Comparison of blood volume biofeedback hemodialysis and conventional hemodialysis on cardiovascular stability and blood pressure control in hemodialysis patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Despite the improvements in hemodialysis (HD) technology, 20-30% of sessions are still complicated by hypotension or hypotension-related symptoms. Biofeedback systems have proven to reduce the occurrence of such events, but no conclusive findings can lead to wider adoption of these systems. We conducted this systematic review and meta-analysis of randomized clinical trials to establish whether the use of blood volume tracking systems compared to conventional hemodialysis (C-HD) reduces the occurrence of intradialytic hypotension. METHODS: The PRISMA guidelines were used to carry out this systematic review. Randomized clinical trials that evaluated the incidence of intradialytic hypotension during C-HD and blood volume tracking-HD were searched in the current literature. PROSPERO registration number: CRD42023426328. RESULTS: Ninety-seven randomized clinical trials were retrieved. Nine studies, including 347 participants and 13,274 HD treatments were considered eligible for this systematic review. The results showed that the use of biofeedback systems reduces the risk of intradialytic hypotension (log odds ratio = 0.63, p = 0.03) in hypotension-prone patients (log odds ratio = 0.54, p = 0.04). When analysis was limited to fluid overloaded or hypertensive patients, it did not show the same effect (log odds ratio = 0.79, p = 0.38). No correlation was found in systolic blood pressure drop during dialysis and in post-dialysis blood pressure. CONCLUSIONS: The use of blood volume tracking systems may be effective in reducing the incidence of intradialytic hypotension and allowing for easier attainment of the patients' ideal dry body weight. New studies to examine the long-term effects of the use of blood volume tracking systems on real hard endpoints are needed.

Resposta vascular após implante de stents liberadores de biolimus A9 compolímero bioabsorvível e stents liberadores de everolimus com polímero durável. Resultados da análise de tomografia de coerência óptica do estudo randomizado BIOACTIVE / Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer. Results of the optical coherence tomography analysis of the BIOACTIVE randomized trial

No estudo BIOACTIVE, avaliamos as respostas vasculares após implante do stent eluidor de biolimus A9 (SEB; BioMatrix®) e o stent eluidor de everolimus (SEE; XIENCE V®). Apresentamos a análise detomografia de coerência óptica (OCT) 6 meses pós-intervenção. Métodos: Os pacientes foram randomizados para tratamento com SEB (n = 22) ou SEE (n = 18). O desfecho primário foi a frequência de hastes não cobertas e mal apostas pela OCT. Resultados: A OCT foi realizada em 26 pacientes (SEB: n = 15; SEE: n = 11) e foram analisadas 749 imagens tomográficas e 7.725 hastes de stent. SEB e SEE apresentaram áreas luminais e dos stents semelhantes.A área de hiperplasia neointimal, a espessura neointimal e o porcentual de obstrução intra-stent (8,44 ± 5,10% vs. 9,21 ± 6,36%; p = 0,74) foram similares. As taxas de hastes não cobertas (SEB: 2,10 ± 3,60% vs. SEE: 2,46 ± 2,15%; p = 0,77) e mal apostas (SEB: 0,48 ± 1,48% vs. SEE 0,44 ± 1,05%; p = 0,94) foram baixas e semelhantes. A frequência de frames com sinais compatíveis com infiltrado inflamatório peri-haste foi baixa e similar entre SEB (15,53 ± 20,77%) e SEE (11,70 ± 27,51%; p = 0,68).Conclusões: Stents farmacológicos de segunda geração SEB e SEE se mostraram igualmente eficientes emsuprimir a formação neointimal aos 6 meses, com respostas vasculares favoráveis. A frequência de framescom sinais de infiltrado peri-haste por paciente foi baixa, e menor do que a historicamente observada comos stents farmacológicos de primeira geração...

In BIOACTIVE study, we evaluated vascular responses after the implant of biolimus A9-eluting stent (BES; BioMatrixTM) and the everolimus-eluting stent (EES; XIENCE VTM). In this study, we present the optical coherence tomography analysis (OCT) 6 months post-intervention. Methods: Patients were randomized to treatment with BES (n = 22) or EES (n = 18). The primary outcome was the frequency of non-covered, poorly positioned struts by OCT.Results: OCT was performed in 26 patients (BES: n = 15; EES: n = 11) and 749 tomographic images and 7,725stent struts were analyzed. BES and EES showed similar luminal and stent areas. Neointimal hyperplasia area, neointimal thickness and the percentage of in-stent obstruction (8.44 ± 5.10% vs. 9.21 ± 6.36%; p = 0.74) were similar. The rates of not covered struts (BES: 2.10 ± 3.60% vs. ESS: 2.46 ± 2.15%, p = 0.77) and poorly positioned struts (BES: 0.48 ± 1.48% vs. EES 0.44 ± 1.05%, p = 0.94) were similarly low. The frequency of frames with signs consistent with peri-strut inflammatory infiltrate was low and similar between BES (15.53 ± 20.77%) and EES (11.70 ± 27.51%; p = 0.68). Conclusions: The second-generation drug-eluting stents BES and EES were equally effective at suppressing the neointimal formation after 6 months, with favorable vascular responses. The frequency of frameswith peri-strut infiltrate signals per patient was low, and lower than that observed historically with firstgenerationdrug-eluting stents...

