Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure

Thromboxane synthase (TBXAS1), a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. Thromboxane A2 has been implicated in modulating cell cytotoxicity and in tumor growth and metastasis. Twelve coding-region variants were identified in the human TBXAS1 gene in 48 African-American and 46 Caucasian individuals, of which eight were amino-acid substitutions. The latter were confirmed in an independent Caucasian population (n=94 unrelated individuals). We performed an evolutionary analysis of patterns of nucleotide diversity and identified patterns of amino acid replacement in human-mouse comparisons consistent with purifying selection on an inter-species time scale using the McDonald-Kreitman test. We also observed patterns of nucleotide diversity within humans consistent with purifying selection acting on existing polymorphism using Tajima's D within coding regions. These evolutionary tests suggest that some of the rare coding variations observed in the human population are deleterious. We used two sequence-homology-based software programs and molecular modeling to predict the potential impact of these polymorphisms on TBXAS1 function. The c.772C>T (p.Lys258Glu), c.1249C>G (p.Gln417Glu), and c.1348G>A (p.Glu450Lys) substitutions are predicted as most likely to alter protein function; another, c.1352C>A (p.Thr451Asn), may also affect function. Given the evolutionary evidence, these variants may be functional and therefore of relevance for disease endpoints related to inflammation and angiogenesis, as well as for the pharmacogenetics of non-steroidal anti-inflammatory drugs.     

Ill-health retirement: national rates and updated guidance for occupational physicians

BACKGROUND: Advising on ill-health retirement is an important role of most practising occupational physicians. In recent years, the eligibility criteria and process for gaining early retirement benefits have changed in many pension schemes in the UK. AIM: To investigate the variation in rates of retirement due to ill-health in National Health Service (NHS) Trusts and Local Authorities and to update previously published guidance on ill-health retirement with specific reference to pension schemes with eligibility criteria that include permanence of incapacity due to ill-health. METHODS: Rates of retirement were calculated for 222 NHS Trusts and 132 Local Authorities with more than 1500 employees. Literature searches and consensus statements by the authors. RESULTS: Rates of retirement were widely distributed in the NHS Trusts and Local Authorities. The median rates of retirement were 2.11 (IQR 1.37-2.91)/1000 active members and 4.10 (IQR 3.01-6.10)/1000 employees, respectively (P<0.001). Difficulties in the doctor-patient relationship and in ascertaining the true functional ability of some patients were identified. CONCLUSION: There continues to be marked variation in rates of early retirement due to ill-health within and between organizations that warrants further investigation. The general and specific guidance that appears as an appendix in Supplementary data to this paper should help occupational physicians to make equitable recommendations when assessing applications for early retirement benefits and fitness to work.     

The assessment of cartilage degradation in vivo: development of an immunoassay for the measurement in body fluids of type II collagen cleaved by collagenases

A monoclonal antibody has been developed which recognizes a neoepitope in type II collagen which is generated by the intrahelical cleavage of collagenases. Antibody reactivity is directed at the carboxyl-terminus of the TCA or 3/4 piece of the degraded alpha1(II) chain. Reactivity is dependent upon hydroxylation of proline. Evidence is provided suggesting that epitope binding involves the recognition of a conformational neoepitope. Using an ELISA, we show that this neoepitope can be detected in the urines and sera of nonarthritic persons and patients with rheumatoid arthritis (RA). An increased content is observed in the sera and urines of patients. The assay may be of value in studying cartilage type II degradation both in vitro and in vivo such as in those with arthritis.     

Acute renal failure: definitions, diagnosis, pathogenesis, and therapy

Acute renal failure (ARF), characterized by sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes, and maintain fluid balance, is a frequent clinical problem, particularly in the intensive care unit, where it is associated with a mortality of between 50% and 80%. In this review, the epidemiology and pathophysiology of ARF are discussed, including the vascular, tubular, and inflammatory perturbations. The clinical evaluation of ARF and implications for potential future therapies to decrease the high mortality are described.     

Unusual transoral penetrating injury of the foramen magnum: case report

OBJECTIVE AND IMPORTANCE: Penetrating injuries of the cranium and spine are frequent to the civilian neurosurgical practice. Although a variety of unusual objects have been reported, to our knowledge, there has never been a craniocerebral or spinal injury caused by a fish. An unusual case of transoral penetration of the foramen magnum by a billed fish is described. The history, radiographic studies, and treatment are presented. CLINICAL PRESENTATION: A fisherman struck by a jumping fish initially presented with severe neck pain and stiffness, bleeding from the mouth, and a laceration in the right posterior pharynx. A computed tomographic scan of the cervical spine revealed a wedge-shaped, hyperdense object extending from the posterior pharynx into the spinal canal between the atlas and the occiput. Because of the time factor involved, the fisherman was brought directly to surgery for transoral removal of the object. INTERVENTION: The patient was placed under general anesthesia, and with a tonsillar retractor, a kipner, and hand-held retractors, the object was visualized and identified as a fish bill. Further dissection above the anterior aspect of the atlas permitted removal of the object by means of a grabber from an arthroscopic set. No expression of cerebrospinal fluid was noted, and a Penrose drain was placed. CONCLUSION: The patient was treated under the assumption that penetrating foreign objects in continuity with the cerebrospinal fluid space and the outside environment should be removed as soon as possible. The patient was provided appropriate antibiotics to treat potential infection of normal pharyngeal flora and organisms unique to the marine environment. The patient recovered and did not experience any residual neurological deficit.