Direct to Operating Room for Decompressive Craniotomy/Craniectomy in Patients With Traumatic Brain Injury.

BACKGROUND: Emergent decompressive craniotomy/craniectomy can be a lifesaving surgical intervention for select patients with traumatic brain injury. Prompt management is critical as early decompression can impact traumatic brain injury outcomes. OBJECTIVE: This study aims to describe the feasibility and clinical impact of a new pathway for transporting patients with severe traumatic brain injury directly to the operating room from the trauma bay for decompressive craniotomy/craniectomy. METHODS: This is a retrospective cohort preintervention and postintervention study of severe traumatic brain injury patients undergoing decompressive craniectomy/craniotomy at a Midwestern U.S. Level I trauma center between 2016 and 2022. In the new pathway, the in-house trauma surgeon takes the patient directly to the operating room with the neurosurgery advanced practice provider to drape and prepare the patient for surgery while the neurosurgeon is en route to the hospital. RESULTS: A total of 44 patients were studied, five (5/44, 11.4%) of which were in the preintervention group and 39 (39/44, 88.6%) in the postintervention group. The median arrival-to-operating room time was shorter in the postintervention cohort (1.4 hr) than in the preintervention cohort (1.5 hr). In examining night shifts only, the preintervention cohort had shorter arrival-to-operating room times (1.2 hr) than the postintervention cohort (1.5 hr). CONCLUSION: The study demonstrated that the new pathway is feasible and expedites patient transport to the operating room while awaiting the arrival of the on-call neurosurgeon.

Essential Oils Can Mitigate Adverse Effects of Prolonged Masking in the Hospital Setting.

Adverse symptoms of prolonged masking were reported by personnel. A drop of essential oil was added to the mask to mitigate these effects and significantly lessened symptoms. Symptoms declined by almost half, including anxiety, nausea, and indigestion. This simple intervention can mitigate adverse effects of prolonged masking in the hospital setting.

State of Science in Alarm System Safety: Implications for Researchers, Vendors, and Clinical Leaders.

Alarm fatigue is a complex phenomenon that needs to be assessed within the context of the clinical setting. Considering that complexity, the available information on how to address alarm fatigue and improve alarm system safety is relatively scarce. This article summarizes the state of science in alarm system safety based on the eight dimensions of a sociotechnical model for studying health information technology in complex adaptive healthcare systems. The summary and recommendations were guided by available systematic reviews on the topic, interventional studies published between January 2019 and February 2022, and recommendations and evidence-based practice interventions published by professional organizations. The current article suggests implications to help researchers respond to the gap in science related to alarm safety, help vendors design safe monitoring systems, and help clinical leaders apply evidence-based strategies to improve alarm safety in their settings. Physiologic monitors in intensive care units-the devices most commonly used in complex care environments and associated with the highest number of alarms and deaths-are the focus of the current work.

"Getting to Know Them": Person-Centered Care for Patients With Dementia in Acute Care.

Older adults with dementia are reported to have twice as many hospital stays as their age-matched counterparts without dementia. Acute care hospitals are generally not equipped to provide best care for persons with dementia. The purpose of the current qualitative study was to gain an understanding of the needs and perspectives of nursing staff and patient care technicians regarding delivering person-centered care (PCC) to patients with dementia. Nine focus groups (N = 49) were conducted. Participants discussed the importance of "getting to know them" as the basis for their care. Several themes emerged that served to support or detract from providing PCC: (a) communication, (b) education, and (c) care environment. Findings from this study support the desire of nurses and patient care technicians to provide PCC, highlight challenges, and indicate needed system-level changes to education, communication, and the care environment to support best practices. [Journal of Gerontological Nursing, 47(5), 37-44.].

Optimization of a nicotine degrading enzyme for potential use in treatment of nicotine addiction.

