Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation

Background: HLA directed antibodies play an important role in acute and chronic allograft rejection. During viral infection of a patient with HLA antibodies, the HLA antibody levels may rise even though there is no new immunization with antigen. However it is not known whether the converse occurs, and whether changes on non-donor specific antibodies are associated with any outcomes following HLA antibody incompatible renal transplantation. Methods: 55 patients, 31 women and 24 men, who underwent HLAi renal transplant in our center from September 2005 to September 2010 were included in the studies. We analysed the data using two different approaches, based on; i) DSA levels and ii) rejection episode post transplant. HLA antibody levels were measured during the early post transplant period and corresponding CMV, VZV and Anti-HBs IgG antibody levels and blood group IgG, IgM and IgA antibodies were quantified. Results: Despite a significant DSA antibody rise no significant non-donor specific HLA antibody, viral or blood group antibody rise was found. In rejection episode analyses, multiple logistic regression modelling showed that change in the DSA was significantly associated with rejection (p = 0.002), even when adjusted for other antibody levels. No other antibody levels were predictive of rejection. Increase in DSA from pre treatment to a post transplant peak of 1000 was equivalent to an increased chance of rejection with an odds ratio of 1.47 (1.08, 2.00). Conclusion: In spite of increases or decreases in the DSA levels, there were no changes in the viral or the blood group antibodies in these patients. Thus the DSA rise is specific in contrast to the viral, blood group or third party antibodies post transplantation. Increases in the DSA post transplant in comparison to pre-treatment are strongly associated with occurrence of rejection

ABCD² risk score does not predict the presence of cerebral microemboli in patients with hyper-acute symptomatic critical carotid artery stenosis

ABCD² risk score and cerebral microemboli detected by transcranial Doppler (TCD) have been separately shown to the predict risk of recurrent acute stroke. We studied whether ABCD² risk score predicts cerebral microemboli in patients with hyper-acute symptomatic carotid artery stenosis. We studied 206 patients presenting within 2 weeks of transient ischaemic attack or minor stroke and found to have critical carotid artery stenosis (≥50%). 86 patients (age 70±1 (SEM: years), 58 men, 83 Caucasian) had evidence of microemboli; 72 (84%) of these underwent carotid endarterectomy (CEA). 120 patients (age 72±1 years, 91 men, 113 Caucasian) did not have microemboli detected; 102 (85%) of these underwent CEA. Data were analysed using X2 and Mann-Whitney U tests and receiver operating characteristic (ROC) curves. 140/206 (68%: 95% CI 61.63 to 74.37) patients with hyper-acute symptomatic critical carotid stenosis had an ABCD2 risk score ≥4. There was no significant difference in the NICE red flag criterion for early assessment (ABCD² risk score ≥4) for patients with cerebral microemboli versus those without microemboli (59/86 vs 81/120 patients: OR 1.05 ABCD² risk score ≥4 (95% CI 0.58 to 1.90, p=0.867)). The ABCD² risk score was <4 in 27 of 86 (31%: 95% CI 21 to 41) embolising patients and in 39 of 120 (31%: 95% CI 23 to 39) without cerebral microemboli. After adjusting for pre-neurological event antiplatelet treatment (APT), area under the curve (AUC) of ROC for ABCD2 risk score showed no prediction of cerebral microemboli (no pre-event APT, n=57: AUC 0.45 (95% CI 0.29 to 0.60, p=0.531); pre-event APT, n=147: AUC 0.51 (95% CI 0.42 to 0.60, p=0.804)). The ABCD² score did not predict the presence of cerebral microemboli or carotid disease in over one-quarter of patients with symptomatic critical carotid artery stenosis. On the basis of NICE guidelines (refer early if ABCD² ≥4), assessment of high stroke risk based on ABCD² scoring may lead to inappropriate delay in urgent treatment in many patients

Multimodal analysis of the effects of dexamethasone on high-altitude cerebral oedema : protocol for a pilot study

