Risk of myeloid neoplasms after solid organ transplantation.

Solid organ transplant recipients have elevated cancer risks, owing in part to pharmacologic immunosuppression. However, little is known about risks for hematologic malignancies of myeloid origin. We linked the US Scientific Registry of Transplant Recipients with 15 population-based cancer registries to ascertain cancer occurrence among 207 859 solid organ transplants (1987-2009). Solid organ transplant recipients had a significantly elevated risk for myeloid neoplasms, with standardized incidence ratios (SIRs) of 4.6 (95% confidence interval 3.8-5.6; N=101) for myelodysplastic syndromes (MDS), 2.7 (2.2-3.2; N=125) for acute myeloid leukemia (AML), 2.3 (1.6-3.2; N=36) for chronic myeloid leukemia and 7.2 (5.4-9.3; N=57) for polycythemia vera. SIRs were highest among younger individuals and varied by time since transplantation and organ type (Poisson regression P<0.05 for all comparisons). Azathioprine for initial maintenance immunosuppression increased risk for MDS (P=0.0002) and AML (2-5 years after transplantation, P=0.0163). Overall survival following AML/MDS among transplant recipients was inferior to that of similar patients reported to US cancer registries (log-rank P<0.0001). Our novel finding of increased risks for specific myeloid neoplasms after solid organ transplantation supports a role for immune dysfunction in myeloid neoplasm etiology. The increased risks and inferior survival should heighten clinician awareness of myeloid neoplasms during follow-up of transplant recipients.

Antioxidant effects of ryegrass phenolics in lamb liver and plasma.

Sixteen lambs were divided into two groups and fed two different diets. Eight lambs were stall-fed with a concentrate-based diet (C), and the remaining eight lambs were allowed to graze on Lolium perenne (G). The antioxidant status was measured in the liver and plasma samples before and after solid-phase extraction (SPE) to probe the antioxidant effects that grass phenolic compounds may have conferred onto the animal tissues. The liver and plasma samples from grass-fed lambs displayed a greater antioxidant capacity than the tissues from C lamb group, but only if samples had not been passed through SPE cartridges. Finally, the feed and animal tissues, which had been purified by SPE, were analysed by liquid chromatography combined with mass spectrometry (LC���MS) to identify phenolic compounds present in L. perenne and to evaluate the results from the antioxidant assays. It would appear that the improvement of the antioxidant capacity of lamb liver and plasma from lambs fed ryegrass was not related to the direct transfer of phenolic compounds from grass to the animal tissues.

Risk of lymphoma subtypes after solid organ transplantation in the United States.

BACKGROUND: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. METHODS: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987-2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. RESULTS: The risk varied widely across subtypes, with strong elevations (SIRs 10-100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2-4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys. CONCLUSION: Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.

Effects of interleukin-6 treatment on neurovascular function, nerve perfusion and vascular endothelium in diabetic rats.

AIM: Interleukin-6 (IL-6), a member of the neuropoietic cytokine family, participates in neural development and has neurotrophic activity. Recent research has also indicated actions to improve vasa nervorum function in diabetes. Both these facets are potentially relevant for treatment of diabetic neuropathy. The aim of this study was to determine whether IL-6 treatment corrected changes in neurovascular function in streptozotocin-induced diabetic rats. METHODS: After 1 month of diabetes, rats were given IL-6 for 1 month. The rats were subjected to sensory testing and measurements of nerve conduction velocities and nerve blood flow by hydrogen clearance microelectrode polarography. Further groups were used to study responses of the isolated gastric fundus and renal artery. Results were statistically analysed using ANOVA and post hoc tests. RESULTS: Diabetic rats showed mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia. The former was unaffected by IL-6 treatment, whereas the latter two measures were corrected. Immunohistochemical staining of dorsal root ganglia for IL-6 did not reveal any changes with diabetes or treatment. The results showed that 22 and 17.4% slowing of sciatic motor and saphenous sensory nerve conduction velocities, respectively, with diabetes were improved by IL-6. Sciatic endoneurial perfusion was halved by diabetes and corrected by IL-6. A 40.6% diabetic deficit in maximal non-adrenergic, non-cholinergic relaxation of gastric fundus to nerve stimulation was unaffected by IL-6. Renal artery endothelium-dependent relaxation was halved by diabetes, the endothelium-derived hyperpolarizing factor (EDHF) component being severely attenuated. IL-6 did not affect nitric oxide-mediated vasorelaxation, but markedly improved EDHF responses. CONCLUSIONS: IL-6 improved aspects of small and large nerve fibre and vascular endothelium dysfunction in diabetic rats. The functional benefits related to increased nerve blood flow via an EDHF mechanism, and IL-6 could have therapeutic potential in diabetic neuropathy and vasculopathy, which should be further evaluated.