BACKGROUND: Smoking and tobacco use continue to be the largest preventable causes of death globally. A novel therapeutic approach has recently been proposed: administration of an enzyme that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects. Pre-clinical proof of concept has been previously established through dosing the amine oxidase NicA2 from Pseudomonas putida in rat nicotine self-administration models of addiction. RESULTS: This paper describes efforts towards optimizing NicA2 for potential therapeutic use: enhancing potency, improving its pharmacokinetic profile, and attenuating immunogenicity. Libraries randomizing residues located in all 22 active site positions of NicA2 were screened. 58 single mutations with 2- to 19-fold enhanced catalytic activity compared to wt at 10 µM nicotine were identified. A novel nicotine biosensor assay allowed efficient screening of the many primary hits for activity at nicotine concentrations typically found in smokers. 10 mutants with improved activity in rat serum at or below 250 nM were identified. These catalytic improvements translated to increased potency in vivo in the form of further lowering of nicotine blood levels and nicotine accumulation in the brains of Sprague-Dawley rats. Examination of the X-ray crystal structure suggests that these mutants may accelerate the rate limiting re-oxidation of the flavin adenine dinucleotide cofactor by enhancing molecular oxygen's access. PEGylation of NicA2 led to prolonged serum half-life and lowered immunogenicity observed in a human HLA DR4 transgenic mouse model, without impacting nicotine degrading activity. CONCLUSIONS: Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.

Telemedicine: Does it have a place in surgical oncology practice?

BACKGROUND: Telemedicine has gained traction in surgical subspecialties, particularly since the COVID-19 pandemic. This study aims to identify whether telemedicine can be appropriately integrated within surgical oncology practice. METHODS: This retrospective study evaluated patients who received either telemedicine or office follow-up after undergoing surgical oncology operations between 2016 and 2021. The telemedicine group (TG) and office group (OG) received a 15-question survey regarding their satisfaction with their care. Patient outcomes and responses were analyzed utilizing propensity-score matching in 1:1 fashion. RESULTS: Telemedicine group and OG each had 21 patients. Length of stay, complication frequency, follow-up frequency, and readmissions frequency within 90-days were comparable between groups. Telemedicine group expressed comparable satisfaction with postoperative care relative to OG (95.2% vs. 85.7%, p = 0.61). All telemedicine patients said they would utilize telemedicine again in the future and would recommend its use to others. CONCLUSION: Patient satisfaction with postoperative telemedicine follow-up is comparable to those with in-person follow-up.

Does Hispanic ethnicity play a role in outcomes for diverticular surgery in the USA?

OBJECTIVE: The aim of this study is to investigate whether origins of ethnicity affect the outcomes of surgery for diverticulitis in the USA. DESIGN: The American College of Surgeons National Surgical Quality Improvement Programme database from 2008 to 2017 was used to identify patients undergoing colectomy for diverticulitis. Patient demographics, comorbidities, procedural details and outcomes were captured and compared by ethnicity status. RESULTS: A total of 375 311 surgeries for diverticulitis were included in the final analysis. The average age of patients undergoing surgery for diverticulitis remained consistent over the time frame of the study (62 years), although the percentage of younger patients (age 18-39 years) rose slightly from 7.8% in 2008 to 8.6% in 2017. The percentage of surgical patients with Hispanic ethnicity increased from 3.7% in 2008 to 6.6% of patients in 2017. Hispanic patients were younger than their non-Hispanic counterparts (57 years vs 62 years, p<0.01) at time of surgery. There were statistically significant differences in the proportion of laparoscopic cases (51% vs 49%, p<0.01), elective cases (62% vs 66%, p<0.01) and the unadjusted rate of postoperative mortality (2.8% vs 3.4%, p<0.01) between Hispanic patients compared with non-Hispanic patients, respectively. Multivariable logistic regression models did not identify Hispanic ethnicity as a significant predictor for increased morbidity (p=0.13) or mortality (p=0.80). CONCLUSION: Despite a significant younger population undergoing surgery for diverticulitis, Hispanic ethnicity was not associated with increased rates of emergent surgery, open surgery or postoperative complications compared with a similar non-Hispanic population.

Asthma in the elderly: diagnosis and management.

