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.

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.

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.

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.

Investigation of a simple, retrospective test for in-flight hyperventilation.

The experiment was designed to study the feasibility of using a single rebreathing estimate of mixed venous carbon dioxide tension (PvCO2) was a simple field test for hyperventilation in pilots. The results confirmed that the fall of end tidal carbon dioxide tension (P(ET)CO2) during hyperventilation and rise during recovery was exponential. The results also showed that the relationships between PvCO2 and P(ET)CO2 values during the unsteady states of carbon dioxide washout and accumulation may be described as a loop which encloses the theoretically derived line for the steady-state relationships. The deviation from the steady-state line appears on theoretical consideration to be directly proportional to carbon dioxide elimination rate, and indirectly proportional to cardiac output. Because of the exponential recovery, and because one value of PvCO2 could correspond to a range of values of P(ET)CO2, it is concluded that a field test for hyperventilation based on a single rebreathing estimate of PvCO2 would not be of value. The finding of a low value of PvCO2 would, however, be an indication that hyperventilation had taken place.

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.

Hyperventilation in aircrew: a review.

The causes and effects of hyperventilation, relevant to the flight environment, have been reviewed and one case history is presented. Methods of investigating in-flight hyperventilation are discussed.

Hyperventilation in flight.

Hyperventilation in flight may be caused by environmental, psychological, pharmacological, and pathological factors. The effects are discussed and two case histories are presented, illustrating the development and effect of hyperventilation in training or aircrew under stress. Investigation of in-flight hyperventilation is technically very difficult, but positive acceleration, hypoglycaemia, and anxiety are important contributory factors. The incidence of hyperventilation must be reduced by educating aircrew in its aetiology, early recognition, and treatment.

Effects of hypocapnia on psychomotor and intellectual performance.

Nine subjects performed five psychomotor tasks (two motor, two intellectual, and one combined motor and short-term memory) at three levels of PACO2 (38.5, 25.0 and 15.0 torr) with voluntary hyperventilation at 20 l/min. There were no performance decrements at PACO2 levels of 38.5 and 25.0 torr. At a PACO2 of 15.0 torr, there were no decrements of intellectual performance but there were highly significant decrements in motor performance. It is suggested that a lack of regional cerebral hypoxia, arising from compensating changes in regional cerebral blood flow, could be responsible for the preservation of intellectual performance at a PACO2 of 15 torr.

Effect on performance of cycling deep body temperature between 37.0 and 37.6 degrees C.

Previous experiments (1.2) showed that performance of of a pursuit rotor task is worse during heating than during cooling at deep body temperatures of 37.9-38.5 degrees C. Performance of the same task and of a manikin task has now been studied in a similar experiment while core temperature was cycled between 37.0 and 37.6 degrees C. No change in performance was observed between heating and cooling. It is concluded that decrements in performance during heating only develop above a critical absolute level of deep body temperature. The critical level of deep body temperature, above which performance of the rotary pursuit task is degraded, is 37.6-37.9 degrees C, and this can be related to affective thermal sensation.

Separation of the effects of raised skin and core temperature on performance of a pursuit rotor task.

Performance of a pursuit rotor task was studied during induced cycles of core temperature between limits of 37.9 degrees C and 38.5 degrees C. At each level of core temperature tested (37.9 degrees C, 38.5 degrees C, and 38.5 degrees C) performance was significantly worse during heating, when skin temperatures were high, than during cooling. The observed decrements were 13.6% at 37.9 degrees C, 16.0% at 38.2 degrees C and 18.1% at 38.5 degrees C. While it may be true that the performance changes were caused by changes in the level of skin temperature, the direction and rate of change of both core and skin temperatures may be important determinants of performance. The results are discussed in relation to current arousal theory.

Effect of induced cyclic changes of deep body temperature on task performances.

Performance of three tests was studied during induced cycles of deep body temperature between limits of 37.8 degrees C and 38.9 degrees C. During heating phases skin temperature was 38.8 degrees C and during cooling it was 36.1 degrees C. A verbal transformation test, performed at the midpoint of each temperature cycle, showed no significant effect from the large differences in skin temperature and subjective comfort between heating and cooling. The test was considered to be insufficiently difficult. A pursuit rotor test and a colour/word interference test, performed at the end of the heating and cooling phases, showed mean decrements in performance of 15% and 4%, respectively. These results are related to the measured levels of deep body and skin temperature and to subjective assessments of comfort.

Prediction of body temperatures during exercise in flying clothing.

A mathematical model has been used to describe experimental results for core and skin temperatures in subjects undergoing a rest/activity cycle in two aircrew clothing assemblies at two environmental temperatures (wet bulb, globe temperature (WBGT) indices of 25.9 and 28.9 degrees C). The model presented compares well with published data for subjects in standard aircrew equipment assemblies. Aircrew flying at a WBGT of 28.9 degrees C in chemical defence clothing may reach an unacceptable level of mean body temperature within 40 min and deep body temperature will rise at 1 degree C.hr-1. To prevent deterioration in flying performance during repeated sorties, an alteration in the work/rest activity pattern or the introduction of effective cabin or personal conditioning systems may be required,

Effect of direction and rate of change of deep body and skin temperatures on performance of a rotary pursuit task.

Performance at a pursuit rotor task has been studied during the overshoot of core temperature caused by sudden cooling after heating, and the undershoot caused by sudden heating after cooling. Conditions were chosen so that effects of the absolute levels of core and skin temperature could be discounted. The results showed that the direction of change of core and skin temperature, rates of change of core temperature between -0.07 and +0.06 degrees C/min, and rates of change of skin temperature between -1.0 and +1.0 C/min did not affect performance; particular circumstances of this experiment, expecially the short duration of the changes in direction studied, make this conclusion tentative. Comparison with earlier studies indicates that the major determinants of performance at elevated body temperatures are absolute levels of mean skin temperature, with the absolute level of core temperature having a less significant role.

Cockpit thermal stress and aircrew thermal strain during routine Jaguar operations.

Thermal data have been obtained from Jaguar aircraft flying routine, warm-weather operations in Sardinia. These data have been analysed in terms of the ambient and cockpit wet bulb globe temperatures (WBGT) and the mean body temperature (Tb) of the pilot. In contrast to similar data previously obtained from Harrier and Buccaneer aircraft, no interrelationships could be demonstrated between ambient WBGT at ground level and either cockpit WBGT or pilot Tb. Relationships which could be described by equations of negative slope were obtained between Tb and sortie time and between cockpit WBGT and sortie time. A model has been derived for predicting aircrew thermal strain in the Jaguar from cockpit temperature and sortie time.

Effect of induced cyclic changes of deep body temperature on performance in a flight simulator.

Previous studies have shown that performance of a simple, motor task may be degraded by heating the skin when the body temperature is above a critical level of 37.6 degrees C. The experiment reported here confirms these findings for performance in a simple flight simulator. The significance of the results is discussed with reference to flight in high-performance aircraft.

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.