Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx.

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.

Impact of augmented renal clearance on anticoagulant therapy in critically ill patients with coronavirus disease 2019: A retrospective cohort study.

INTRODUCTION: This study aimed to determine the impact of augmented renal clearance (ARC) on anticoagulation therapy in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: This retrospective cohort study included adult patients with severe COVID-19 with ARC who had been treated at our hospital between 2020 and 2021. We measured the estimated glomerular filtration rate calculated by the Chronic Kidney Disease Epidemiology Collaboration formula (eGFRCKD-EPI) every morning, and ARC condition was defined as eGFRCKD-EPI ≥ 130 mL/min/1.73 m2. Multivariate regression analysis with Huber-White sandwich estimator was performed to examine the association of unfractionated heparin (UH) dosage between blood test timings with activated partial thromboplastin time (APTT) compared with and without ARC. RESULTS: We identified 38 enrolled patients: seven and 31 in the ARC and non-ARC groups, respectively. In the ARC coexisting condition, a higher dose of UH, which corresponded to the total dose in 24 h from the previous day, was required to achieve the same APTT prolongation, with a significant difference (p < 0.001). CONCLUSIONS: Our study suggests that careful monitoring and consideration of higher UH doses in critically ill patients with COVID-19 is necessary because anticoagulation failure can occur during ARC.

Tissue damage between barbed suture and conventional sutures in animal laboratory model using scanning electron microscopy.

This study aimed to compare the tissue damage caused by barbed sutures and conventional sutures using scanning electron microscopy (SEM). Porcine myocardium was incised and sutured using different thread types: barbed suture, (STRATAFIX® Spiral PDS PLUS) and conventional sutures, (VICRYL® and PDS Plus®). Needle hole shapes were examined at magnifications of 30×-100×. VICRYL® suture damaged the tissue and created large gaps around the needle holes. The tissue around the needle holes was smoother and less damaged in the single suture ligations with PDS®; however, a large gap had formed. In the continuous suture with STRATAFIX®, the tissue around the needle holes was significantly smoother and minimally damaged, with no noticeable gaps around the needle holes. Barbed sutures reduced the load on needle holes and minimised tissue damage owing to the dispersion of traction forces by the barbs compared with conventional sutures.

Decreased neutrophil counts prolong inflammation in acute pancreatitis and cause inflammation spillover to distant organs.

BACKGROUND/OBJECTIVE: Acute pancreatitis is an aseptic inflammation caused by pathologically activated pancreatic enzymes and inflammatory mediators produced secondarily by neutrophils and other inflammatory cells and is one of the most difficult diseases to treat. This study aimed to investigate the role of neutrophils in pancreatitis by examining tissue dynamics. METHODS: We created a model of caerulein-induced pancreatitis in 12-week-old male granulocyte colony-stimulating factor knockout mice (G-CSF-KO) and wild-type littermate control mice (six intraperitoneal injections of caerulein [80 µg/kg body weight] at hourly intervals for 2 days). Mice were sacrificed 0, 3, 6, 12, 24, 36, 48, 72, and 168 h after caerulein administration and examined histologically. RESULTS: The survival rate after one week of caerulein administration was 100 % in the control mice, whereas it was significantly lower (10 %) in the G-CSF-KO mice. Histological examination revealed significant hemorrhage and inflammatory cell migration in the G-CSF-KO mice, indicating prolonged inflammation. CONCLUSION: Prolonged inflammation was observed in the G-CSF-KO mice. Tissue cleanup by neutrophils during the acute phase of inflammation may influence healing through the chronic phase.

Delayed diagnosis of Lemierre's syndrome in a patient with severe coronavirus disease 2019: importance of comprehensive oral and neck examination - a case report.