The National Asthma Education and Prevention Program's "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma" apply to all ages. This review discusses additional specific points for elderly patients. These patients are very heterogeneous. Their asthma can have begun at any time and can vary greatly in severity. It is frequently associated not only with any of the diseases that affect older persons but also with comorbid lung diseases. Many patients have irreversible airway obstruction, which is due to severe airway remodeling, chronic obstructive pulmonary disease, or bronchiectasis. Diagnosis should include chest radiography and computed tomographic scanning to diagnose other lung diseases if FEV1 remains low after treatment. Asthma pathogenesis includes not only IgE-mediated allergy but also innate immune inflammation from endotoxin and trypsin-like proteases, and therefore evaluation and control of environmental exposures is an important part of management. Pharmacologic treatment, too, is adjusted to achieve and maintain control and is basically the same for all ages, except that elderly patients have reduced response to bronchodilators and increased side effects from beta adrenergic agonists and glucocorticoids. Many elderly patients have difficulty inhaling aerosols, and therefore nebulizers might be a better delivery system. Oral medications have the benefit of greater ease of administration and greater efficacy on the peripheral airways. Leukotriene antagonists and low-dose theophylline are often helpful additives to aerosol glucocorticoids. Oral glucocorticoids might be indicated for severe asthma.

Environmental and occupational allergies.

Airborne allergens are the major cause of allergic rhinitis and asthma. Daily exposure comes from indoor sources, chiefly at home but occasionally at schools or offices. Seasonal exposure to outdoor allergens, pollens, and molds is another important source. Exposure to unusual substances at work causes occupational asthma, accounting for about 5% of asthma in adults. Indoor and outdoor air pollutants trigger airway inflammation and increase the severity of asthma. Diesel exhaust particles increase the production of IgE antibodies. Identification and reduction of exposure to allergens is a very important part of the management of respiratory allergic diseases. The first section of this chapter discusses domestic allergens, arthropods (mites and cockroaches), molds, and mammals (pets and mice). Indoor humidity and water damage are important factors in the production of mite and mold allergens, and discarded human food items are important sources of proliferation of cockroaches and mice. Means of identifying and reducing exposure are presented. The second section discusses outdoor allergens: pollens and molds. The particular plants or molds and the amount of exposure to these allergens is determined by the local climate, and local pollen and mold counts are available to determine the time and amount of exposure. Climate change is already having an important effect on the distribution and amount of outdoor allergens. The third section discusses indoor and outdoor air pollution and methods that individuals can take to reduce indoor pollution in addition to eliminating cigarette smoking. The fourth section discusses the diagnosis and management of occupational asthma.

Case discussion in blood glucose variability.

Stress-induced hyperglycemia has been associated with poor outcomes and death in critically ill patients. Blood glucose (BG) variability, a component of stress-related hyperglycemia has recently been reported as a significant independent predictor of intensive care unit and hospital mortality. We sought to evaluate three cases in which intensive insulin therapy was administered using a standardized insulin dosing protocol to normalize the BG and reduce glycemic variability. Point-of-care BG values and other clinical measures were obtained from the medical record of three patients who received intensive insulin therapy. This was a convenience sample of three patients where the BG level had stabilized on a consistent intravenous insulin dose rate for up to 20 hours in a surgical trauma intensive care unit. Data were collected manually and electronically using the Remote Automated Laboratory System-Tight Glycemic Control Module (RALS-TGCM) BG management and monitoring system. Each case presentation describes a critically ill, nondiabetic patient, requiring continuous intravenous insulin therapy for hyperglycemia. In each instance, BG variability was present in a worsening patient condition after a period of normalization of hyperglycemia with intensive insulin therapy. Although decreasing BG variability is an important aspect of hyperglycemia management, new onset events of variability may be a sentinel warning or occur as a physiologic response to a worsening patient condition. If so, these events warrant rapid investigation and treatment of the underlying problem.

Improving the Safety, Effectiveness, and Efficiency of Clinical Alarm Systems: Simulation-Based Usability Testing of Physiologic Monitors.

