Distortion of KB estimates of endothelin-1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin-1 clearance mechanism.

Dual endothelin ETA and ETB receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ETB receptor-mediated clearance of endothelin-1 at specific vascular sites may compromise this targeted therapy. Concentration-response curves (CRC) to endothelin-1 or the ETB agonist sarafotoxin S6c were constructed, with endothelin receptor antagonists, in various rat and mouse isolated arteries using wire myography or in rat isolated trachea. In rat small mesenteric arteries, bosentan displaced endothelin-1 CRC competitively indicative of ETA receptor antagonism. In rat small pulmonary arteries, bosentan 10 µmol L-1 left-shifted the endothelin-1 CRC, demonstrating potentiation consistent with antagonism of an ETB receptor-mediated endothelin-1 clearance mechanism. Removal of endothelium or L-NAME did not alter the EC50 or Emax of endothelin-1 nor increase the antagonism by BQ788. In the presence of BQ788 and L-NAME, bosentan displayed ETA receptor antagonism. In rat trachea (ETB ), bosentan was a competitive ETB antagonist against endothelin-1 or sarafotoxin S6c. Modeling showed the importance of dual receptor antagonism where the potency ratio of ETA to ETB antagonism is close to unity. In conclusion, the rat pulmonary artery is an example of a special vascular bed where the resistance to antagonism of endothelin-1 constriction by ET dual antagonists, such as bosentan or the ETB antagonist BQ788, is possibly due to the competition of potentiation of endothelin-1 by blockade of ETB -mediated endothelin-1 clearance located on smooth muscle and antagonism of ETA - and ETB -mediated contraction. This conclusion may have direct application for the efficacy of endothelin-1 antagonists for treating PAH.

Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro.

BACKGROUND: Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: bosentan, pulmonary artery 6.28±0.13 and radial artery 6.04±0.10; macitentan, pulmonary artery 8.02±0.13 and radial artery 7.49±0.08; and ambrisentan, pulmonary artery 7.38±0.13 and radial artery 6.96±0.10. CONCLUSIONS: Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.

May-Thurner variant secondary to degenerative lumbar spondylolisthesis: a case report.

May-Thurner syndrome (MTS) is a rare condition in which patients develop iliofemoral deep venous thrombosis due to an anatomical variant in which the right common iliac artery overlies and compresses the left common iliac vein against the lumbar spine. We report a case of variant MTS, where vascular distortion secondary to spontaneous spinal arthrodesis of degenerative lumbar spondylolisthesis resulted in left common iliac vein compression and iliofemoral deep vein thrombosis. While the common complications of degenerative spondylolisthesis, such as spinal stenosis, are well described; the potential for pelvic vascular distortion secondary to anterior translation of the lumbar spine is not well recognized. The purpose in presenting this case is to describe the mechanism by which this variant of MTS occurs and highlight the need for vigilance for this unusual clinical entity.

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.

African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors. Blood samples were obtained from 174 African American and 198 white HA subjects and their F8 gene sequences determined. Major histocompatibility complex class II binding and T-cell recognition of polymorphic sequences were evaluated using quantitative binding assays and HLA-DRB1 tetramers. Peptides corresponding to 4 common ns-SNPs showed limited binding to 11 HLA-DRB1 proteins. CD4 T cells from 22 subjects treated with FVIII products having sequences at residues FVIII-484, 1241, and 2238 differing from those of putative proteins encoded by their F8 genes did not show high-avidity tetramer binding, whereas positive-control staining of tetanus-specific CD4 T cells was routinely successful. African Americans with an intron-22 inversion mutation showed a 2-3 times-higher inhibitor incidence than whites with the same mutation (odds ratio = 2.3 [1.1-5.0, P = .04]), but this did not correlate with any of the ns-SNPs. We conclude that immune responses to "sequence-mismatched" FVIII products are unlikely to contribute appreciably to the inhibitor incidence in African Americans.

Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study.

BACKGROUND: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. METHODS: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration-response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. RESULTS: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. CONCLUSIONS: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.

Review: indications for interventional radiology in the management of patients with spinal cord injuries.

OBJECTIVES: To outline a range of minimally invasive image-guided procedures that benefit spinal cord-injured patients and may expedite clinical care. STUDY DESIGN: Pictorial review. RESULTS/CONCLUSIONS: Image-guided procedures have made a significant impact in medical management in many specialties. These techniques continue to evolve rapidly and afford opportunities to reduce patient morbidity and in-patient length of stay.

Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance.