The bioethics of enhancing human performance for spaceflight.

There are many ways of enhancing human performance. For military aviation in general, and for spaceflight in particular, the most important tools are selection, training, equipment, pharmacology, and surgery. In the future, genetic manipulation may be feasible. For each of these tools, the specific modalities available range from the ethically acceptable to the ethically unacceptable. Even when someone consents to a particular procedure to enhance performance, the action may be ethically unacceptable to society as a whole and the burden of risk for the individual may be too great. In addition, there are several characteristics that define the quality and the acceptability of the consent. Each method of enhancing performance will be examined in the context of the principles of medical ethics in a western society: autonomy, non-maleficence, beneficence, and justice. The aim is to draw the attention of aeromedical practitioners to the complexities of ethical dilemmas such as this particular one in order to help them to develop a morally justifiable code of practice that balances society's needs against individual ambitions and corporate goals.

Medical confidentiality and human immunodeficiency virus (HIV) infection: a hypothetical case.

This paper describes a hypothetical case of a HIV positive pilot. It explores legal and ethical aspects of medical confidentiality and discusses who, inside and outside military and medical circles, can be told of his condition in the light of the particular circumstances. Disclosure without the patient's consent is a serious step that should not be undertaken without advice from Service medico-legal departments and medical protection organisations.

Medical confidentiality: the right of a commanding officer to know.

Recent changes in the law and in patients' expectations have necessitated alterations to the way doctors maintain the medical confidentiality of their patients. This paper investigates the ethical and legal aspects of medical confidentiality in general, examines their relation to the military context and analyses the guidance offered. Military personnel give up some individual rights on enlistment. The requirement for the medical officer to share patients' medical information, without consent if necessary, with the Commanding Officer is ethically and legally acceptable provided recruits are adequately warned of this restriction to human rights before joining. Although the paper concentrates on the guidance given in the RAF, the principles are common to the 3 Armed Forces' medical services.

A shot in the arm for the military: consent to immunisation against biological warfare agents.

The risk to Britain's Armed Forces from Biological Warfare (BW) is low but without protection their use would be devastating. Available protective measures include immunisation. The Government owes a legal duty of care to Servicemen to provide protection against a range of hazards, including those of BW. The State also owes Servicemen a duty of care to allow free and informed consent or free and informed refusal to medical procedures, including immunisation. However, refusal by key personnel to accept BW immunisation could degrade operational capability. Resolution between these two, potentially conflicting, duties of care may be controversial. To override a soldier's expressed interests would rank society's needs higher than those of the individual. Yet there are circumstances, such as exposure of Servicemen to BW used by an aggressor, where this would be ethically acceptable. The State's interests, combined with the best interests of the Servicemen, provide adequate ethical argument for both occupational immunisation (where it is an entry criterion for the Armed Forces) and mandatory immunisation (where disciplinary action may be taken against the non-compliant). Historically, both approaches have been used for public health immunisations and the legal framework already exists for both.

Duty of care in immunisation against biological warfare agents.

