An assessment of the distance between the phrenic nerve and major intrathoracic structures.

BACKGROUND: There is a lack of consensus in the literature regarding phrenic nerve proximity to thoracic structures at the level of the diaphragm. This study was undertaken to provide thoracic surgeons data on phrenic nerve location in order to reduce iatrogenic injury during invasive surgery. METHODS: Bilateral thoracic dissection was performed on 43 embalmed human cadavers (25 males; 18 females) and data was obtained from 33 left and 40 right phrenic nerves. The site of phrenic nerve penetration into the diaphragm was identified. Calipers were used to measure the distance from each phrenic nerve to the: inferior vena cava (IVC), descending aorta, esophagus, lateral thoracic wall and anterior thoracic wall. RESULTS: Mean thoracic diameter of male cadavers was significantly greater than that of female cadavers (P value <0.0001). There was no statistically significant difference between the distances from each phrenic nerve to visceral structures between males and females, except regarding the distance from the right phrenic nerve to the anterior thoracic wall where males exhibited significantly greater distances (P value =0.0234). CONCLUSIONS: This study provides important data on phrenic nerve proximity to intrathoracic structures in an effort to help reduce iatrogenic injury during procedures within the thoracic cavity. Although males had a significantly larger thoracic diameter than females, the only statistically significant difference showed that the right phrenic nerve is deeper in the thoracic cavity in males. As this nerve passes closer to visceral structures it may be more susceptible to damage from pathology in surrounding vessels. This may explain the increased incidence of right phrenic nerve damage due to aortic aneurysm in males reported in the literature.

Reimbursement of Drugs for Rare Diseases through the Public Healthcare System in Canada: Where Are We Now?

INTRODUCTION: Over the past 20 years, the number of therapies developed for rare diseases has rapidly increased. Often, these therapies represent the only active treatment for debilitating and/or life-threatening conditions. However, they create significant challenges for public and private payers. Because they target small patient populations, clinical evidence of efficacy/effectiveness is typically limited, while the cost per patient is high. In Canada, each province/territory establishes its own mechanisms for determining which drugs for rare diseases (DRDs) to provide. OBJECTIVES: To compare current mechanisms across provinces and territories, and explore their impact on access. METHODS: A systematic review of relevant published and unpublished documents was performed. Electronic bibliographic databases, the internet, and government websites were scanned using structured search strategies. Information was extracted independently by two researchers, and included aspects such as program type, condition/patient/therapy eligibility criteria, role of health technology assessment (HTA), decision options, ethical assumptions, and stakeholder input. It was validated through member-checking with provincial/territorial policy experts and tabulated to facilitate qualitative analyses. Impact on access was assessed through a cross-province/territory comparison of the coverage status of all non-cancer therapies reviewed by the Common Drug Review for indications affecting <1/2,000 Canadians using the Kappa statistic. Reasons for variations were explored using qualitative techniques. RESULTS: Each province/territory has formal and informal mechanisms through which such therapies may be accessed. In most cases, formal mechanisms constitute the centralized HTA processes that also apply to common therapies. While several provinces have established dedicated processes/programs, whether they have affected access is not clear. Despite broadly comparable approaches, there is less than perfect agreement on publicly funded DRDs across jurisdictions. CONCLUSIONS: Individual jurisdictions have developed different approaches to providing access to these therapies. However, as the number increases, a more systematic approach to decision-making may be needed.

Targeting of humanized antibody D93 to sites of angiogenesis and tumor growth by binding to multiple epitopes on denatured collagens.

A humanized, affinity-matured IgG1 antibody, called D93, and its parental murine IgM HUI77 have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models. In this study, we have identified epitopes for both HUI77 and D93 on human collagen type IV. Several tryptic D93-binding peptides were identified by Western blot analysis and protein sequencing. Epitopes for D93 were ultimately identified by screening a synthetic 16-mer peptide array spanning immunoreactive tryptic peptides. D93 reacted with a peptide corresponding to alpha1(IV) P(1337)-Y(1352) that could inhibit binding of both D93 and HUI77 to denatured collagen IV in a concentration-dependent manner. A 9-mer peptide corresponding to alpha1(IV) G(1344)-Y(1352) showed maximum inhibition of D93 and HUI77 antibody binding to denatured collagen IV, and was critically dependent on the presence of hydroxyproline. D93 bound with similar affinity to denatured collagen IV and synthetic peptides with a K(D) of 1-10 microM for monovalent and of 30-63 nM for bivalent binding. Potential epitopes for D93 are highly repeated in multiple collagen types of diverse vertebrate species explaining reactivity of D93 with denatured collagens types I-V from chicken to man. Our data suggest that D93 inhibits angiogenesis and tumor growth by blockade of cryptic bioactive signals on proteolyzed collagens with importance for growth of tumors and new blood vessels.

Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach.

Matrix metalloproteases (MMPs) secreted by both tumor and endothelial cells proteolytically degrade collagen during tumor growth and neo-vascularization. This exposes cryptic binding sites on collagen with functional relevance for angiogenesis. In this report, we characterized a novel humanized monoclonal IgG1 antibody, D93. After humanization, the antibody retained the binding specificity of the parental murine IgM antibody for denatured (dn) collagen. D93 recognized dn-collagen but not native (nat) collagen of different species, including mouse, chicken, and human, indicating that its cryptic binding site(s) is conserved across species. In immunohistochemistry (IHC) studies, D93 stained the basement membrane of blood vessels in several xenograft human tumors or in surgically removed tumor tissues from patients with different types of malignancies. D93 staining was rarely or not present in normal blood vessels of healthy tissues. In in vivo experiments, D93 significantly inhibited basic fibroblast growth factor (bFGF)-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) and the tumor growth of pre-established orthotopic human breast (MDA-MB-435) tumors in mice. D93 i.v. administered in mice was subsequently detected in the subendothelial basement membrane of tumor blood vessels but not blood vessels of normal tissues. Inhibition of growth of pre-established orthotopic human breast MDA-MB-435 tumors was more effective when D93 was combined with Taxol, than either treatment alone. In addition, tumors from animals treated with D93 and/or Taxol showed significantly reduced levels of the endothelial cell-marker CD31. Our data suggest that blockade of cryptic epitopes exposed on collagen IV during angiogenesis and tumor growth by a monoclonal antibody may provide a novel therapeutic modality for treatment of cancer and pathogenic neo-vascularization.

Dental identification problems in the Abu Dhabi air accident

The forensic odontological examination of 112 victims in the 1983 air accident near Abu Dhabi is described with particular reference to the problems encountered in the age assessment of the 26 children, and serves to illustrate that dental identification in aviation accidents may be of only limited application in Asian victims. Following this accident, other means of identification had misguidedly been removed by the recovery teams. Of those identified, half were by dental mean alone, but this amounted to only 6.24

of the total number of victims.(AU)