fever, cough, or shortness of breath. Based on individual examination findings, fever, tachypnea, or hypoxia were only present in a limited portion of cases, as follows: 43 of 84 encounters (51.2%), 42 of 131 (32.1%), and 60 of 112 (53.6%), respectively. Advanced care was typically not required, although in 24 encounters (16.3%), patients received care associated with aerosol-generating procedures. As of June 1, 2020, mortality among the study cohort was 52.4% (65 patients)., Conclusions and Relevance: The findings of this cohort study suggest that screening based on conventional COVID-19 symptoms or corresponding examination findings of febrile respiratory illness may not possess the necessary sensitivity for early diagnostic suspicion, at least in the prehospital emergency setting. The findings have potential implications for early identification of COVID-19 and effective strategies to mitigate infectious risk during emergency care.

We undertook a quality improvement project to address challenges with pulmonary artery catheter (PAC) line maintenance in a setting of low-baseline central-line infection rates. We observed a subsequent reduction in Staphylococcal PAC line infections and a trend toward a reduction in overall PAC infection rates over 1 year.

Objective: Restenosis limits the durability of all cardiovascular reconstructions. Vascular smooth muscle cell (VSMC) proliferation drives this process, but an intact, functional endothelium is necessary for vessel patency. Current strategies to prevent restenosis employ antiproliferative agents that affect both VSMCs and endothelial cells (ECs). Knockdown of the myristoylated alanine-rich C kinase substrate (MARCKS) arrests VSMC proliferation and paradoxically potentiates EC proliferation. MARCKS knockdown decreases expression of the kinase interacting with stathmin (KIS), increasing p27 kip1 expression, arresting VSMC proliferation. Here, we seek to determine how MARCKS influences KIS protein expression in these two cell types., Methods: Primary human coronary artery VSMCs and ECs were used for in vitro experiments. MARCKS was depleted by transfection with small interfering RNA. Messenger RNA was quantitated with the real-time reverse transcription polymerase chain reaction. Protein expression was determined by Western blot analysis. Ubiquitination was determined with immunoprecipitation. MARCKS and KIS binding was assessed with co-immunoprecipitation. Intimal hyperplasia was induced in CL57/B6 mice with a femoral artery wire injury. MARCKS was knocked down in vivo by application of 10 μM of small interfering RNA targeting MARCKS suspended in 30% Pluronic F-127 gel. Intimal hyperplasia formation was assessed by measurement of the intimal thickness on cross sections of the injured artery. Re-endothelialization was determined by quantitating the binding of Evans blue dye to the injured artery., Results: MARCKS knockdown did not affect KIS messenger RNA expression in either cell type. In the presence of cycloheximide, MARCKS knockdown in VSMCs decreased KIS protein stability but had no effect in ECs. The effect of MARCKS knockdown on KIS stability was abrogated by the 26s proteasome inhibitor MG-132. MARCKS binds to KIS in VSMCs but not in ECs. MARCKS knockdown significantly increased the level of ubiquitinated KIS in VSMCs but not in ECs. MARCKS knockdown in vivo resulted in decreased KIS expression. Furthermore, MARCKS knockdown in vivo resulted in decreased 5-ethynyl-2'-deoxyuridine integration and significantly reduced intimal thickening. MARCKS knockdown enhanced endothelial barrier function recovery 4 days after injury., Conclusions: MARCKS differentially regulates the KIS protein stability in VSMCs and ECs. The difference in stability is due to differential ubiquitination of KIS in these two cell types. The differential interaction of MARCKS and KIS provides a possible explanation for the observed difference in ubiquitination. The effect of MARCKS knockdown on KIS expression persists in vivo, potentiates recovery of the endothelium, and abrogates intimal hyperplasia formation., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is being considered for temporizing catastrophic hemorrhage before arriving at a specialty center for definitive surgical management., Case: We describe the clinical case of a 72-year-old male with a ruptured infrarenal aortic abdominal aneurysm initially stabilized with REBOA at an outside facility and transferred to our care. Transport time was >100 minutes. Despite successful surgical repair of the ruptured aneurysm, the patient expired from multiple-organ failure likely related to ischemia-reperfusion injuries from prolonged balloon occlusion of the aorta., Conclusions: Ischemia-mitigating techniques and therapies need to improve drastically before the clinical application of REBOA can be effectively extended to outside the vicinity of specialty centers., (Published by Elsevier Inc.)