Background Acute mountain sickness (AMS) is a cluster of symptoms that commonly occur in those ascending to high altitudes. Symptoms can include headaches, nausea, insomnia and fatigue. Exposure to high altitude can also lead to high-altitude cerebral oedema (HACE), which is a potential cause of death whilst mountaineering. Generally, AMS precedes the development of HACE. Historical studies have demonstrated the effectiveness of regular dexamethasone administration in reducing the symptoms of AMS. However, the mechanism by which dexamethasone works to reduce symptoms AMS remains poorly understood. Further studies, simulating altitude using hypoxic tents, have characterised the effect of prolonged exposure to normobaric hypoxia on cerebral oedema and blood flow using MRI. This randomised trial assesses the effect of dexamethasone on hypoxia-induced cerebral oedema in healthy adult volunteers. Methods/design D4H is a double-blind placebo-controlled randomised trial assessing the effect of dexamethasone on hypoxia-induced cerebral oedema. In total, 20 volunteers were randomised in pairs to receive either 8.25 mg dexamethasone or normal saline placebo intravenously after 8 h of hypoxia with an FiO2 of 12%. Serial MRI images of the brain and spinal cord were obtained at hours 0, 7, 11, 22 and 26 of the study along with serum and urinary markers to correlate with the severity of cerebral oedema and the effect of the intervention. Discussion MRI has been used to identify changes in cerebral vasculature in the development of AMS and HACE. Dexamethasone is effective at reducing the symptoms of AMS; however, the mechanism of this effect is unknown. If this study demonstrates a clear objective benefit of dexamethasone in this setting, future studies may be able to demonstrate that dexamethasone is an effective therapy for oedema associated with brain and spinal cord ischaemia beyond AMS

Magnetic resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema

Rapid ascent to high altitude commonly results in acute mountain sickness, and on occasion potentially fatal high-altitude cerebral edema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. We report a study in which 12 subjects were exposed to a FiO2 = 0.12 for 22 h and underwent serial magnetic resonance imaging sequences to enable measurement of middle cerebral artery velocity, flow and diameter, and brain parenchymal, cerebrospinal fluid and cerebral venous volumes. Ten subjects completed 22 h and most developed symptoms of acute mountain sickness (mean Lake Louise Score 5.4; p < 0.001 vs. baseline). Cerebral oxygen delivery was maintained by an increase in middle cerebral artery velocity and diameter (first 6 h). There appeared to be venocompression at the level of the small, deep cerebral veins (116 cm3 at 2 h to 97 cm3 at 22 h; p < 0.05). Brain white matter volume increased over the 22-h period (574 ml to 587 ml; p < 0.001) and correlated with cumulative Lake Louise scores at 22 h (p < 0.05). We conclude that cerebral oxygen delivery was maintained by increased arterial inflow and this preceded the development of cerebral edema. Venous outflow restriction appeared to play a contributory role in the formation of cerebral edema, a novel feature that has not been observed previously

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study

Background: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (Vo2peak). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. Study Design: Prospective matched-cohort study. Setting & Participants: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. Predictor: CKF versus essential hypertension without cardiovascular disease. Measurements & Outcomes: Vo2peak was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in Vo2peak between study groups, statistically significant predictors of Vo2peak in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. Results: Vo2peak was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P < 0.001). Independent predictors of Vo2peak for CKF included left ventricular (LV) filling pressure (E/mean e′; unstandardized regression coefficient: change in Vo2peak [in mL/min·kg] per 1-unit change of variable = −5.1) and pulse wave velocity (−4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (−8.8). The interaction effect of Vo2peak between patient groups with LV mass index (P < 0.001), LV end-diastolic volume index (P < 0.001), and peak heart rate (P < 0.01) were significantly stronger in the hypertension group, whereby higher values led to greater Vo2peak. Limitations: Skeletal muscle strength was not assessed. Conclusion: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension

National Health Service healthcare staff experience and practices regarding complementary and alternative medicine: an online survey.

The use of complementary and alternative medicine (CAM) is increasing. The most common reported reason for CAM use is dissatisfaction with conventional healthcare. Several studies have reported factors influencing CAM usage and beliefs in the general public but the beliefs of healthcare staff are less well known. This paper reports the results of an online survey of 537 healthcare staff. Our study demonstrated an increased rate of patient referral for CAM from both personal CAM users and those trained in CAM. There was a high level of optimism amongst respondents as to the role CAM may play in patient care with mental health, depression and palliative care cited as the areas with highest expected benefit. Doctors were generally less optimistic about the likelihood of benefit compared to other healthcare staff. Implications for clinical practice, future research and staff education are discussed

Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas

The incidence of blood flow through intracardiac shunt and intrapulmonary arteriovenous anastomoses (IPAVA) may differ between Sherpas permanently residing at high altitude (HA) and sea-level (SL) inhabitants as a result of evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics. To test this hypothesis we compared sea-level inhabitants at SL (SL-SL; n = 17), during acute isocapnic hypoxia (SL-HX; n = 7) and following 3 weeks at 5050 m (SL-HA; n = 8 non-PFO subjects) to Sherpas at 5050 m (n = 14). inline image, heart rate, pulmonary artery systolic pressure (PASP) and cardiac index (Qi) were measured during 5 min of room air breathing at SL and HA, during 20 min of isocapnic hypoxia (SL-HX; inline image = 47 mmHg) and during 5 min of hyperoxia (inline image = 1.0; Sherpas only). Intracardiac shunt and IPAVA blood flow was evaluated by agitated saline contrast echocardiography. Although PASP was similar between groups at HA (Sherpas: 30.0 ± 6.0 mmHg; SL-HA: 32.7 ± 4.2 mmHg; P = 0.27), it was greater than SL-SL (19.4 ± 2.1 mmHg; P < 0.001). The proportion of subjects with intracardiac shunt was similar between groups (SL-SL: 41%; Sherpas: 50%). In the remaining subjects, IPAVA blood flow was found in 100% of subjects during acute isocapnic hypoxia at SL, but in only 4 of 7 Sherpas and 1 of 8 SL-HA subjects at rest. In conclusion, differences in resting pulmonary vascular regulation, intracardiac shunt and IPAVA blood flow do not appear to account for any adaptation to HA in Sherpas. Despite elevated pulmonary pressures and profound hypoxaemia, IPAVA blood flow in all subjects at HA was lower than expected compared to acute normobaric hypoxia

Changes in body composition and average daily energy expenditure of men and women during arduous extended polar travel

Weight and skin-fold measurements were made at five-day intervals during a 47-day expedition by six men and three women from the edge of the sea ice to the South Pole. From these, together with detailed manual records of the nutrition for individual participants, the average daily energy expenditure was determined before and after a resupply at approximately mid-point of the expedition. For all participants body weight fell during the expedition with the overall loss being much smaller for the three female participants (-4.0, -4.0, -4.4kg) than for the male participants, (mean±sd) -8.6±2.0kg. Fat weight fell approximately linearly during the expedition with a total loss of (-4.1, -6.5 and -2.5kg) for the three female participants and -6.8±1.7kg for the male participants. Individual fat-free weight changed by a smaller amount overall: (0.13, 2.5 and -1.8kg) for the three female participants; -1.8±2.0kg for the male participants who, with one exception, lost fat-free tissue All participants showed a substantial variation in fat-free tissue weight during the expedition. Analysis of the daily energy expenditure showed adequate nutrition but the intake fell for the second part of the expedition although the reasons for this are unclear, but adaptation to the cold, altitude and workload are possible explanations. The validity of this time-averaged measurement for individual participants was determined from analysing moments about the mean of time-series actigraphy data from wrist worn devices. The mean and autocorrelation function of the actigraphy data across subjects were analysed to determine whether measures could be compared between participants. The first, second and third moment about the mean of the day-to-day activity was found to be time-invariant for individual subjects (χ2, p&gt;0.05) and the normalized mean and autocorrelation measured over a day for each participant indistinguishable from the mean of the group (χ2, p&gt;0.05) allowing both longitudinal and cross-sectional analysis

Hypoxia, not pulmonary vascular pressure induces blood flow through intrapulmonary arteriovenous anastomoses

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times-a-day for 48 h) to prevent increases in PASP, and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ+HCO3-) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic-hypoxia condition to determine pH, [HCO3-], and PaCO2. AZ decreased pH (-0.08 ± 0.01), [HCO3-] (-7.1 ± 0.7 mmol/l), and PaCO2 (-4.5 ± 1.4 mmHg; p<0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (p<0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (p<0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (p<0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H+ concentration or PaCO2. Abbreviations list: AZ, acetazolamide; FEV1, forced expiratory volume in 1 second; FIO2, fraction of inspired oxygen; FVC, forced vital capacity; Hb, total haemoglobin; HPV, hypoxic pulmonary vasoconstriction; HR, heart rate; IPAVA, intrapulmonary arteriovenous anastomoses; MAP, mean arterial pressure; PASP, pulmonary artery systolic pressure; PETCO2, end-tidal partial pressure of carbon dioxide; PETO2, end-tidal partial pressure of oxygen; PFO, patent foramen ovale; PVR, pulmonary vascular resistance; Q̇c, cardiac output; RVOT, right ventricular outflow tract; SpO2, oxyhaemoglobin saturation; SV, stroke volume; TRV, tricuspid regurgitant velocity; V̇E, minute ventilation; VTI, velocity-time integra

Mortality on Mount Everest, 1921-2006: descriptive study

Objective To examine patterns of mortality among climbers on Mount Everest over an 86 year period