BACKGROUND: Given the widespread prevalence of the coronavirus disease 2019 (COVID-19), oral and neck examinations tend to be avoided in patients with suspected or confirmed COVID-19. This might delay the diagnosis of conditions such as Lemierre's syndrome, which involves symptoms resembling COVID-19-related throat manifestations. CASE PRESENTATION: A 24-year-old man without any underlying conditions was diagnosed with COVID-19 7 days before presentation. He was admitted to another hospital 1 day before presentation with severe COVID-19 and suspected bacterial pneumonia; accordingly, he was started on treatment with remdesivir and meropenem. Owing to bacteremic complications, the patient was transferred to our hospital for intensive care. On the sixth day, the patient experienced hemoptysis; further, a computed tomography (CT) scan revealed new pulmonary artery pseudoaneurysms. Successful embolization was performed to achieve hemostasis. In blood cultures conducted at the previous hospital, Fusobacterium nucleatum was isolated, suggesting a cervical origin of the infection. A neck CT scan confirmed a peritonsillar abscess and left internal jugular vein thrombus; accordingly, he was diagnosed with Lemierre's syndrome. The treatment was switched to ampicillin/sulbactam, based on the drug susceptibility results. After 6 weeks of treatment, the patient completely recovered without complications. CONCLUSION: This case highlights the significance of thorough oral and neck examinations in patients with suspected or diagnosed COVID-19 for the detection of throat and neck symptoms caused by other conditions.

Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia.

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1ß was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.

Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection.

The potential for a rapid increase in severity is among the most frightening aspects of severe acute respiratory syndrome coronavirus 2 infection. Evidence increasingly suggests that the symptoms of coronavirus disease-2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) differ from those of classic ARDS. Recently, the severity of COVID-19 has been attributed to a systemic, thrombotic, and inflammatory disease that damages not only the lungs but also multiple organs, including the heart, brain, toes, and liver. This systemic form of COVID-19 may be due to inflammation and vascular endothelial cell injury. The vascular endothelial glycocalyx comprises glycoproteins and plays an important role in systemic capillary homeostasis maintenance. The glycocalyx covers the entire vascular endothelium, and its thickness varies among organs. The endothelial glycocalyx is very thin in the pulmonary capillaries, where it is affected by gaseous exchange with the alveoli and the low intravascular pressure in the pulmonary circulation. Despite the clearly important roles of the glycocalyx in vascular endothelial injury, thrombosis, vasculitis, and inflammation, the link between this structure and vascular endothelial cell dysfunction in COVID-19 remains unclear. In this prospective review, we summarize the importance of the glycocalyx and its potential as a therapeutic target in cases of systemic COVID-19.

Specific Deletion of p16INK4a with Retention of p19ARF Enhances the Development of Invasive Oral Squamous Cell Carcinoma.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16INK4a-specific loss with retention of the p19ARF gene (p16INK4a-/-). 4NQO-treated p16-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16INK4a-specific loss with retention of p19ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.

Possible involvement of Syndecan-1 in the state of COVID-19 related to endothelial injury.

BACKGROUND: The coronavirus infection 2019 (COVID-19) is associated with microvascular endothelial injury. Here, we report that syndecan-1, a component of endothelial glycocalyx, may reflect the disease state of COVID-19 related to endothelial injury. CASE PRESENTATION: A patient with COVID-19 was transferred to the intensive care unit of our hospital. Computed tomography of the chest showed bilateral ground glass opacities, which was diagnosed as acute respiratory syndrome. The PaO2/FIO2 ratio gradually increased from 158 on hospitalization to 300 on Day 11, on which day the ventilator was withdrawn. However, serum syndecan-1 (SDC-1) level gradually decreased from 400.5 ng/ml at hospitalization to 165.1 ng/ml on Day 5. On Day 6, serum SDC-1 level increased to 612.9 ng/ml owing to a systemic thrombosis with an increase in D-dimer. Serum SDC-1 level then decreased until 206.0 ng/ml on Day 11 after a decrease in D-dimer. The patient was transferred to another hospital on Day 21 after hospitalization. CONCLUSIONS: In this case report, changes in serum SDC-1 level closely reflected the change in disease condition in a patient with COVID-19. Serum SDC-1 may be a useful biomarker for monitoring the disease state of critically ill patients with COVID-19.

Validity and risk factor analysis for helicopter emergency medical services in Japan: a pilot study.