We describe the cases of 2 patients who had septic thrombophlebitis and were successfully managed with endovascular thrombectomy. Patient A developed septic thrombophlebitis of the inferior vena cava after several retroperitoneal resections for metastatic renal cell carcinoma. The thrombus was successfully removed via endovascular mechanical balloon thrombectomy. Patient B was a patient with pancreatic adenocarcinoma involving the portal vein who developed a septic inferior vena cava thrombus extending from the level and beyond the renal veins, for which she underwent endovascular thrombectomy. We argue that this approach is safe and feasible. It should be considered as a supplemental treatment modality for select decompensating patients who require lifesaving interventions and have contraindications to traditional management of surgical thrombectomy or excision of the involved venous segment.

We report a case of a complex chronic type B aortic dissection treated by thoracic endovascular aortic repair and laser fenestration of the false septum to preserve flow to branch vessels originating from both the true and false lumen. Dissections complicated by thoracoabdominal aneurysmal degeneration with critical organs being perfused by branches arising from both true and false lumens are rare and leave limited options for repair. Despite advancements in endovascular techniques, fenestration remains one of the only means of preserving flow to both the true and false lumens and thus was necessary in the management of our patient. This novel procedure allows complex aortic dissections to be addressed endovascularly, which increases the flexibility and management of this challenging problem that previously required an open repair with significant morbidity.

Surgical site infections (SSIs) have always complicated recovery after surgery, being associated with increased cost of hospitalization, length of stay, and mortality. The most significant measure to reduce the incidence of SSI was the standardization of prophylactic antibiotic administration in patients undergoing surgical procedures. Since then, countless measures have been proposed to improve rates of SSI and patient outcome, but few have been as efficacious as prophylactic antibiotics. Therefore, SSI continues to plague clinicians and patients in modern health care. This review focuses on current and future efforts at SSI control., (Copyright © 2017 Society for Vascular Nursing, Inc. Published by Elsevier Inc. All rights reserved.)

The partial hepatectomy (PH) model is widely used to study liver regeneration. Currently, the extent of regeneration is analyzed by measuring the weight of the liver post-mortem or by magnetic resonance imaging. In this study we aimed to determine whether liver volume gain can be accurately measured using micro-computed tomography (microCT). Approximately 42% of the liver was removed by ligation in C57BL/6 N mice. Mice were divided into two study groups. In group 1 conventional characterization of liver hyperplasia was performed by weighing the liver post-mortem. In group 2, liver volume gain was determined by microCT volume estimation. MicroCT results showed equivalent regeneration rates compared with the conventional method without the need to mathematically determine initial liver weights before PH. This parameter is strongly influenced by the age, strain and sex of the mice. In addition non-invasive microCT determination of volume gain over multiple time-points using the same animal reduces the number of animals needing to be used (in line with the 3R principle of replacement, reduction and refinement).