Evidence of antibody isotype/subtype switching may provide prognostic value regarding the state of immune responses to therapeutic proteins, e.g. anti-factor VIII (FVIII) antibodies that develop in many hemophilia A patients, clinically termed "inhibitors". A sensitive, high- information-content surface plasmon resonance (SPR) assay has been developed to quantify IgG subtype distributions and the domain specificity of anti-drug antibodies. Plasma samples from 22 subjects with an allo- or auto-immune reaction to FVIII were analyzed. Pre-analytical treatment protocols were developed to minimize non-specific binding and specific matrix interference due to von Willebrand factor-FVIII interactions. The dynamic range for IgG quantification was 0.2-5 µg/ml (∼1-33 nM), allowing characterization of inhibitor-positive samples. Subtype-specific monoclonal antibodies were used to quantify the IgG subtype distribution of FVIII-specific antibodies. Most samples obtained from multiply-infused inhibitor subjects contained IgG4 antibodies. Several distinct phenotypes were assigned based on the IgG subtype distribution: IgG1, IgG4, IgG1 & IgG4, and IgG1, IgG2 & IgG4. An IgG1-only response was found in mild/moderate HA subjects during early FVIII infusions, and analysis of serial samples followed antibody class switching as several subjects' immune responses developed. Competition studies utilizing a recombinant FVIII-C2 domain indicated 40-80% of FVIII-specific antibodies in most samples were directed against this domain.

Diagnosing and managing spinal injury in patients with ankylosing spondylitis.

BACKGROUND: Individuals with ankylosing spondylitis are at an increased risk of vertebral fractures. These are often unstable, leading to primary and secondary neurological injury and conferring high levels of morbidity and mortality. Fractures in these patients can occur after minimal trauma and are easily missed, with potentially disastrous consequences. OBJECTIVES: To educate health professionals who may be involved in the initial assessment and management of ankylosing spondylitis patients with possible spinal injuries, despite not being spinal specialists. CASE REPORTS: We present three cases from our own hospital, which illustrate the pitfalls associated with traumatic spinal injury in ankylosing spondylitis. Case 1 shows why delayed presentation of spinal injury is common, as well as demonstrating the need for multiple imaging modalities in some patients. Case 2 is an example of primary neurological injury in this patient group, and case 3 highlights the risk of secondary neurological injury, as well as the effect of multiple comorbidities on patient outcomes. CONCLUSIONS: It is important that staff in the Emergency Department have an understanding of the extreme caution that is needed in the management of possible spinal injuries in patients with or suspected of having ankylosing spondylitis.

Interobserver agreement of magnetic resonance imaging signs of osteomyelitis in pelvic pressure ulcers in patients with spinal cord injury.

OBJECTIVE: To examine the interobserver reliability of magnetic resonance imaging (MRI) signs of osteomyelitis in complex chronic pressure ulcers in patients with spinal cord injury (SCI). DESIGN: Retrospective review study. SETTING: Specialist SCI rehabilitation center. PARTICIPANTS: Adult patients with SCI and pressure ulceration investigated with MRI. INTERVENTIONS: Analysis of MRI examinations and clinical records collected over a 4-year period. Images were independently assessed by 2 experienced radiologists for osteomyelitis based on assigned predictive indicators including cortical bone erosion, soft tissue edema, deep collections, heterotopic new bone, hip effusion, and abnormal signal change of the marrow. MAIN OUTCOME MEASURES: Interobserver agreement for indicative MRI signs of osteomyelitis in complex pressure ulcers. RESULTS: Thirty-seven patients underwent 41 MRI scans. Concordance for marrow edema was 71% on both short tau inversion recovery and T1-weighted sequences, and for cortical erosion was 85%. CONCLUSIONS: For the assessment of pelvic osteomyelitis related to pressure ulcers, the T1-weighted MRI signal for marrow edema and cortical erosion has strong interobserver agreement.

A pharmacological investigation of the venom extract of the Australian box jellyfish, Chironex fleckeri, in cardiac and vascular tissues.

The pharmacology of Australian box jellyfish, Chironex fleckeri, unpurified (crude) nematocyst venom extract (CVE) was investigated in rat isolated cardiac and vascular tissues and in anaesthetised rats. In small mesenteric arteries CVE (0.01-30 µg/ml) caused contractions (EC(50) 1.15±0.19 µg/ml) that were unaffected by prazosin (0.1 µM), bosentan (10 µM), CGRP(8-37) (1 µM) or tetrodotoxin (1 µM). Box jellyfish antivenom (5-92.6 units/ml) caused rightward shifts of the CVE concentration-response curve with no change in the maximum. In the presence of l-NAME (100 µM) the sensitivity and maximum response to CVE were increased, whilst MgSO(4) (6 mM) decreased both parameters. CVE (1-10 µg/ml) caused inhibition of the contractile response to electrical sympathetic nerve stimulation. Left atrial responses to CVE (0.001-30 µg/ml) were bi-phasic, composed of an initial positive inotropy followed by a marked negative inotropy and atrial standstill. CVE (0.3 µg/ml) elicited a marked decrease in right atrial rate followed by atrial standstill at 3 µg/ml. These responses were unaffected by 1 µM of propranolol, atropine or CGRP(8-37). Antivenom (54 and 73 units/ml) caused rightward shifts of the CVE concentration-response curve and prevented atrial standstill in left and right atria. The effects of CVE do not appear to involve autonomic nerves, post-synaptic α(1)- or ß(1)-adrenoceptors, or muscarinic, endothelin or CGRP receptors, but may occur through direct effects on the cardiac and vascular muscle. Box jellyfish antivenom was effective in attenuating CVE-induced responses in isolated cardiac and vascular tissues.