BACKGROUND: Some emergency departments use triage scales, such as the Canadian Triage and Acuity Scale and Japan Urgent Stroke Triage Score, to detect life-threatening situations. However, these protocols have not been used for aeromedical services. Therefore, we investigated the factors predicting these life-threatening situations in aeromedical services as a pilot study for establishing the protocol. METHOD: We retrospectively evaluated helicopter emergency medical service cases from 1 April 2015 to 31 March 2020 at Gifu University Hospital using the mission records. We only evaluated cases dealing with suggested internal medicine issues. We excluded cases influenced by external factors such as trauma or cases that included hospital-to-hospital transportation, focusing only on prehospital care. We evaluated the validity of the medical emergencies based on the needs for emergency interventions and hospital admission and of the suggested diagnoses and associated risk factors. RESULT: A total of 451 cases were suitable for inclusion in the study. In the analysis for all emergency calls, 235 (52.11%) cases needed emergency intervention and 300 (64.4%) required hospital admission. The suggested diagnosis was valid for 261 (57.87%) cases. After the first assessment by emergency medical technicians, 75 cases were removed. Analysis after this first assessment found that 52.31% cases required emergency intervention, 70.26% needed admission, and the suggested diagnosis was valid for 69.41% of cases. In the analysis of emergency calls, the multivariate analysis of some key variables identified age, playing sports, and gasping as risk factors for emergency intervention. Hospital admission risk factors included being age only. The suggested diagnosis was valid only for sports situations. In the analysis after the first assessment by an emergency medical technician, risk factors for emergency intervention included being age being male, playing sports, and gasping, and those for hospital admission was being age, being male, and experiencing stroke symptoms and/or disturbance of consciousness. The suggested diagnosis was valid only for sports situations. CONCLUSION: Some 'second' keywords/phrases predict medical emergencies. Therefore, the dispatch commander should gather these keyword/phrases to assess.

Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in Lipopolysaccharide-Induced Experimental Endotoxemia.

Neutrophil elastase (NE) is necessary for effective sterilization of phagocytosed bacterial and fungal pathogens; however, NE increases alveolocapillary permeability and induces proinflammatory cytokine production in sepsis-induced acute respiratory distress syndrome. Under septic conditions, the pulmonary endothelial glycocalyx covering on the healthy endothelium surface is injured, but the contribution of NE to this injury remains unknown. Our aim was to examine whether NE-induced pulmonary endothelial injury is associated with endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 9- to 12-week-old granulocyte colony-stimulating factor knockout (G-CSFKO) mice, which harbor few neutrophils, and littermate control mice; in a second assay, mice were injected with the NE-inhibitor sivelestat (0.2 mg/kg) at 3, 6, 9, and 12 hours after LPS administration. Subsequently, vascular endothelial injury was evaluated through ultrastructural analysis. At 48 hours after LPS injection, survival rate was more than threefold higher among G-CSFKO than control mice, and degradation of both thrombomodulin and syndecan-1 was markedly attenuated in G-CSFKO compared with control mice. Ultrastructural analysis revealed attenuated vascular endothelial injury and clear preservation of the endothelial glycocalyx in G-CSFKO mice. Moreover, after LPS exposure, survival rate was approximately ninefold higher among sivelestat-injected mice than control mice, and sivelestat treatment potently preserved vascular endothelial structures and the endothelial glycocalyx. In conclusion, NE is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions.

Multiple trauma including pelvic fracture with multiple arterial embolization: an autopsy case report.

BACKGROUND: Pelvic fracture with high energy trauma has a high mortality rate, especially in men. In addition, severe multiple trauma, major hemorrhage, and administration of red blood cells predict mortality in elderly patients with pelvic fracture. We herein report a rare case in which multiple arterial embolization occurred after pelvic fracture. CASE PRESENTATION: An 83-year-old male cyclist was transported to our hospital after being struck by a car. On arrival, he was diagnosed with multiple trauma, including rib fractures with hemothorax, lumbar fractures of the transverse process, and injuries in the right acetabulum, left adrenal gland, and liver. He underwent massive transfusion and transcatheter arterial embolization due to extravasation from the right superior gluteal artery and left adrenal gland. On the second day, owing to right lower leg ischemia, serum creatinine kinase and myoglobin levels were markedly elevated from the reference value; hence, a right above-knee amputation was performed 12 h after the accident. However, both protein levels remained high after amputation, resulting in acute renal injury, which was treated via hemodiafiltration on hospital day 3. In addition, sustained low efficiency hemodialysis and plasma exchange were performed on hospital day 4. Despite these treatments, the patient's hemodynamics did not improve, and he died on hospital day 8. The autopsy revealed necropsy of the iliopsoas muscles and the digestive tract. CONCLUSIONS: The causes of the patient's death were considered to be persistent rhabdomyolysis and severe hypotension due to iliopsoas necrosis and peritonitis due to digestive tract necrosis. Multiple arterial embolization caused by consumption coagulopathy associated with multiple trauma may account for severe outcomes in this case.

