Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system.

BACKGROUND: A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). METHODS: After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). RESULTS: Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin-eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. CONCLUSIONS: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling.

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology.

Current intraoperative storage and handling practices of autologous bypass conduit: A survey of the royal australasian college of surgeons.

During bypass surgery for peripheral arterial occlusive disease and ischaemic heart disease, autologous graft conduit including great saphenous veins and radial arteries are frequently stored in solution. Endothelial damage adversely affects the performance and patency of autologous bypass grafts, and intraoperative graft storage solutions have been shown to influence this process. The distribution of storage solutions currently used amongst Cardiothoracic and Vascular Surgeons from Australia and New Zealand is not well defined in the literature. The aim of this study was to determine current practices regarding autologous graft storage and handling amongst this cohort of surgeons, and discuss their potential relevance in the context of early graft failure. From this survey, the most frequently used storage solutions were heparinized saline for great saphenous veins, and pH-buffered solutions for radial arteries. Duration of storage was 30-45 min for almost half of respondents, although responses to this question were limited. Further research is required to investigate whether ischaemic endothelial injury generates a prothrombotic state, whether different storage media can alter this state, and whether this is directly associated with clinical outcomes of interest such as early graft failure.

Brain stem death induces pro-inflammatory cytokine production and cardiac dysfunction in sheep model.

INTRODUCTION: Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-h ovine model of BSD. METHODS: Twelve healthy female sheep (37-42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 h. Plasma and BAL endothelin-1 and cytokines (IL-1ß, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. RESULTS: Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 h post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1 × 109 cells/L [95% confidence interval (CI) 2.06-4.14] vs. 6 × 109 cells/L [95%CI 3.92-7.97]; p < 0.01) and BAL (4.5 × 109 cells/L [95%CI 0.41-9.41] vs. 26 [95%CI 12.29-39.80]; p = 0.03) after 6 h of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18-24.37] vs. 78.68 pM [95%CI 53.16-104.21]; p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69-5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 h. CONCLUSIONS: BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.

Diagnosis and management of hemangiomas and vascular malformations of the head and neck.

Vascular anomalies are congenital errors in vascular development. They frequently involve the head, neck, and oral cavity. Subdivided into vascular tumors (hemangiomas) and vascular malformations, vascular anomalies remain poorly understood. However, growing interest and recent advances in the diagnosis, management, and molecular characterization of these lesions are improving treatment strategies. The role of the multidisciplinary team cannot be overstated. This review provides both basic and up-to-date knowledge on the most common vascular anomalies encountered by physicians and practitioners. Because treatment options for vascular anomalies are widely variable and often debated, this report aims to provide a comprehensive approach to these lesions based upon current concepts and practical clinical experience.

Toward a 1550 nm InGaAs photoconductive switch for terahertz generation.

We report a terahertz (THz) photoconductive switch made from a composite of metal ErAs nanoparticles embedded in In(0.53)Ga(0.47)As and coupled to a square spiral antenna. The THz output power was measured in a 77 K cryostat by using a standard hyperhemisphere-lens package, a Golay cell outside the cryostat, and a quasi-optical filter bank for spot frequency spectral measurements. Results indicate an average output power of approximately 12 microW at 22 V bias using 140 mW of optical pump power from a subpicosecond fiber mode-locked laser. In addition, the THz spectra displayed invariance to bias voltage despite operating near impact ionization.

Acquired von Willebrand syndrome in respiratory extracorporeal life support: a systematic review of the literature.

BACKGROUND AND OBJECTIVE: Venovenous extracorporeal membrane oxygenation (VV ECMO) and extracorporeal CO2 removal (ECCO2R) are increasingly used in the management of severe respiratory failure. With bleeding complications being one of the major risks of these techniques, our aim in this systematic review was to assess the available literature on acquired von Willebrand syndrome (AvWS) and extracorporeal support. AvWS has previously been associated with bleeding and shear stress. DESIGN AND DATA SOURCES: A systematic review, using Medline via PubMed, was performed to identify eligible studies up to January 2017. RESULTS AND CONCLUSION: The prevalence of AvWF among patients on VV ECMO or ECCO2R is high, but only a limited number of studies are reported in the literature. AvWS testing should be performed, including vWF multimer analysis, vWF activity and vWF antigen concentration. The extent to which vWF contributes to bleeding during ECMO, or how much changes in ECMO management can influence high molecular weight vWF multimer levels, cannot be answered from the currently available evidence and there remains a need for future studies.

Nasal septal melanoma.

The controversial issues on management of nasal septal melanoma center around the extent of pretreatment evaluation. Probably the minimum required is a chest radiograph, CBC, and liver function test (Dr. Westbrook). The use of bone scan and CT scans of brain, lungs, and abdomen (Drs. Suen and Medina) is controversial and of little yield. Aside from distant metastasis to the lung, liver, and brain, the regional metastatic spread pattern includes the nodal groups of the buccal, submental, and submandibular areas, with the possibility of bilateral involvement. All consultants agreed that the primary tumor should be treated with a wide local excision; however, there is no agreement as to the extent of nodal groups included in the nodal dissection. No consultant recommended primary septal reconstruction. The use of postoperative radiotherapy in high-dose fractions remains experimental, in the protocol research stage.