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Extramammary Paget disease (EMPD) is an uncommon tumor that presents in apocrine-rich skin as an irregular, pruritic plaque. Histopathologically, EMPD consists of an intraepidermal proliferation of atypical epithelioid cells. Rarely, the tumor cells contain intracytoplasmic melanin pigment, and the lesion clinically and histopathologically can mimic a melanocytic proliferation., Observations: A 51-year-old female with a history of breast carcinoma presented with a pigmented patch on her right thigh of 6 months duration. The clinical impression was an atypical melanocytic nevus. Histopathologic examination revealed an intraepidermal proliferation of epithelioid cells along the dermal-epidermal junction with pagetoid migration. The tumor cells exhibited increased cytoplasm containing conspicuous melanin pigment and enlarged oval-irregular nuclei. Immunohistochemical studies showed the tumor cells to be strongly and diffusely positive for cytokeratin 8/18, cytokeratin 7 and p63; focally and weakly positive for epithelial membrane antigen (EMA), but negative for cytokeratin 5/6, Cam5.2, carcinoembryonic antigen (CEA), human melanoma black 45 (HMB-45), tyrosinase and Sox-10, supporting the diagnosis of pigmented EMPD. The lesion was subsequently excised, and the patient is free of disease after 24 months., Conclusion: We present this unusual case of pigmented EMPD arising on the thigh to draw attention to the entity and to underscore the potentially misleading clinical, histopathologic and immunophenotypic features that mimic other cutaneous intraepidermal lesions., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: High platelet reactivity (HPR) under treatment with clopidogrel or aspirin is associated with adverse outcome. We aimed to investigate whether high platelet reactivity (HPR) to both aspirin and clopidogrel is a stronger predictor of adverse events compared to isolated HPR to clopidogrel or aspirin., Methods: In this prospective cohort study platelet reactivity to adenosine diphosphate (ADP) and arachidonic acid (AA) was assessed by Multiple Electrode Aggregometry (MEA) in 403 patients undergoing percutaneous coronary intervention. The rates of the composite of cardiac adverse events (acute coronary syndrome, stent thrombosis, stroke, death and revascularization) were recorded during 12-month follow-up., Results: The composite endpoint of cardiovascular adverse events occurred more often in patients with high platelet reactivity (HPR) to both agonists ADP and AA (37.5%) than in those with isolated HPR to ADP (33.3%), AA (25.6%) or without any HPR (18.6%; p=0.003). Classification tree analysis indicated that any HPR emerged as an independent predictor influencing outcome, which was associated with a 1.75 higher risk of cardiac adverse events (OR=1.75: 95%CI=1.1-2.9). Interestingly, the predictive value of HPR tended to be greater among patients with diabetes mellitus (OR=2.18; 95%CI=1.20-3.95). C-reactive protein and diabetes mellitus were independent predictors of high platelet reactivity to both agonists., Conclusions: Dual low responsiveness to clopidogrel and aspirin is a strong predictor of cardiac adverse events, especially in patients with diabetes mellitus, which underlines the need for personalized antiplatelet treatment., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Motor vehicle crashes involving civilian and emergency vehicles (EVs) have been a known problem that contributes to fatal and nonfatal injuries; however, characteristics associated with civilian drivers have not been examined adequately. This study used data from The National Highway Traffic Safety Administration's Fatality Analysis Reporting System and the National Automotive Sampling System General Estimates System to identify driver, roadway, environmental, and crash factors, and consequences for civilian drivers involved in fatal and nonfatal crashes with in-use and in-transport EVs. In general, drivers involved in emergency-civilian crashes (ECCs) were more often driving: straight through intersections (vs. same direction) of four-points or more (vs. not at intersection); where traffic signals were present (vs. no traffic control device); and at night (vs. midday). For nonfatal ECCs, drivers were more often driving: distracted (vs. not distracted); with vision obstructed by external objects (vs. no obstruction); on dark but lighted roads (vs. daylight); and in opposite directions (vs. same directions) of the EVs. Consequences included increased risk of injury (vs. no injury) and receiving traffic violations (vs. no violation). Fatal ECCs were associated with driving on urban roads (vs. rural), although these types of crashes were less likely to occur on dark roads (vs. daylight). The findings of this study suggest drivers may have difficulties in visually detecting EVs in different environments., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

