A Model to Study Time Lagged Interactions, Source Connectivity and Source Activities Using Multi-channel EEG.

A computational model to examine time lagged interactions; identify number of interacting pairs of neuronal sources; and determine source activities from multi-channel EEG measurements is described. It is based on the imaginary part of the cross spectrum between the EEG channels. The imaginary part of the cross spectrum between the EEG channels provides the most suitable property that reflects the presence of interacting sources. The model assumes that not all sources are activated simultaneously and that there is a time lag amongst some of them. A new analytical expression derived for the imaginary part of cross spectrum between channels shows that it is different from the zero lag case. A method is then proposed to identify time lag interactions, by studying its variation as a function of frequency. Assuming pair wise interaction between sources, the model shows that simultaneous diagonalization at different frequencies of symmetric matrices formed by multiplying the anti-symmetric matrix of the imaginary part of cross spectrum with its transpose will provide information on the number of interacting source pairs as a function of frequency. The matrix that simultaneously diagonalizes all the symmetric matrices is identified as the mixing matrix. This can be used to obtain the source activities.

A kinetic scheme to examine the role of glial cells in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that leads to severe impairments in cognitive functions including memory and learning. An improved kinetic model is proposed here to understand the pathogenesis of AD in particular the role of glial cells in the presence of amyloid plaques and neurofibrillary tangles (NFTs). The kinetic model describes the production of activated microglia and astroglia. It involves two rate equations and incorporates the dual role of these glial cells which can function as neuroprotective and as neurotoxic cells. Examination of the steady state solutions of the model predicts an increase in population of these glial cells as (AD) progresses, and that this continues to increase linearly even after the amyloid population has reached a plateau.This is in agreement with experimental data. Limiting AD to the effect of amyloid peptides alone is incorrect and the role of neurofibrillary tangles, clearance rate of dead neurons and neuroinflammation from glial cells are vital and must be included in understanding the pathogenesis of AD. The study shows that increasing the clearance of dead neurons and use of any method to deactivate the glial cells will diminish the progression of AD.

Examining nonlinearity using complexity and entropy.

A method based on complexity and Shannon entropy along with surrogate data testing is described to detect nonlinearity in biosignals. The importance of denoising is illustrated in the detection of nonlinearity. The procedure is tested on synthetic linear and Lorenz data and on a large set of surface and intracranial electroencephalographic (EEG) signals. This method provides a measure of the complexity and entropy associated with nonlinearity. The results indicate that EEG signals measured during a seizure and from intracranial recordings show more nonlinearity when compared with surface EEG data and eyes open more than eyes closed signals.

Dementia and Hopfield model.

Disruption in the neural network has been observed in the clinical studies on dementia. This is investigated here, theoretically, via the macroscopic thermodynamic properties of the Hopfield model to determine whether such a disruption in the network is possible. The analysis is carried out using a mean field theory. The results show a bifurcation in the network in the absence of direct energy input. This is seen when the average connective energy of the neuron becomes equal to or less than its thermal energy. The number of firing neurons that exceed the inactive neurons is then zero and the behavior of the neurons is random. The model further suggests that direct energy input will postpone the degradation of the neural network, suggesting that external mental stimuli will slow this disruption. However, if the neuronal connections are already weak, then improvements will not be marked.

Dense neuron system interacting with the gravitational potential.

A theoretical model is developed to study the role of the gravitational potential between neurons in the brain under conditions of zero gravity. The model includes firing and non-firing neurons in a neural network where the source of interaction is the gravitational potential. The importance of this study is its ability to examine the role of the weak gravitational potential alone without the inclusion of other interactions between neurons. The results of the study show density fluctuations contain components from thermal effects and gravitational interactions. It also shows collective oscillatory behavior amongst neurons from gravitational interactions. The study provides a simple alternate mechanism to understand organized behavior of neurons in the brain under conditions of zero gravity.

Literature review of passenger lymphocyte syndrome following renal transplantation and two case reports.