Preauricular approach to infratemporal fossa.

We present an approach to the skull base that allows access to both the infratemporal fossa and the middle cranial fossa with minimal morbidity. This approach is different from most of the previously described approaches in that it uses a preauricular incision, preserves the facial nerve, and avoids the mastoid bone. It involves dividing the zygomatic arch and displacing it inferiorly, dividing the malar eminence (zygoma) and displacing it anteriorly, and cutting the coronoid process and retracting it superiorly with the attached temporalis muscle. Reconstruction is accomplished by using the temporalis muscle or a pericranial flap to cover the dura, a free fat graft to fill the space left by tumor excision, and by wiring the zygomatic arch and malar eminence into their original positions. Case reports of both benign and malignant lesions are presented.

Surgical management of advanced scalp cancer.

A series of 53 advanced scalp cancer patients treated with surgery is presented. A review of these patients concludes: 1) local tumor growth--not distant metastasis--is the primary problem; 2) management is based on the tendency of a tumor to spread laterally early in its development with a deep invasion occurring later on; 3) when deep invasion occurs, radical excision and reconstruction is indicated to control the disease; 4) recurrence following adequate local therapy requires a change in treatment modality.

Analysis of disability resulting from treatment including radical neck dissection or modified neck dissection.

A multiinstitutional study to define the impact of total treatment programs involving radical neck dissection (RND) and modified neck dissection (MND) on patients' permanent disability was undertaken. A total of 243 patient responses were included in the study. Comparative analyses between the treatment groups show no advantage of one surgical operation over the other in returning patients to their pretreatment employment status. Radiation therapy was identified as adding significantly to the patient's permanent disability.

A unique microvascular phenotype shared by juvenile hemangiomas and human placenta.

BACKGROUND: Juvenile hemangiomas are common, benign tumors, distinctive for their perinatal presentation, rapid growth during the first year of life, and subsequent involution. We recently reported that endothelia of hemangiomas highly express GLUT1, a glucose transporter normally restricted to endothelia with blood-tissue barrier function, as in brain and placenta. OBJECTIVE: To investigate possible further similarities between hemangioma and placental vessels. DESIGN: In a retrospective study of a variety of vascular tumors and anomalies, we assessed lesional immunoreactivities for the placenta-associated vascular antigens FcgammaRII, Lewis Y antigen (LeY), merosin, and GLUT1. SETTING: A university-affiliated pediatric hospital. MAIN OUTCOME MEASURE: Immunoreactivities scored for each antigen were summarized according to lesional type, compared with those of normal skin, brain, and placenta, and correlated with patient age, sex, and lesional location. RESULTS: All of 66 hemangiomas (patients aged 22 days to 7 years) showed intense immunoreactivity for FcgammaRII, merosin, LeY, and GLUT1. No immunoreactivities for these markers were seen in any of 26 vascular malformations, 4 granulation tissue specimens, 13 pyogenic granulomas, or in the tumor vasculature of 6 malignant tumors of nonvascular origin. Microvascular immunoreactivity for all 4 markers was observed in placental chorionic villi, but was absent in microvessels of normal skin and subcutis. Brain microvessels expressed only GLUT1 and merosin. CONCLUSIONS: A distinct constellation of tissue-specific markers is uniquely coexpressed by hemangiomas and placental microvessels. These findings imply a unique relationship between hemangioma and the placenta and suggest new hypotheses concerning the origin of these tumors.

Evaluation of the effectiveness of postoperative radiation therapy for the control of local disease.

Although we agree that postoperative irradiation does improve the local and regional control, our findings indicate that the rate of control, especially local control, is somewhat less than 90 percent. Our data reveal a recurrence rate of 32.7 percent in advanced, stage III and IV, squamous cell carcinomas in the head and neck treated by surgery and postoperative irradiation; this rate may be even greater with longer follow-up. We recommend that surgeons avoid "close" surgical margins (less than 5 mm) when resecting primary cancers and not rely too heavily on radiation therapy to control residual subclinical disease. It appears that continued study is needed to establish the true efficacy of irradiation in the control of subclinical disease, and that local recurrence must be differentiated from regional recurrence when reporting these results.

Functional evaluation of the spinal accessory nerve after neck dissection.

The pain and dysfunction associated with a loss of innervation by the spinal accessory nerve has motivated surgeons to modify the classic radical neck dissection. A prospective study of 109 patients who underwent either a radical neck dissection or a modification of it with preservation of the spinal accessory nerve revealed that those patients in whom the nerve, muscle, and vein were preserved had less dysfunction (30 percent) than those with nerve preservation only (50 percent) or classic radical neck dissection (60 percent). In addition, even when the functional disability was the same, there was less associated pain with nerve-sparing procedures. Furthermore, a large group of patients (40 percent) who underwent classic radical neck dissection had minimal disability. Given these results, a prospective study of recurrence data in these patients is indicated.