Clinical and MRI considerations in sports-related knee joint cartilage injury and cartilage repair.

Cartilage injuries of the knee occur frequently in professional and amateur athletes and can be associated with severe debilitation and morbidity. They are commonly associated with ligament injuries but also may be frequently isolated. Increasing awareness and advances in magnetic resonance imaging (MRI) have led to increasing diagnosis and recognition of these injuries. Articular cartilage is just 2 to 4 mm thick and is avascular, alymphatic, and aneural. It has a limited capacity for healing, and there has been increasing use of cartilage repair techniques to treat these lesions in the active population. Strategies for cartilage repair include marrow stimulation techniques such as microfracture/drilling, osteochondral grafting, and autologous chondrocyte transplants. MRI is an important tool in the diagnosis and grading of cartilage injury and is useful in the follow-up and monitoring of these repair procedures. It is important for radiologists and clinicians to be aware of the capabilities and limitations of MRI in assessing cartilage injury and to be familiar with common postsurgical appearances to facilitate assessment and follow-up in this population. This article reviews the clinical findings and MRI imaging appearances of cartilage injury. The management options are discussed as well as common postsurgical appearances following the various interventions.

Volumetric diffusers: pseudorandom cylinder arrays on a periodic lattice.

Most conventional diffusers take the form of a surface based treatment, and as a result can only operate in hemispherical space. Placing a diffuser in the volume of a room might provide greater efficiency by allowing scattering into the whole space. A periodic cylinder array (or sonic crystal) produces periodicity lobes and uneven scattering. Introducing defects into an array, by removing or varying the size of some of the cylinders, can enhance their diffusing abilities. This paper applies number theoretic concepts to create cylinder arrays that have more even scattering. Predictions using a boundary element method are compared to measurements to verify the model, and suitable metrics are adopted to evaluate performance. Arrangements with good aperiodic autocorrelation properties tend to produce the best results. At low frequency power is controlled by object size and at high frequency diffusion is dominated by lattice spacing and structural similarity. Consequently the operational bandwidth is rather small. By using sparse arrays and varying cylinder sizes, a wider bandwidth can be achieved.

Treatment of Morton's neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases.

OBJECTIVE: Morton's neuroma is a common cause of forefoot pain. For this study, we assessed the efficacy of a series of sonographically guided alcohol injections into the lesion. SUBJECTS AND METHODS: One hundred one consecutive patients with Morton's neuroma were included in this prospective series. An average of 4.1 treatments per person were administered, and follow-up images were obtained at a mean of 21.1 months after the last treatment (range, 13-34 months). RESULTS: Technical success was 100%. Partial or total symptom improvement was reported by 94% of the patients, with 84% becoming totally pain-free. The median visual assessed pain score decreased from 8 before treatment to 0 after treatment (p < 0.001). Transitory increased local pain occurred in 17 cases (16.8%). There were no major complications. Thirty patients underwent sonography at 6 months after the last injection and showed a 30% decrease in the size of the neuroma. CONCLUSION: We conclude that alcohol injection of Morton's neuroma has a high success rate and is well tolerated. The results are at least comparable to surgery, but alcohol injection is associated with less morbidity and surgical management may be reserved for nonresponders.

Long-distance decoy-state quantum key distribution in optical fiber.

The theoretical existence of photon-number-splitting attacks creates a security loophole for most quantum key distribution (QKD) demonstrations that use a highly attenuated laser source. Using ultralow-noise, high-efficiency transition-edge sensor photodetectors, we have implemented the first version of a decoy-state protocol that incorporates finite statistics without the use of Gaussian approximations in a one-way QKD system, enabling the creation of secure keys immune to photon-number-splitting attacks and highly resistant to Trojan horse attacks over 107 km of optical fiber.

Numbering of lumbosacral transitional vertebrae on MRI: role of the iliolumbar ligaments.