Passenger lymphocyte syndrome (PLS) is an immune-mediated hemolysis. It occurs following ABO blood group mismatched solid organ and/or bone marrow transplantation between donor and recipient. We report two cases of PLS occurring after renal transplantation. Both recipients received live related kidney transplants; one from his mother and the other from his brother. The direction of blood group transfer, from donor to recipient, was O Rh D+ to A Rh D+ in both cases. Approximately 12 days after transplantation, both recipients showed a rapid fall in their hemoglobin levels with no identifiable bleeding source. DAT positive hemolysis was confirmed and anti-A antibodies were detected in recipient sera, confirming a diagnosis of PLS. Both cases required blood transfusion support to maintain their hemoglobin and both had good renal outcomes. We have identified 99 PLS cases following renal transplant in the English literature. Previous ABO sensitization, donor blood group O to recipient blood group A or B transfer, and ciclosporin treatment have been identified as risk factors for PLS. Clinical outcomes in general are good; nonetheless, cases of graft failure and deaths have been reported. Early diagnosis and appropriate treatment are important in at risk individuals.

Antenatal screening for pre-eclampsia: evaluation of the NICE and pre-eclampsia community guidelines.

The NICE and PRECOG guidelines are based on systematic reviews of risk factors for pre-eclampsia to identify mothers at risk before 20 weeks' gestation. Cases (64) and controls (112) were classified retrospectively as screen positive or negative as recommended by the two guidelines The NICE guideline had a higher sensitivity rate of 77% (95% CI 65-87%) vs 59% (95% CI 46-71%) but a lower specificity of 54% (95% CI 44-64%) vs 81% (95% CI 73-88%) with the PRECOG guideline. Based on an incidence of pre-eclampsia of 4% the positive predictive values of PRECOG and NICE guidelines were estimated at only 11% and 7%, respectively. The most discriminatory risk factor was history of pre-eclampsia in a previous pregnancy. Neither guideline has a reasonable performance and cannot be recommended for use in clinical practice. Resources should rather be focussed on development of new strategies to identify women at risk of pre-eclampsia.

Blood pressure guidelines in chronic kidney disease: a critical review.

The primary purpose of guidelines should be to improve patient care by providing an avenue for healthcare professionals to participate in the assessment of appropriate care, based on sound medical reasoning and robust scientific knowledge. Guidelines are usually meant to be evidence-based when they are derived from systemic reviews of the relevant literature. Nephrology as a medical subspeciality lags behind other clinical disciplines when it comes to availability of high-quality clinical studies with hard clinical outcomes. In the absence of robust clinical evidence, recommendations in renal guidelines are overwhelmingly opinion-based and reflect the experience of the various experts. Unfortunately, no guidelines are detailed enough to provide recommendations for individual patients with different types and severity of co-morbidities. We propose that guidelines should be viewed as desirables and should not replace a common sense clinical approach to patient care by an autonomously practicing competent clinician.

Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension.

Cardiovascular disease remains the most common cause of mortality in patients with end-stage kidney disease treated by regular hemodialysis. To improve blood pressure control and reduce cardiovascular risk, the United Kingdom Renal Association standards committee introduced pre- and post-dialysis target blood pressures of less than 140/90 and 130/80 mm Hg, respectively. We audited blood pressure control and symptomatic intradialytic hypotension requiring fluid resuscitation in the Greater London area renal centers that serve 2630 patients. The study captured 7890 hemodialysis sessions during a 1-week period where only 36% of the patients achieved the pre-dialysis target and 42% the post-dialysis target, with a wide variation between centers. Different antihypertensive medication prescriptions did not affect achievement of these targets. Fifteen percent of the patients suffered symptomatic hypotension requiring fluid resuscitation associated with significantly greater interdialytic weight gains. Our study found that intradialytic hypotension was significantly greater in centers that achieved better post-dialysis blood pressure targeting.

The importance of dialysate sodium concentration in determining interdialytic weight gains in chronic hemodialysis patients: the PanThames Renal Audit.

BACKGROUND AND OBJECTIVES: There is controversy as to the optimum dialysate sodium to be used for hemodialysis patients, with reports of hypertension and increased interdialytic weight gains with high sodium dialysates and intradialytic hypotension and cramps with low sodium dialysates. METHODS: We analyzed the effect of different dialysate sodium concentrations during a one-week period in an audit of 2187 established patients regularly receiving dialysis three times a week. Patients were given general dietary advice to restrict dietary sodium intake, but no systematic assessment of dietary sodium intake was undertaken. RESULTS: The prescription of a dialysate sodium concentration of 140 mmol/L and >140 mmol/L, was associated with greater interdialytic weight gains, 3.5% and 4.1% respectively, compared to 2.8% and 2.7% for those using dialysate sodium concentrations of 137 and 136 mmol/L, respectively (p0<.05). The mean pulse pressure was greater patients dialyzing using a sodium of 140 mmol/L, compared to 136 mmol/L, 70 (13) vs 63 (15) mmHg (p<0.011). In addition, 13.5% of patients using the highest sodium dialysate suffered symptomatic intradialytic hypotension requiring intravenous fluid resuscitation, compared to 2.7% who used the lowest sodium concentrate (p<0.05). CONCLUSIONS: This analysis would support the use of lower dialysate sodium concentrations to aid in reducing interdialytic weight gains and subsequent intradialytic hypotension.