It is known that distraction reduces the benefits of collision avoidance systems by slowing a driver's response. The current study examined the impact of a drivers' use of an in-vehicle intersection crossing assist system under demanding cognitive load conditions. Forty eight drivers crossed a busy rural intersection in a simulated environment while completing four blocks of trials, in half of which they used the assist system and engaged in a working memory task. Participants were dichotomized into older and younger age groups. The results showed a tendency towards conservative driving in a single-task condition when only using the assist system. A similar shift in driving style was observed when drivers crossed the intersection while engaged in a secondary task. Using the in-vehicle intersection crossing assist system under cognitively demanding conditions did not result in adverse consequences-the impact of distraction was different compared to a typical collision avoidance system. Older drivers showed some evidence of more conservative intersection crossing, however they also appeared to rely more on the in-vehicle assist system when presented with an extraneous additional task., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background & Aims: Interleukin-6 (IL-6) is a crucial factor in liver regeneration following partial hepatectomy (PH); however, the role of IL-6 and IL-6 trans-signaling in particular, in hepatocyte mitosis remains controversial. IL-6 trans-signaling relies upon the release of the soluble IL-6R (sIL-6R), which binds IL-6 to form an agonistic IL-6/sIL-6R complex. Herein we have examined the hypothesis that IL-6 trans-signaling plays a crucial and distinct role in liver regeneration following PH., Methods: The specific IL-6/sIL-6R antagonist, sgp130Fc, was expressed in mice and analyzed for its effect on hepatocyte mitosis following PH. Alternatively, we examined the effect of the IL-6/sIL-6R super-agonist, Hyper-IL-6, or IL-6 expressed either alone or in combination with hepatocyte growth factor (HGF) on hepatocyte mitosis in the absence of PH., Results: Following PH, the dramatic rise of circulating IL-6 levels is accompanied by a concurrent ∼2-fold increase in circulating sIL-6R levels. Ectopic expression of sgp130Fc reduced hepatocyte mitosis by about 40% at early times following PH, while substantially reducing AKT, but not STAT3, activation. But, ectopic Hyper-IL-6 expression in mice without PH was not mitogenic to hepatocytes in vivo. Rather, Hyper-IL-6, but not IL-6, markedly increased HGF-induced hepatocyte mitosis. This cooperative effect correlated with greater resistance of HIL-6 than IL-6 to HGF-mediated reduction of AKT activation, rather than changes in STAT3 or MAPK signaling, and was completely blocked by PI3K inhibition., Conclusions: Following PH, IL-6/sIL-6R cooperates with growth factors, through a PI3K/AKT-dependent mechanism to promote entry of hepatocytes into the cell cycle., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Interleukin-6 (IL-6) plays an important role in liver regeneration and protection against liver damage. In addition to IL-6 classic signaling via membrane bound receptor (mIL-6R), IL-6 signaling can also be mediated by soluble IL-6R (sIL-6R) thereby activating cells that do not express membrane bound IL-6R. This process has been named trans-signaling. IL-6 trans-signaling has been demonstrated to operate during liver regeneration. We have developed methods to specifically block or mimic IL-6 trans-signaling. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling whereas an IL-6/sIL-6R fusion protein (Hyper-IL-6) mimics IL-6 trans-signaling. Using these tools we investigate the role of IL-6 trans-signaling in CCl₄ induced liver damage. Blockade of IL-6 trans-signaling during CCl₄ induced liver damage led to higher liver damage, although induction of Cyp4502E1 and thus bioactivation of CCl₄ was unchanged. Depletion of neutrophils resulted in reduced liver transaminase levels irrespective of IL-6 trans-signaling blockade. Furthermore, IL-6 trans-signaling was important for refilling of hepatocyte glycogen stores, which were depleted 24 h after CCl₄ treatment. We conclude that IL-6 trans-signaling via the soluble IL-6R is important for the physiologic response of the liver to CCl₄ induced chemical damage., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Interleukin-6 (IL-6) has been suggested to play a pivotal role in liver regeneration. IL-6 on target cells activates a receptor complex consisting of the IL-6 receptor (IL-6R) and the signal transducing receptor subunit gp130. Not all cells in the body express the IL-6R on the cell surface. IL-6 can signal via two different pathways: classical signaling via the membrane bound IL-6R and IL-6 trans-signaling via a naturally occurring soluble IL-6R (sIL-6R). This second pathway widens the scope of IL-6 signaling since also cells expressing no membrane bound IL-6R can be stimulated by the trans-signal pathway. Mimicking IL-6 trans-signaling via a designer molecule, Hyper-IL-6 has been shown to accelerate liver regeneration. Another designer molecule, sgp130Fc, specifically blocks IL-6 trans-signaling. Using these proteins we investigated the contribution of IL-6 classic- and trans-signaling in the liver. Here we review the role of IL-6 signaling in response to liver damage and during liver regeneration., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The cytokine interleukin-6 (IL-6) is important for liver regeneration. IL-6 can stimulate target cells either by binding to the membrane-bound IL-6 receptor (IL-6R) leading to dimerization and activation of gp130 or by binding to a soluble IL-6R that results in an activation of gp130 independently of membrane-bound IL-6R, a process called trans-signaling. We have established a transgenic mouse line, in which only trans-signaling is abrogated whereas signaling via the membrane-bound IL-6R is intact. In the present study we employed this mouse model to ask whether the activity of IL-6 during repair of mild liver damage acts via classic or trans-signaling. We analyzed liver regeneration and showed that intracellular signaling, proliferation, and glycogenolysis are reduced in the transgenic mice and thus are regulated by IL-6 trans-signaling. Taken together our results show that upon liver damage, activation of the gp130 pathway depends on the sIL-6R.