OBJECTIVE: The objective of this study was to determine whether identification of the iliolumbar ligaments is of practical use for numbering lumbosacral transitional vertebrae (LSTV). MATERIALS AND METHODS: Five hundred consecutive lumbar spine MRI studies were reviewed. A standard protocol of sagittal and axial T1-weighted and T2-weighted spin-echo sequences was used. The sagittal images were assessed for the presence of an LSTV, and axial images were assessed for the level of origin of the iliolumbar ligaments. RESULTS: Of the 500 patients, 433 (86.6%) had normal lumbosacral segmentation and 67 (13.4%) had a transitional lumbosacral junction. The iliolumbar ligament was identified at L5 in all patients with normal lumbosacral segmentation (n = 433), bilaterally in 432 and unilaterally in one. Using the identification of the iliolumbar ligaments as a marker of the L5 vertebral level, we numbered 46 of the 67 LSTV as L5 transitions and 21 as S1 transitions. CONCLUSION: The iliolumbar ligament is readily identifiable on axial lumbar spine MRI and always arises from L5. We suggest that its position can be used to confidently assign lumbar levels in patients with LSTV.

Molecular mimicry in mercury toxicology.

Molecular mimicry occurs when one molecular entity is "mistaken" for another by cellular or other biological processes, and is thought to arise from structural similarities between the two molecules in question. It has been postulated by others to be important in the mechanism of uptake of toxic metal species into living tissues. A widely accepted example is the transport of methylmercury-cysteine species, which are thought to mimic the amino acid methionine. We have used mass spectrometry and mercury L(III)-edge X-ray absorption spectroscopy to understand the solution structure of complexes between methylmercury and cysteine. With a view to understanding the basis of the suggested molecular mimicry mechanisms, we have used computational chemistry to compare the structure of methionine with that of the dominant solution species L-cysteinato(methyl)mercury(II), and the structure of cystine with that of mercury(II) bis-L-cysteineate. We conclude that the structural similarities between metal compounds and natural products are insufficient to support a mechanism based on molecular mimicry, but instead, mechanisms involving a less-specific mimicry based on similarity with the L(alpha) region of the amino acid part of the molecule.

Image-guided percutaneous biopsy of intramedullary lytic bone lesions: utility of aspirated blood clots.

The diagnostic value of aspirating blood clots while performing percutaneous biopsy of intramedullary lytic bone lesions was assessed. This was a retrospective analysis of 400 patients with intramedullary lytic bone lesions who underwent image-guided needle biopsy. The nature of the specimens obtained was noted from the histopathology records. In 83 (20.8%) of the 400 patients, the specimen obtained was either blood clot only or essentially blood clot with only tiny fragments of bone or soft tissue. Lesional tissue was present on needle biopsy specimens in 65 (78.3%) of the 83 cases, while in 18 (21.7%) cases no lesional tissue was obtained. In 24 of the 83 cases, there was no surgical histological diagnosis available. In the 59 cases where surgical histological diagnosis was available for comparison, the diagnostic accuracy for needle biopsy was 73%. Percutaneous biopsy provided the diagnosis allowing appropriate further management in 62 cases, for an overall diagnostic yield of 75%. The results of our study show a sufficiently good diagnostic value in obtaining blood clots as to necessitate routine attempts at obtaining such material while performing percutaneous biopsy of intramedullary lytic bone lesions.

Renal angioplasty in non-atheromatous renal artery stenosis: technical results and clinical outcome in 43 patients.

This study retrospectively reviewed the technical and clinical results of percutaneous transluminal renal artery angioplasty (PTRA) for non-atheromatous renal artery stenosis (RAS) in a Tertiary Renal Referral Centre. Forty-three patients (including 9 children) underwent 49 PTRA procedures for stenoses of 63 arteries over the period 1984-2001 (14 patients had bilateral stenosis treated during one procedure. There were 29 females and 14 males (age range 1-72 years, median 37 years). The etiology of the RAS was classical beaded FMD (medial fibroplasia) in 24, atypical or "variant FMD" with a more focal stenosis (intimal fibroplasia) in 11, neurofibromatosis type 1 (NF) in 7 and Takayasu's Arteritis in 1. Five of the NF patients had angioplasty for stenoses following vascular repair procedures. A technically good result was obtained in 34/34 arteries with "classical" RAS, 9/13 atypical arteries, 11/15 arteries of NF patients and in the one Takayasu's case. Clinical follow-up for a mean of 16 months revealed a cure rate of hypertension in classical FMD of 35% with improvement in a further 55%. In the atypical FMD cases, follow-up was obtained on 6 patients with 2 cures and the other 4 demonstrating benefit. There was a better chance of cure in younger patients. In native artery PTRA in children with NF, only 1 out of 3 patients was 'cured' post-PTRA, and 2 out of 3 failed. However, in postsurgical stenoses in NF patients 1 out of 4 patients was 'cured' and 3 out of 4 improved. In conclusion, classical FMD responds well to PTRA with better results in younger patients. Atypical FMD, especially in children and when associated with NF, is less predictable. Stenoses consequent to revascularization surgery respond well to PTRA.