BACKGROUND: Clinical alarm system safety is a national patient safety goal in the United States. Physiologic monitors are associated with the highest number of device alarms and alarm-related deaths. However, research involving nurses' use of physiologic monitors is rare. Hence, the identification of critical usability issues for monitors, especially those related to patient safety, is a nursing imperative. OBJECTIVE: This study examined nurses' usability of physiologic monitors in intensive care units with respect to the effectiveness and efficiency of monitor use. METHODS: In total, 30 nurses from 4 adult intensive care units completed 40 tasks in a simulation environment. The tasks were common monitoring tasks that were crucial for appropriate monitoring and safe alarm management across four categories of competencies: admitting, transferring, and discharging patients using the monitors (7 tasks); managing measurements and monitor settings (23 tasks); performing electrocardiogram (ECG) analysis (7 tasks); and troubleshooting alarm conditions (3 tasks). The nurse-monitor interaction was video-recorded. The principal investigator and two expert intensive care units nurse educators identified, classified, and validated task success (effectiveness) and the time of task completion (efficiency). RESULTS: Among the 40 tasks, only 2 (5%) were successfully completed by all the nurses. At least 1-27 (3%-90%) nurses abandoned or did not correctly perform 38 tasks. The task with the shortest completion time was "take monitor out of standby" (mean 0:02, SD 0:01 min:s), whereas the task "record a 25 mm/s ECG strip of any of the ECG leads" had the longest completion time (mean 1:14, SD 0:32 min:s). The total time to complete 37 navigation-related tasks ranged from a minimum of 3 min 57 s to a maximum of 32 min 42 s. Regression analysis showed that it took 6 s per click or step to successfully complete a task. To understand the nurses' thought processes during monitor navigation, the authors analyzed the paths of the 2 tasks with the lowest successful completion rates, where only 13% (4/30) of the nurses correctly completed these 2 tasks. Although 30% (9/30) of the nurses accessed the correct screen first for task 1 and task 2, they could not find their way easily from there to successfully complete the 2 tasks. CONCLUSIONS: Usability testing of physiologic monitors revealed major ineffectiveness and inefficiencies in the current nurse-monitor interactions. The results indicate the potential for safety and productivity issues in completing routine tasks. Training on monitor use should include critical monitoring functions that are necessary for safe, effective, efficient, and appropriate monitoring to include knowledge of the shortest navigation path. It is imperative that vendors' future monitor designs mimic clinicians' thought processes for successful, safe, and efficient monitor navigation.

INO-4800 DNA vaccine induces neutralizing antibodies and T cell activity against global SARS-CoV-2 variants.

Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine-induced immunity. Here we compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.

Innovative Frontline Nurse Leader Professional Development Program.

Frontline nurse leaders direct staff and unit systems while ensuring that quality, safe patient care is provided. It is unknown if frontline nurse leaders oriented with only on-the-job-training are competent and if a professional development program will improve their competencies. This project's purpose was to measure self-assessed competencies, using the Nurse Manager Inventory Tool, of 38 frontline nurse leaders. This project used a quasi-experimental design and utilized pre- and postsurvey for evaluation purposes of a leadership development curriculum.

Adjuvant Screen Identifies Synthetic DNA-Encoding Flt3L and CD80 Immunotherapeutics as Candidates for Enhancing Anti-tumor T Cell Responses.

Overcoming tolerance to tumor-associated antigens remains a hurdle for cancer vaccine-based immunotherapy. A strategy to enhance the anti-tumor immune response is the inclusion of adjuvants to cancer vaccine protocols. In this report, we generated and systematically screened over twenty gene-based molecular adjuvants composed of cytokines, chemokines, and T cell co-stimulators for the ability to increase anti-tumor antigen T cell immunity. We identified several robust adjuvants whose addition to vaccine formulations resulted in enhanced T cell responses targeting the cancer antigens STEAP1 and TERT. We further characterized direct T cell stimulation through CD80-Fc and indirect T cell targeting via the dendritic cell activator Flt3L-Fc. Mechanistically, intramuscular delivery of Flt3L-Fc into mice was associated with a significant increase in infiltration of dendritic cells at the site of administration and trafficking of activated dendritic cells to the draining lymph node. Gene expression analysis of the muscle tissue confirmed a significant up-regulation in genes associated with dendritic cell signaling. Addition of CD80-Fc to STEAP1 vaccine formulation mimicked the engagement provided by DCs and increased T cell responses to STEAP1 by 8-fold, significantly increasing the frequency of antigen-specific cells expressing IFNγ, TNFα, and CD107a for both CD8+ and CD4+ T cells. CD80-Fc enhanced T cell responses to multiple tumor-associated antigens including Survivin and HPV, indicating its potential as a universal adjuvant for cancer vaccines. Together, the results of our study highlight the adjuvanting effect of T cell engagement either directly, CD80-Fc, or indirectly, Flt3L-Fc, for cancer vaccines.