Background/aims: We studied the impact of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on inflammation-driven hepatocarcinogenesis., Methods: HB-EGF expression was determined by qRT-PCR and immunodetection in hepatocellular adenoma and carcinoma and in mesenchymal (MC) and parenchymal liver cells obtained from different models of inflammation. The functions of HB-EGF in early hepatocarcinogenesis were assessed in co-cultures of unaltered and initiated/premalignant hepatocytes., Results: In human and rat (pre)malignant liver lesions, HB-EGF levels were comparable to that of the surrounding tissue. In inflamed livers HB-EGF was expressed predominantly in MC and was further increased by pro-inflammatory lipopolysaccharide (LPS) or linoleic acid hydroperoxide (LOOH). In culture, DNA-replication occurred rather in initiated/premalignant than unaltered hepatocytes and was further elevated by LOOH- or LPS-stimulated MC-supernatants. The supernatant effects were abrogated by pre-incubation with HB-EGF-neutralizing antisera. HB-EGF itself induced DNA-replication and mitosis preferentially in the initiated/premalignant cells. When transducing hepatocytes with a dominant-negative ErbB1-construct, HB-EGF-induced DNA-replications were blocked completely in unaltered hepatocytes but incompletely in initiated/premalignant cells, which suggests elevated ErbB-mediated signal transduction in first stages of hepatocarcinogenesis., Conclusions: Pro-inflammatory stimuli induce the release of HB-EGF from MC, which stimulates DNA-replication in initiated/premalignant hepatocytes. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.

Background/aims: Activins A and E negatively regulate hepatic cell number by inhibiting cell replication and inducing apoptosis. Follistatin and follistatin-like 3 bind activins and antagonise their biological activities. Aim of our study was to investigate, whether activins and follistatins may play a role in hepatocarcinogenesis., Methods: Expression levels of follistatin, follistatin-like 3, and activin subunits beta(A) as well as beta(E) were investigated in chemically induced rat and human liver tumours by real-time PCR and immunohistochemistry. In addition, the effects of follistatin and activin A on DNA synthesis of normal as well as preneoplastic hepatocytes and hepatoma cells were analysed., Results: Follistatin was overexpressed while both activin subunits were downregulated in the majority of rat and human liver tumours. Follistatin-like 3 expression was low in normal but enhanced in malignant rat liver. In human normal liver, in contrast, it was abundantly expressed but downregulated in liver cancer. Administration of follistatin to normal and preneoplastic hepatocytes stimulated DNA synthesis preferentially in preneoplastic rat hepatocytes, whereas activin A repressed it., Conclusions: The balanced expression of follistatins and activins becomes deregulated during hepatocarcinogenesis. The sensitivity of preneoplastic hepatocytes to activin signals suggests the activin/follistatin system as promising target for therapeutic intervention.

Hepatocellular carcinoma almost always arises in chronically inflamed livers. We developed a culture model to study the role of non-parenchymal cells (NPCs) for inflammation-driven hepatocarcinogenesis. Rats were treated with the carcinogen N-nitrosomorpholine, which induced initiated hepatocytes expressing the marker placental glutathione-S-transferase (GSTp). After 21 days two preparations of hepatocytes were made: (i) conventional ones (Hep-conv) containing NPCs and (ii) hepatocytes purified of NPCs (Hep-pur). Initiated hepatocytes, being positive for GSTp (GSTp-pos) were present in both preparations and were cultured along with normal hepatocytes, being negative for GSTp (GSTp-neg). Under any culture condition DNA synthesis was approximately 4-fold higher in GSTp-pos than in GSTp-neg hepatocytes demonstrating the inherent growth advantage of the first stages of hepatocarcinogenesis. Hepatocytes showed approximately 3-fold lower rates of DNA synthesis in Hep-pur than in Hep-conv, which was elevated above Hep-conv levels by addition of NPC or NPC-supernatant. Pretreatment of NPCs with proinflammatory lipopolysaccharide (LPS) further increased DNA synthesis. Thus, NPCs release soluble growth stimulators. Next we investigated the effect of specific cytokines produced by NPCs. Tumour necrosis factor alpha and interleukin 6 barely altered DNA synthesis, whereas hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and the heparin-binding epidermal growth factor-like growth factor (HB-EGF) were potent inducers of DNA replication in both, GSTp-neg and GSTp-pos cells. In conclusion, DNA synthesis of hepatocytes is increased by factors released from NPCs, an effect augmented by LPS-stimulation. NPC-derived cytokines, such as KGF, HGF and HB-EGF, stimulate DNA synthesis preferentially in initiated hepatocytes, presumably resulting in tumour promotion. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.