Pathogenesis of Alzheimer's Disease Examined Using a Modified Puri-Li Model that Incorporates Calcium Ion Homeostasis.

The Puri-Li kinetic model is modified to include neuronal calcium ion homeostasis to study the effect of calcium ions on the production of amyloid-ß peptides (Aß), microglia, and astroglia during the pathogenesis of Alzheimer's disease (AD). This is carried out by solving the modified Puri-Li model under steady-state conditions. The derived expressions show that the inclusion of calcium ions has altered the steady-state populations of Aß, microglia, and astroglia. The calcium ions activate the synthesis of Aß which in turn increases the calcium ions entering the cytoplasm of the neuronal cells, thus creating a positive loop. The study also shows that as AD progresses, the inclusion of calcium ions enhances the production of microglia and astroglia. Examination of the steady-state solutions of microglia and astroglia shows that equilibrium conditions are achieved by microglia and astroglia destroying neurons. These model results are in agreement with experimental findings, which show a feed back loop between calcium ion levels and Aß; population increase in microglia, astroglia during AD; and microglia, astroglia acting as inflammatory cells producing toxins to destroy neurons during AD. Increased production of Aß, microglia, and astroglia resulting from increased levels of calcium ions suggests that controlling the calcium ion levels could present a therapeutic strategy to combat AD.

De novo HNF1 homeobox B mutation as a cause for chronic, treatment-resistant hypomagnesaemia.

29-year-old female presenting with an 8-year history of unexplained hypomagnesaemia, which was severe enough to warrant intermittent inpatient admission for intravenous magnesium. Urinary magnesium was inappropriately normal in the context of hypomagnesaemia indicating magnesium wasting. Ultrasound imaging demonstrated unilateral renal cysts and computed tomography of kidneys, ureters and bladder showed a bicornuate uterus. Referral to genetic services and subsequent testing revealed a de novo HNF1B deletion. LEARNING POINTS: HNF1B loss-of-function mutations are one of the most common monogenic causes of congenital anomalies of the kidney and urinary tract.Those with HNF1B mutations may have some of a constellation of features (renal and hepatic cysts, deranged liver function tests, maturity onset diabetes of the young type 5 (MODY5), bicornuate uterus, hyperparathyroidism, hyperuricaemic gout, but presenting features are highly heterogeneous amongst patients and no genotype/phenotype correlation exists. HNF1B mutations are inherited in an autosomal dominant pattern but up to 50% of cases are de novo.HNF1B mutations can be part of the Chr17q12 deletion syndrome, a contiguous gene deletion syndrome.Inorganic oral magnesium replacements are generally poorly tolerated with side effects of diarrhoea. Organic magnesium compounds, such as magnesium aspartate, are better absorbed oral replacement therapies.

A new method using coherence to obtain the model order in the evaluation of partial directed coherence.

Recently partial directed coherence has been introduced to study interrelations in multivariate time series, using the vector autoregressive model. In this procedure the choice of the model order is not clear. The use of spectral density has been suggested [B. Schelter, M. Winterhalder, B. Hellwig, B. Guschlbauer, C.H. Lucking, J. Timmer, Direct or indirect? Graphical models for neural oscillators, J. Physiol. (Paris) 99 (2006) 37-46]. This was examined along with a new method which employs coherence. The studies indicate that coherence provides an accurate estimate of the order unlike the spectral density, which underestimated the value of the order leading to inaccurate values for the partial directed coherence. On the other hand the use of coherence gave the correct value for the order, leading to accurate values for the partial directed coherence.

Examining the Role of Microglia and Astroglia During the Pathogenesis of Alzheimer's Disease via the Puri-Li Model.