In peacetime, the Crown owes a duty of care to members of the Armed Forces to provide adequate medical support. This includes the provision of safe and effective vaccines. A Serviceman who considers himself harmed by immunisation against biological warfare (BW) agents would have access to legal action in the tort of negligence. However, the outcome would be uncertain because of the absence of clear precedent in respect of the Crown's duty of care in the period of transition between peace and war and the statutory right of the Government to bar proceedings against the Crown for alleged negligence during time of war. Moreover, no claimant has yet succeeded in any common law action in the United Kingdom for vaccine damage because of the difficulty of proving causation. The Serviceman would not be covered by the Criminal Injuries Compensation (Overseas) Scheme. Likewise, he would not be eligible for payment under the Vaccine Damage Payments Act 1979 unless the Act was amended. The Serviceman would therefore have to rely on the current pension system that is accessible, relatively generous and, until recently, independent of the Ministry of Defence.

Risk reduction strategies in coronary artery disease.

The growing knowledge of the basic science of the atherosclerotic plaque, the identification of modifiable risk factors, and the development of the effective medical therapies have provided the physician with powerful tools to alter the course of atherosclerotic disease in the post myocardial infarction patient. Lipids have emerged as a primary target for modification in addition to attention to traditional lifestyle modification such as smoking cessation, diet, and exercise. This article reviews lipid management as well as therapy and goals. Traditional and some "new" risk factors are also addressed. The risk of subsequent events in the post myocardial infarction patient can be dramatically altered, thus the patient who follows suggested guidelines can expect to have improved quality and quantity of life after an infarction.

Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens.

1. This study was directed at exploring the structure-activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB(1) and vanilloid receptors in the mouse vas deferens. 2. pK(i) values for displacement of [(3)H]-resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N-(4-hydroxyphenyl)-arachidonylamide (AM404; 6.18) and N-(3-methoxy-4-hydroxy)benzyl-arachidonylamide (arvanil; 6.77). 3. pEC(50) values for stimulating (45)Ca(2+) uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC(50)=7.37), a compound with the same substituted benzyl polar head group as arvanil. 4. In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically-evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pK(B)=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 microM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pK(B)=6.02) and less susceptible to antagonism by SR141716A (pK(B)=8.66) than methanandamide (pK(B)=9.56). WIN55212 was antagonized by SR141716A (pK(B)=9.02) but not by capsazepine (10 microM). 5. In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB(1) receptors, both receptor types appear to contribute to anandamide-induced inhibition of evoked contractions.

O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties.

Cannabinoids have low water solubility, necessitating the use of a solubilizing agent. In this paper we investigated whether a novel water-soluble cannabinoid, 3-(5'-cyano-1', 1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)-Delta(8)- tetrahydroca nnabinol hydrochloride (O-1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle. O-1057 displaced [(3)H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB(1) or CB(2) cannabinoid receptors, with pK(i) values of 8.36 and 7.95 respectively. It also displaced [(3)H]-CP55940 from specific binding sites on rat brain membranes (pK(i) = 7.86). O-1057 inhibited forskolin-stimulated cyclic AMP production by both CB(1)- and CB(2)-transfected CHO cells (pEC(50) = 9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of Delta(9)-tetrahydrocannabinol. In the mouse isolated vas deferens, O-1057 inhibited electrically-evoked contractions with pEC(50) and E(max) values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pK(B) of SR141716A against O-1057 (8.90) approximating to that against CP55940 (8.97). O-1057 also behaved as a CB(1) receptor agonist in vivo, reducing mouse spontaneous activity and rectal temperature when injected intravenously and inducing antinociception in the mouse tail flick test when given intravenously (ED(50) = 0.02 mg kg(-1)), intrathecally, intracerebroventricularly or by gavage. In all these assays, O-1057 was more potent than Delta(9)-tetrahydrocannabinol and, at 0.1 mg kg(-1) i.v., was antagonized by SR141716A (3 mg kg(-1) i.v.). These data demonstrate the ability of the water-soluble cannabinoid, O-1057, to act as a potent agonist at CB(1) and CB(2) receptors and warrant investigation of the clinical potential of O-1057 as an analgesic.

Isolation and characterization of 22S outer arm dynein from Tetrahymena cilia.