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to ß-1 integrin reduction, costameric instability, and dilated cardiomyopathy.

Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the muscle-specific ß1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. ß1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper ß1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.

Anti-apoptosis in nonmyocytes and pro-autophagy in cardiomyocytes: two strategies against postinfarction heart failure through regulation of cell death/degeneration.

Anti-apoptotic therapy for cardiomyocytes could be an effective strategy for preventing or treating heart failure. Notably, however, morphological evidence definitively demonstrating cardiomyocyte apoptosis has been very rare in actual heart diseases such as acute myocardial infarction and heart failure. By contrast, within the postinfarction heart, interstitial noncardiomyocytes such as granulation tissue cells do die via apoptosis to form scar tissue. Blockade of this apoptosis improves survival and mitigates ventricular remodeling and dysfunction during the chronic stage. Possible mechanisms to explain this benefit might be preservation of infarcted wall thickness and preservation of myofibroblasts, which could promote infarct shrinkage; both would reduce wall stress through Laplace's law. On the other hand, autophagy is an intracellular degradation mechanism that compensates for energy insufficiency by digesting and recycling intracellular components, and is often observed in cardiomyocytes within failing hearts with various origins including postinfarction. Starvation strongly induces and activates autophagic degeneration within cardiomyocytes. When that activation is inhibited, the starved animals suffer from heart failure. Promoting autophagy through caloric restriction or several reagents not only reduces the acute infarct size but also mitigates postinfarction cardiac remodeling and dysfunction during chronic stages. Moreover, augmenting autophagy by the treatment with resveratrol or exercise can bring about reverse remodeling in failing hearts with a large old myocardial infarction. In conclusion, we propose two strategies for managing postinfarction heart failure through control of cell death/degeneration: (1) anti-apoptosis in granulation tissue noncardiomyocytes; and (2) pro-autophagy in salvaged cardiomyocytes.

Three-dimensional ultrastructure of capillary endothelial glycocalyx under normal and experimental endotoxemic conditions.

BACKGROUND: Sugar-protein glycocalyx coats healthy endothelium, but its ultrastructure is not well described. Our aim was to determine the three-dimensional ultrastructure of capillary endothelial glycocalyx in the heart, kidney, and liver, where capillaries are, respectively, continuous, fenestrated, and sinusoidal. METHODS: Tissue samples were processed with lanthanum-containing alkaline fixative, which preserves the structure of glycocalyx. RESULTS: Scanning and transmission electron microscopy revealed that the endothelial glycocalyx layer in continuous and fenestrated capillaries was substantially thicker than in sinusoids. In the heart, the endothelial glycocalyx presented as moss- or broccoli-like and covered the entire luminal endothelial cell surface. In the kidney, the glycocalyx appeared to nearly occlude the endothelial pores of the fenestrated capillaries and was also present on the surface of the renal podocytes. In sinusoids of the liver, glycocalyx covered not only the luminal side but also the opposite side, facing the space of Disse. In a mouse lipopolysaccharide-induced experimental endotoxemia model, the capillary endothelial glycocalyx was severely disrupted; that is, it appeared to be peeling off the cells and clumping. Serum concentrations of syndecan-1, a marker of glycocalyx damage, were significantly increased 24 h after administration of lipopolysaccharide. CONCLUSIONS: In the present study, we visualized the three-dimensional ultrastructure of endothelial glycocalyx in healthy continuous, fenestrated, and sinusoidal capillaries, and we also showed their disruption under experimental endotoxemic conditions. The latter may provide a morphological basis for the microvascular endothelial dysfunction associated with septic injury to organs.

Postinfarction Cardiac Remodeling Proceeds Normally in Granulocyte Colony-Stimulating Factor Knockout Mice.