The Puri-Li kinetic model is explored here to study the contribution of microglia and astroglia during the pathogenesis of Alzheimer's disease (AD). This is carried out by solving the Puri-Li model under steady-state conditions. The derived expressions show that both of them play a role in the pathogenesis of AD. Examination of the steady-state solutions where microglia and astroglia are involved shows that equilibrium conditions are achieved by microglia and astroglia destroying neurons. These findings from this model are in agreement with the results in the literature, where microglia and astroglia are considered to act as inflammatory cells producing toxins to destroy neurons. In addition, the study also showed that the number ratio of the total astroglial cells to the total microglial cells increases with the progression of AD. With advances in three dimensional imaging and selective staining, this ratio could be used as a valuable marker to monitor AD.

Preprocessing RR interval time series for heart rate variability analysis and estimates of standard deviation of RR intervals.

Heart rate variability is concerned with the analysis of the fluctuations in the interval between heart beats known as RR intervals. The long time RR time series obtained suffer from non-stationarity and the presence of ectopic beats, which prevents extraction of useful statistical information. The paper describes a wavelet-based technique for trend removal and a nonlinear filter to remove ectopic beats. This attempts to correct the limitations observed in a recent advanced heart rate toolkit [J. Niskanen, M.P. Tarvainen, P.O. Ranta-aho P.A. Karjalainen, Software for advanced HRV analysis, Comput. Meth. Prog. Biomed.,76 (2004) 73-81] when preprocessing. The results are encouraging. The preprocessed data are then used to obtain the standard deviation of RR interval time series (SDRR) of 15 healthy patients and 15 patients suffering from congestive heart failure. The results demonstrate the importance of preprocessing. The analysis show that the SDRR values of congestive heart failure patients are depressed compared to the healthy group.

Development of an alert system for subjects with paroxysmal atrial fibrillation.

BACKGROUND: Knowledge of the onset of atrial fibrillation (AF) episodes in patients with paroxysmal atrial fibrillation (PAF) will enable them to better manage this condition. Current advances in mobile technology allow RR interval data to be obtained in real time. An analysis technique using RR interval data is presented with a view to alert a subject before a PAF episode. METHOD: The method is based on a time series of standard deviation and 0.99 quantile values of the spectral entropy, constructed from RR data. The RR data are taken from three time periods. The first time period has no occurrences of AF for 45 min to either side of the time period. The second time period just precedes an AF attack. Both of these are of thirty minutes duration. The third time period of approximately 5 min follows the second, and is when AF occurs. RESULTS: Twenty-two PAF subjects were studied and in all cases there was a steady increase in the values of these indices as the onset of the AF attack approached. CONCLUSION: This method of analysis of RR interval data shows potential use to alert a PAF subject before the onset of an AF episode.

Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients.

BACKGROUND: Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function. METHODS: Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation. RESULTS: After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8+/-1.6 (mean +/- SEM) to 44.1+/-6.8 pmol/L (P<0.001) in association with a threefold increase in urine cGMP excretion (573+/-195 pmol/min baseline to 1823+/-545 pmol/ min; P<0.001), marked natriuresis (207+/-34 micromol/min baseline to 416+/-62 micromol/min; P<0.001), fractional sodium excretion (3.3+/-0.5% baseline to 5.6+/-0.7%; P<0.01), and diuresis (3.4+/-0.5 ml/min baseline to 7.4+/-1 ml/min; P<0.001). All parameters remained elevated above baseline for the remaining 7-hr study period. In response to candoxatrilat, the glomerular filtration rate rose by 19% (P=0.01), renal plasma flow by 7% (P=0.04), renal blood flow by 13% (P=0.03) in association with an increase in filtration fraction from 24+/-2% to 28+/-2% (P=0.002) and small fall in renal vascular resistance from 0.38+/-0.04 to 0.30+/-0.04 mmHg x min x 1.73 m2 x ml(-1) (P=0.02). There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) microg/min (P<0.01). CONCLUSIONS: Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.

Oxidative consumption of nitric oxide: a potential mediator of uremic vascular disease.