As illustrated elsewhere in this volume, Tetrahymena is an extraordinary experimental system in which molecular genetics, biochemistry, and cytology can be applied to the study of a cell biological problem. Our long-term goal is to understand how the different structural domains of dynein contribute to its function. Our strategy is to create targeted modifications in an axonemal dynein heavy chain gene, recover the dynein protein from cilia, and evaluate the in vitro activity of the isolated dynein. In this chapter, we have summarized our procedures for the isolation and characterization of the ciliary outer arm dynein.

Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors.

1. We have extended previous investigations of four analogues of Delta8-tetrahydrocannabinol (Delta8-THC): 6'-azidohex-2'-yne-Delta8-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta8-THC (O-1238) and octyl-2'-yne-Delta8-THC (O-584) and its 1-deoxy-analogue (O-1315). 2. O-1184, O-1238 and O-584 displaced [3H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pKi values of 8.28 to 8.45 (CB1) and 8.03 to 8.13 (CB2). The pKi values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2). 3. All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells (pEC50=9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line. 4. In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC50=10.18 and Emax=70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB1-transfected CHO cells. 5. In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC50=8.59), enhanced by O-1184 and O-584 (pEC50=8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315. 6. At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC50 of CP55940 from 8.61 to 7.42 (O-1184) or from 8. 54 to 7.44 (O-1238). 7. These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta8-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors.

Samuel Franklin Cody: aviation and aeromedical evacuation pioneer.

In the summer of 1913, Woodrow Wilson had just become the 28th President of the United States and King George V was on the throne of the United Kingdom. It was nearly 10 yr since the historical flight at Kitty Hawk and 3 yr since Blériot had first flown the English Channel. At Farnborough, "Colonel" Samuel F. Cody, originally a horseman, hunter, crack shot, showman and theatrical impresario from the USA, was preparing a new floatplane for a round Britain flying race. One of the features of the floatplane, a biplane with a four bladed pusher propeller, was that it had already demonstrated its ability to carry passengers. Cody calculated that it would allow him to carry five passengers for a 4-h flight and may even have medical uses. He arranged a demonstration of its potential as an air ambulance at Farnborough. This paper describes, with the use of photographs of the event, the airplane, the demonstration and the reasons why it would be left to others to carry out the first, real aeromedical evacuation 4 yr later.

Cochliobolic acid, a novel metabolite produced by Cochliobolus lunatus, inhibits binding of TGF-alpha to the EGF receptor in a SPA assay.

Cochliobolic acid (1), a novel biologically active natural product, is produced by submerged fermentation of Cochliobolus lunatus. Compound 1 was determined to be a novel polyketide possessing a substituted tetrahydrofuran ring, a conjugated polyene chain and a 1,2-diketone moiety, by interpretation of NMR, MS, and UV/vis spectroscopic data. Compound 1 inhibits the binding of TGF-alpha to the EGF receptor of the human epidermal cell line A431 in a SPA assay with an IC50 of 1.6 microM.

Structural elucidation of XR586, a peptaibol-like antibiotic from Acremonium persicinum.

A novel peptide, XR586, has been isolated from fermentations of Acremonium persicinum (Xenova culture collection number X21488). The structure of XR586 has been elucidated by means of NMR spectroscopy, electrospray and fast-atom bombardment MS, derivatization and enzymic digestion. It has been shown to be helical by CD measurements. XR586 shows many structural and conformational features in common with peptaibols, particularly the zervamicins. Peptaibol antibiotics are peptides, typically of 15-20 residues, containing a large proportion of alpha-aminoisobutyric acid (Aib) residues. These peptides adopt a helical conformation in solution and display anti-bacterial and toxic properties due to their ability to form pores in membranes. However, while XR586 contains several Aib residues, it lacks a terminal phenylalaninol and terminates in the sequence Phe-Gly. The lack of reduction of the penultimate residue at the C-terminus may indicate that this step is normally at the end of the biosynthetic pathway of peptaibols and occurs with cleavage of Gly. The 1H chemical shift assignments of XR586 are reported in Supplementary Publication SUP 50179 (3 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1996) 313, 9 ("Deposition of data').