Treatment with granulocyte colony-stimulating factor (G-CSF) reportedly mitigates postinfarction cardiac remodeling and dysfunction. We herein examined the effects of G-CSF knockout (G-CSF-KO) on the postinfarction remodeling process in the hearts of mice. Unexpectedly, the acute infarct size 24 hours after ligation was similar in the two groups. At the chronic stage (4 weeks later), there was no difference in the left ventricular dimension, left ventricular function, or histological findings, including vascular density, between the two groups. In addition, expression of vascular endothelial growth factor (VEGF) was markedly up-regulated in hearts from G-CSF-KO mice, compared with wild-type mice. Microarray failed in detecting up-regulation of VEGF mRNA, whereas G-CSF administration significantly decreased myocardial VEGF expression in mice, indicating that G-CSF post-transcriptionally down-regulates VEGF expression. When G-CSF-KO mice were treated with an anti-VEGF antibody (bevacizumab), cardiac remodeling was significantly aggravated, with thinning of the infarct wall and reduction of the cellular component, including blood vessels. In the granulation tissue of bevacizumab-treated hearts 4 days after infarction, vascular development was scarce, with reduced cell proliferation and increased apoptosis, which likely contributed to the infarct wall thinning and the resultant increase in wall stress and cardiac remodeling at the chronic stage. In conclusion, overexpression of VEGF may compensate for the G-CSF deficit through preservation of cellular components, including blood vessels, in the postinfarction heart.

Caveolin modulates integrin function and mechanical activation in the cardiomyocyte.

ß1 integrins (ß1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Given their close localization, as well as their role in mechanotransduction and signaling, we hypothesized that caveolin (Cav) proteins might regulate integrins in the CM. ß1 localization, complex formation, activation state, and signaling were analyzed using wild-type, Cav3 knockout, and Cav3 CM-specific transgenic heart and myocyte samples. Studies were performed under basal and mechanically loaded conditions. We found that: (1) ß1 and Cav3 colocalize in CM and coimmunoprecipitate from CM protein lysates; (2) ß1 is detected in a subset of caveolae; (3) loss of Cav3 caused reduction of ß1D integrin isoform and active ß1 integrin from the buoyant domains in the heart; (4) increased expression of myocyte Cav3 correlates with increased active ß1 integrin in adult CM; (5) in vivo pressure overload of the wild-type heart results in increased activated integrin in buoyant membrane domains along with increased association between active integrin and Cav3; and (6) Cav3-deficient myocytes have perturbed basal and stretch mediated signaling responses. Thus, Cav3 protein can modify integrin function and mechanotransduction in the CM and intact heart.

Integrins and integrin-associated proteins in the cardiac myocyte.

Integrins are heterodimeric, transmembrane receptors that are expressed in all cells, including those in the heart. They participate in multiple critical cellular processes including adhesion, extracellular matrix organization, signaling, survival, and proliferation. Particularly relevant for a contracting muscle cell, integrins are mechanotransducers, translating mechanical to biochemical information. Although it is likely that cardiovascular clinicians and scientists have the highest recognition of integrins in the cardiovascular system from drugs used to inhibit platelet aggregation, the focus of this article will be on the role of integrins specifically in the cardiac myocyte. After a general introduction to integrin biology, the article will discuss important work on integrin signaling, mechanotransduction, and lessons learned about integrin function from a range of model organisms. Then we will detail work on integrin-related proteins in the myocyte, how integrins may interact with ion channels and mediate viral uptake into cells, and also play a role in stem cell biology. Finally, we will discuss directions for future study.

Simple pneumopericardium due to blunt trauma progressing to tension pneumopericardium during transportation.

Patients with simple pneumopericardium due to blunt thoracic trauma occasionally progressed to tension pneumopericardium, although pneumopericardium is believed to be benign in general. A 65-year-old man had both arms caught in a grinding machine and his face struck hard at work. He was diagnosed with bilateral degloving injuries of both arms and mediastinal emphysema on computed tomography. He required transfer to an advanced emergency medical service center for treatment. Although he was hemodynamically stable then, the patient's condition deteriorated during transportation. The patient returned to the local hospital as cardiopulmonary resuscitation continued, repeat computed tomography was performed, which showed a substantial pneumopericardium and exacerbation of mediastinal and subcutaneous emphysema. After then, cardiopulmonary resuscitation was discontinued because there was no response. For the patient to be rescued in this situation, thoracotomy is required, although it should be reserved for patients with evidence of hemodynamic compromise attributable to cardiac tamponade.