Surgical Inpatient's Attitudes Toward Resident Participation: All About Expectations.

OBJECTIVE: Determine whether an educational video can improve surgical inpatients' attitudes toward resident participation in their care. METHODS: Patients admitted to the Trauma/Emergency General Surgery Service at University Hospital (San Antonio, Texas) were randomly divided into control and intervention groups. Patients in the intervention group viewed a short educational video about the role and responsibilities of medical students, residents, and attending surgeons. All patients then completed a previously published survey. RESULTS: A total of 140 patients responded to the survey (control = 81 and intervention = 59 patients). Overall, 86.4% of patients were welcoming of resident participation. Patients who were expecting residents to be involved in their care had attitudes that are more favorable on almost all survey questions regardless of their study condition. However, patients in the intervention group who expected resident involvement in their care had more favorable attitudes about senior residents (postgraduate year 3-5) assisting in routine or complicated surgery than those in the control group who were expecting resident involvement (both p ≤ 0.001). This same group of patients also had more favorable attitudes about surgical outcomes and overall surgical health when residents are involved (p = 0.004, p = 0.001, respectively). Most patients (79%) said they had no residents previously involved in their care, or they were unsure if residents were previously involved. CONCLUSIONS: Patient expectation of resident involvement is one of the most important factors influencing perceptions of inpatients about resident participation in surgery. Our goal should be early and frequent discussion with patients about resident involvement in order to foster an atmosphere of trust, including full transparency regarding resident involvement in surgical procedures. An educational video may help introduce the roles of trainees and attending surgeons but should not be used in lieu of direct discussion with patients.

Protection against Borreliella burgdorferi infection mediated by a synthetically engineered DNA vaccine.

Lyme disease is the most common vector-borne disease in North America. The etiological agent is the spirochete Borreliella burgdorferi, transmitted to mammalian hosts by the Ixodes tick. In recent years there has been an increase in the number of cases of Lyme disease. Currently, there is no vaccine on the market for human use. We describe the development of a novel synthetically engineered DNA vaccine, pLD1 targeting the outer-surface protein A (OspA) of Borreliella burgdorferi. Immunization of C3 H/HeN mice with pLD1 elicits robust humoral and cellular immune responses that confer complete protection against a live Borreliella burgdorferi bacterial challenge. We also assessed intradermal (ID) delivery of pLD1 in Hartley guinea pigs, demonstrating the induction of robust and durable humoral immunity that lasts at least 1 year. We provide evidence of the potency of pLD1 by showing that antibodies targeting the OspA epitopes which have been associated with protection are prominently raised in the immunized guinea pigs. The described study provides the basis for the advancement of pDL1 as a potential vaccine for Lyme disease control.

Active immunoprophylaxis with a synthetic DNA-encoded monoclonal anti-respiratory syncytial virus scFv-Fc fusion protein confers protection against infection and durable activity.

Respiratory Syncytial virus (RSV) is a major threat to many vulnerable populations. There are currently no approved vaccines, and RSV remains a high unmet global medical need. Here we describe the employment of a novel synthetic DNA-encoded antibody technology platform to develop and deliver an engineered human DNA-encoded monoclonal antibody (dMAbTM) targeting the fusion protein (F) of RSV as a new approach to prevention or therapy of at risk populations. In in vivo models, a single administration of synthetic DNA-encoding the single-chain fragment variable-constant fragment (scFv-Fc) RSV-F dMAb resulted in robust and durable circulating levels of a functional antibody systemically and in mucosal tissue. In cotton rats, which are the gold-standard animals to model RSV infection, we observed sustained scFv-Fc RSV-F dMAb in the sera and lung-lavage samples, demonstrating the potential for both long-lasting immunity to RSV and effective biodistribution. The scFv-Fc RSV-F dMAb harbored in the sera exhibited RSV antigen-specific binding and potent viral neutralizing activity. Importantly, in vivo delivery of synthetic DNA-encoding, the scFv-Fc RSV-F dMAb protected animals against viral challenge. Our findings support the significance of dMAbs as a potential platform technology for durable protection against RSV disease.