Recent data has drawn our attention to the relationship between altered biomechanical properties of the vasculature and left ventricular hypertrophy (LVH) in uremia. We have been able to show that uremia causes functional changes in the conduit vessels of rats, predating structural changes and independent of blood pressure. As nitric oxide (NO) is a potent modulator of the cardiovascular system, we studied the NO pathway in uremia. The existing data are somewhat confusing, with some suggesting up-regulation of the NO system, and others the opposite. When examined critically, however, a pattern emerges, with studies examining NO release showing increased production, whereas those examining NO bioactivity show it to be attenuated. We hypothesized that there is increased NO release, but excess consumption in uremia. Our own data on NO metabolites (NOx) in the serum of healthy young male hemodialysis patients indicate higher concentrations both pre- and post-dialysis compared to controls. As the endothelium is a potential source of NO, we cultured endothelial cells in uremic plasma. These studies demonstrated increased basal NO release from cells cultured under uremic conditions compared to controls. Furthermore, alterations in arginine metabolism appear to play a role, as there is evidence for reduced arginase activity in these cells, thereby increasing arginine availability for the NO pathway. Given the in vivo data and clinical characteristics of the uremic syndrome suggesting reduced NO bioactivity, we examined the possibility that the excess NO generated is being consumed and rendered bio-inactive. Aortae from uremic and control rats were stained for the presence of nitrotyrosine. All uremic aortae stained positively, but nitrotyrosine was not present in any control aortae.

Haemodialysis access: a single centre UK Experience.

BACKGROUND: The aim of this study was to determine whether the US National Kidney Foundation Disease Outcome Quality Initiative (K/DOQI) guidelines on haemodialysis access could be achieved and to examine its relevance to patients on dialysis in the UK. METHOD: A cross sectional study of chronic haemodialysis patients at our institution which involved case note review and measurements of biochemical parameters and dynamic venous pressure (dVP) was performed. Patients with polytetrafluoroethylene (PTFE) grafts were followed prospectively for 18 months. RESULTS: 262 patients were studied - 12%, 43%, 30% and 15% underwent dialysis through dialysis catheters, radial-cephalic fistulae (rAVF), brachial-cephalic fistulae (bAVF) and PTFE grafts respectively. RAVFs, bAVFs and PTFE grafts were the primary access (i.e. the first access created for the patient) in 58%, 35% and 7% respectively. Compared with patients of Caucasian origin, patients of Afro-Caribbean race were 3.80 times (95% confidence limit: 1.51 - 9.53) more likely to have a PTFE graft. Patients with higher 'dry weights' were more likely to have PTFE grafts (p<0.005 by ANOVA). Dialysis adequacy was similar irrespective of type and site of access. We found that 64% of PTFE grafts, 46% of bAVFs and 13% of rAVF had dVPs greater than 150 mmHg, (p<0.0001 by c2). This threshold recommended by DOQI predicted 12 of 13 dysfunctional grafts, but had a positive predictive value of only 50%. CONCLUSION: We have demonstrated that the K/DOQI guidelines are not only achievable, but that they can be exceeded by a considerable margin. Our data also suggest that the demographic details of patients within a unit will influence the achievable proportion of AVF: PTFE grafts (the proportion of PTFE grafts in Afro-Caribbeans being 3 times higher than in whites). Although a dVP >150 mmHg proved sensitive in predicting future graft dysfunction, it had low specificity.

Platelet activation and endogenous thrombin potential in pre-eclampsia.

INTRODUCTION: Platelets and the coagulation system may be involved in the pathogenesis of pre-eclampsia. We investigated whether platelet and coagulation activation markers, are elevated in pre-eclampsia. MATERIALS/METHODS: Case-control study in which activated platelets, platelet-monocyte/ neutrophil aggregates, platelet microparticles (measured by flow cytometry) and four markers of thrombin generation capacity (endogenous thrombin potential (ETP), peak height, lag time and time to peak) using the Calibrated Automated Thrombogram system were assessed in pregnant women of similar gestational age with (n=46) and without (n=46) pre-eclampsia, and in healthy non-pregnant women (n=42). RESULTS: The percentage of, CD62P+ platelets (p=0.013), CD62P+ platelet microparticles (p=0.029) and platelet-monocyte aggregates (p=0.019) were significantly higher in women with pre-eclampsia than the pregnant controls. Both groups of pregnant women had significantly higher ETP and peak height (p <0.001) than the healthy non pregnant group and the women with pre-eclampsia had significantly higher ETP and peak height (p<0.001) than the normotensive pregnant controls. CONCLUSION: In the most comprehensive laboratory analysis to date, we found evidence of both platelet and coagulation activation in women with pre-eclampsia.