A protective role against atherosclerosis can be attributed to angiotensin converting enzyme inhibitors (ACE-I), since they have been shown to reduce mortality in patients at cardiovascular risk. Since plasma levels of adhesion molecules are considered surrogate markers of endothelial cell activation and atherogenesis, we compared the levels of adhesion molecules after treatment with the ACE-I enalapril or the direct angiotensin- receptor antagonist losartan or placebo. In a randomized, controlled trial, 21 hypercholesterolemic volunteers received 50 mg/d losartan or 20 mg/d enalapril or placebo for twelve weeks. Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), vascular adhesion molecule-1 (cVCAM-1), and E-selectin (cE-SEL) were measured by ELISA. Surface expression of ICAM-1 on circulating leukocytes was determined by flow cytometry. Enalapril and losartan but not placebo induced a small but stable decrease of cICAM-1 and cVCAM-1, while cE-SEL and leukocyte expression of ICAM-1 remained unchanged. The lowering of plasma adhesion molecules may indicate an antiatherogenic effect of angiotensin II blockade in hypercholesterolemia. While such preventive effect will have to be proven in clinical trials, our results do not support a preference for either enalapril or losartan with regard to their possible vasoprotective role.

Activins C and E (homodimers of the betaC and betaE subunits), which are almost exclusively expressed in the liver, are members of the transforming growth factor beta (TGFbeta) superfamily of growth factors. We examined their expression in three different hepatoma cell lines and found that, compared with normal liver or primary hepatocytes, human hepatoblastoma (HepG2), human hepatocellular carcinoma (Hep3B) and rat hepatoma (H4IIEC3) cells have either completely lost or drastically reduced the expression of activins C and E. In order to elucidate the biological function of these proteins we transiently transfected HepG2, Hep3B and H4IIEC3 cell lines with rat activin betaC or betaE cDNA to study the consequences of restoring activin expression in hepatoma cells. Transfection with activin betaA, a known inhibitor of hepatic DNA synthesis and inducer of apoptosis, served as a positive control. We found that transfection of the three cell lines with activin betaC or betaE, as well as with activin betaA, reduced the increase in cell number by up to 40% compared with cells transfected with a control plasmid. Co-culture with a CHO cell clone secreting activin C also inhibited HepG2 cell multiplication. Furthermore, the three hepatoma cell lines studied showed an enhanced rate of apoptosis and elevated levels of active caspases in response to activin transfection. These results indicate that activins C and E share the potential to induce apoptosis in liver derived cell lines with activin A and TGFbeta1.

Background: Serotonin is a platelet agonist and potent vasoconstrictor that has recently received attention concerning its potential role in acute coronary artery thrombosis. Selective serotonin-reuptake inhibitors, such as paroxetine, are widely used antidepressant agents. We sought to characterize the potential inhibitory effect of paroxetine on platelet function., Methods: Healthy male volunteers received 20 mg/d paroxetine for 2 weeks in a randomized, double-blind, placebo-controlled, two-way cross-over trial., Results: Paroxetine decreased intraplatelet serotonin concentrations by -83% (P < .01). This inhibited platelet plug formation as reflected by a 31% prolongation of closure time measured with the platelet function analyzer-100 (P < .05). Furthermore, paroxetine lowered expression of the platelet activation marker CD63 in response to two different concentrations of thrombin receptor-activating peptide (P < .01). Plasma concentrations of prothrombin fragment, von Willebrand factor antigen, and circulating P-selectin remained unchanged in either period, indicating that paroxetine does not increase activation of coagulation, endothelium, or platelets in vivo, underlining a favorable safety profile., Conclusions: Paroxetine substantially decreases intraplatelet serotonin content and thereby reduces platelet plug formation under shear stress, and responsiveness to thrombin receptor activating peptide-induced platelet activation. Further studies will reveal whether these pharmacodynamic effects can be exploited for treatment of thrombotic artery disease.