Synthetic nucleic acid antibody prophylaxis confers rapid and durable protective immunity against Zika virus challenge.

Significant concerns have arisen over the past 3 y from the increased global spread of the mosquito-borne flavivirus, Zika. Accompanying this spread has been an increase in cases of the devastating birth defect microcephaly as well as of Guillain-Barré syndrome in adults in many affected countries. Currently there is no vaccine or therapy for this infection; however, we sought to develop a combination approach that provides more rapid and durable protection than traditional vaccination alone. A novel immune-based prophylaxis/therapy strategy entailing the facilitated delivery of a synthetic DNA consensus prME vaccine along with DNA-encoded anti-ZIKV envelope monoclonal antibodies (dMAb) were developed and evaluated for antiviral efficacy. This immediate and persistent protection strategy confers the ability to overcome shortcomings inherent with conventional active vaccination or passive immunotherapy. A collection of novel dMAbs were developed which were potent against ZIKV and could be expressed in serum within 24-48 h of in vivo administration. The DNA vaccine, from a previous development, was potent after adaptive immunity was developed, protecting against infection, brain and testes pathology in relevant mouse challenge models and in an NHP challenge. Delivery of potent dMAbs protected mice from the same murine viral challenge within days of delivery. Combined injection of dMAb and the DNA vaccine afforded rapid and long-lived protection in this challenge model, providing an important demonstration of the advantage of this synergistic approach to pandemic outbreaks.

Novel Peptide-Based PD1 Immunomodulators Demonstrate Efficacy in Infectious Disease Vaccines and Therapeutics.

Many pathogens use the same immune evasion mechanisms as cancer cells. Patients with chronic infections have elevated levels of checkpoint receptors (e.g., programed cell death 1, PD1) on T cells. Monoclonal antibody (mAb)-based inhibitors to checkpoint receptors have also been shown to enhance T-cell responses in models of chronic infection. Therefore, inhibitors have the potential to act as a vaccine "adjuvant" by facilitating the expansion of vaccine antigen-specific T-cell repertoires. Here, we report the discovery and characterization of a peptide-based class of PD1 checkpoint inhibitors, which have a potent adaptive immunity adjuvant capability for vaccines against infectious diseases. Briefly, after identifying peptides that bind to the recombinant human PD1, we screened for in vitro efficacy in reporter assays and human peripheral blood mononuclear cells (PBMC) readouts. We first found the baseline in vivo performance of the peptides in a standard mouse oncology model that demonstrated equivalent efficacy compared to mAbs against the PD1 checkpoint. Subsequently, two strategies were used to demonstrate the utility of our peptides in infectious disease indications: (1) as a therapeutic in a bacteria-induced lethal sepsis model in which our peptides were found to increase survival with enhanced bacterial clearance and increased macrophage function; and (2) as an adjuvant in combination with a prophylactic malaria vaccine in which our peptides increased T-cell immunogenicity and the protective efficacy of the vaccine. Therefore, our peptides are promising as both a therapeutic agent and a vaccine adjuvant for infectious disease with a potentially safer and more cost-effective target product profile compared to mAbs. These findings are essential for deploying a new immunomodulatory regimen in infectious disease primary and clinical care settings.

Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin.

Endorepellin, the COOH-terminal domain of the heparan sulfate proteoglycan perlecan, inhibits several aspects of angiogenesis. We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen I, alpha2beta1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity. The interaction between endorepellin and alpha2beta1 integrin triggers a unique signaling pathway that causes an increase in the second messenger cAMP; activation of two proximal kinases, protein kinase A and focal adhesion kinase; transient activation of p38 mitogen-activated protein kinase and heat shock protein 27, followed by a rapid down-regulation of the latter two proteins; and ultimately disassembly of actin stress fibers and focal adhesions. The end result is a profound block of endothelial cell migration and angiogenesis. Because perlecan is present in both endothelial and smooth muscle cell basement membranes, proteolytic activity during the initial stages of angiogenesis could liberate antiangiogenic fragments from blood vessels' walls, including endorepellin.