Results of BCG adjuvant immunotherapy in 100 patients with epidermoid carcinoma of the head and neck.

One hundred patients with advanced, recurrent, or metastatic squamous cell carcinoma of the head and neck were treated with chemotherapy and BCG as adjuvant immunotherapy. The overall response rate was 35 per cent, and the median duration of response was seventeen weeks. BCG does not prolong duration of remission or survival time.

Management of congenital vascular lesions of the head and neck.

Congenital vascular lesions are often misdiagnosed and, for the most part, left untreated. The absence of a uniformly accepted classification of these lesions and confusion over their natural history are partly responsible. A new classification of these lesions recognizes two distinct groups of lesions, hemangiomas and vascular malformations. Hemangiomas are usually not present at birth, proliferate during the first year of life, and then involute. In contrast, vascular malformations are always present at birth, never proliferate, and never involute. Knowledge of this classification system will facilitate the diagnosis of these lesions and lead to appropriate, individualized treatment.

Chemotherapy for salivary gland cancer.

Salivary gland cancers are usually treated with surgery and irradiation; however, some of the aggressive salivary gland cancers recur or metastasize and are not amendable to treatment with further surgery or irradiation. Little is known about chemotherapy for these palliative situations because of the relatively scarcity of these cancers. The data in the literature has provided little clinical information because all salivary gland cancers are usually lumped together and/or multiple different drug combination are used. In an effort to arrive at a rational basis for recommending specific drug regimens for specific histologic types of salivary gland cancers, a two-part study was undertaken to determine which chemotherapy drugs seem to be effective or ineffective. One part was a literature review, and the second part was a survey of numerous institutions' experiences, including our own. A total of 85 cases of salivary gland cancers treated with chemotherapy were felt to be evaluable for this study. The overall response rate (complete and partial) was 42%. Although disease responded whether it was local, regional, or distant disease, there was a higher response rate in local-regional disease compared to distant metastases. Salivary gland cancers are definitely sensitive to chemotherapy drugs. This study reveals which drugs seem to be effective and provides some rational basis for future chemotherapy trials for salivary gland cancers.

Treatment of hemangiomas of the head and neck.

Hemangiomas are a group of pediatric tumors that present at or soon after birth. Rapid proliferation is seen in the neonatal period, and may continue for the first year of life. Involution follows, and may last as long as 12 years. Since hemangiomas invariably involute, the vast majority have been left untreated. At least 10% to 20% of cases, however, will need active intervention, traditionally in the form of oral Prednisone. The frequent occurrence of life-threatening complications, permanent deformities, and irreversible psychosocial damage in spite of adequate steroid therapy necessitated a fresh look at the management of these lesions. Using recently developed laser technology alone or in combination with surgical excision, the authors have developed guidelines for safe intervention in all stages of the hemangioma cycle. Safe, active intervention in accordance with these guidelines offers an alternative to the more conservative approach previously advocated.

Complications of laser surgery for laryngeal papillomatosis.

Carbon dioxide laser surgery has become the treatment of choice for laryngeal papillomatosis. The purpose of this study was to determine the type, incidence, and severity of complications that occur with laser microlaryngoscopy for a disease that often requires multiple operations. Forty patients with laryngeal papillomatosis underwent a total of 222 carbon dioxide laser laryngoscopies over the 6 1/2-year period from June 1977 through December 1983. The results showed that 13 patients sustained a total of 23 separate complications. Intraoperative complications consisted of one episode of bilateral pneumothorax and one episode of cervical subcutaneous emphysema, both associated with the use of jet ventilation anesthesia, and one episode of a loosened tooth in a child with carious teeth. The delayed complications consisted of 10 patients with anterior laryngeal webbing, 2 patients with posterior webbing, 6 patients with laryngeal edema or fibrosis, and one episode each of prolonged dysphagia and tracheal foreign body. No airway fires occurred. Only 2 of 28 patients who had 5 or fewer laser laryngoscopies developed complications, but 11 or 12 patients undergoing 6 or more laser operations had complications. In summary, although the incidence of life threatening complications was low, the occurrence of minor complications such as small anterior glottic webs and persistent edema was relatively high, especially in those patients who required multiple laser laryngoscopies.

Treatment of oral cavity vascular malformations using the neodymium:YAG laser.

Although rare, hemangiomas and lymphangiomas of the oral cavity are difficult management problems. Surgical resection is still commonly thought of by many when considering treatment. Several articles in 1986 reported good results using the neodymium:yttrium-aluminum-garnet laser for these lesions. Using this laser, we have treated six patients with hemangiomas or lymphangiomas of the oral cavity over the past 4 years. Although most patients have required several treatments, the response has been excellent overall. This report confirms the results of previous studies.