Dissecções de Borda Após Implante Coronário de Suportes Vasculares Biorreabsorvíveis. Análise Seriada com Tomografia de Coerência Óptica / Edge Dissections After the Coronary Implantation of Bioresorbable Scaffolds. Serial Analysis Using Optical Coherence Tomography

Introdução: A incidência de dissecções de borda, após o implante de suportes vasculares biorreabsorvíveis (SVBs), ainda não foi investigada. Esses suportes têm hastes mais espessas e requerem pré-dilatação mais agressiva no implante. Avaliamos a incidência de dissecções de borda após implante de SVBs, seus aspectos morfométricos e o processo de cicatrização, com imagens de tomografia de coerência óptica (OCT) seriadas. Métodos: Incluímos pacientes consecutivos, que foram tratados com SVBs polimérico, e que possuíam avaliação com OCT após o procedimento e aos 6 meses de evolução. Dissecções de borda foram definidas como rupturas da superfície luminal nos 5 mm distais ou proximais ao SVB. Resultados: Das 96 bordas de 48 SVB implantados em 48 lesões de 48 pacientes, 91 bordas estavam disponíveis para a análise. Dissecções foram detectadas pela OCT em 28 bordas (30,7%) de 22 lesões (45,8%), com igual distribuição entre as bordas distais e proximais. Todas as dissecções apareceram como flaps e não foram visualizadas pela angiografia. Doença aterosclerótica esteve presente em 96,4% das bordas dissecadas; a maioria era fibrocalcificada (40,8%) e mais de um terço era rica em lipídio. O comprimento médio das dissecções foi 1,80 mm e a área média dos flaps tinha 0,30 mm. A maioria ...

Background: The incidence of edge dissections after the coronary implantation of bioresorbable scaffolds (BRS) has not been investigated. BRS have thicker struts and require more aggressive pre-dilation for implantation. The incidence of edge dissections after BRS implantation, their morphological aspects and healing process were evaluated using serial optical coherence tomography (OCT) images. Methods: Consecutive patients treated with a polymeric BRS, who had an OCT evaluation after the procedure and at 6-month follow-up, were included in the current analysis. Edge dissections were defined as luminal surface ruptures, 5-mm distally or proximally to the BRS edges. Results: Out of 96 edges from 48 BRS implanted in 48 lesions of 48 patients, 91 edges were available for analysis. Dissections were detected by OCT in 28 edges (30.7%) and in 22 lesions (45.8%), with equal distribution between distal and proximal edges. All dissections appeared as flaps and none were visible by angiography. Atherosclerotic disease was present in 96.4% of all dissected edges; most were fibrocalcific (40.8%), and more than one-third were lipid-rich. Mean dissection length was 1.80 mm, and the mean flap area was 0.30 mm. Most dissections (89.3%) were superficial and restricted to the intima/atheroma layer. At the 6-month follow-up 92.8% of all dissections healed completely, and there was no significant reduction in the luminal dimensions at the edge segments, with only one case of restenosis. ...

The THRombolysis and STatins (THRaST) study.

OBJECTIVE: To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. METHODS: Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. RESULTS: Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26-2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11-1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18-2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19-0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28-0.82; p = 0.007). CONCLUSION: Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

Efficient management of multi-version clinical guidelines.

Clinical medicine and health-care developments in recent years testified a tremendous increase in the number of available guidelines, i.e., "best practices" encoding and standardizing care procedures for a given disease. Clinical guidelines are subject to continuous development and revision by committees of expert physicians and health authorities and, thus, multiple versions coexist as a consequence of the clinical and healthcare activities. Moreover, several alternatives are usually included in order to make the guidelines as general as possible, making them difficult to handle both in manual and automated fashions. In this work, we will introduce techniques to model and to provide efficient personalized access to very large collections of multi-version clinical guidelines, which can be stored both in textual and in executable format in an XML repository. In this way, multiple temporal perspectives, patient profile and context information can be used by an automated personalization service to efficiently build on demand a guideline version tailored to a specific use case.

Risk of recurrent cerebrovascular events in patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study.

BACKGROUND: The optimal management of patients with cryptogenic ischemic stroke found to have a patent foramen ovale (PFO) at diagnostic workup remains unclear. The aims of this observational multicenter study were to evaluate: (1) the risk of recurrent cerebrovascular events in patients with cryptogenic minor ischemic stroke or transient ischemic attack (TIA) and PFO who either underwent percutaneous PFO closure or received only medical treatment, and (2) the risk factors associated with recurrent events. METHODS: Consecutive patients (aged 55 years or less) with first-ever cryptogenic minor ischemic stroke or TIA and PFO were recruited in 13 Italian hospitals between January 2006 and September 2007 and followed up for 2 years. RESULTS: 238 patients were included in the study (mean age 42.2 ± 10.0 years; 118 males); 117 patients (49.2%) received only antithrombotic therapy while 121 patients underwent percutaneous PFO closure (50.8%). Stroke as the qualifying event was more common in the medical treatment group (p = 0.01). The presence of atrial septal aneurysm and evidence of 20 bubbles or more on transcranial Doppler were more common in the PFO closure group (p = 0.002 and 0.02). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17 recurrent events (TIA or stroke; 3.6% per year) were observed; 7 of these events (2.9% per year) occurred in the percutaneous PFO closure group and 10 events (4.2% per year) in the medical treatment group. The rate of recurrent stroke was 0.4% per year in patients who underwent percutaneous closure (1 event) and 3.4% per year in patients who received medical treatment (8 events). On multivariate analysis, percutaneous closure was not protective in preventing recurrent TIA or stroke (OR = 0.1, 95% CI = 0.02-1.5, p = 0.1), while it was barely protective in preventing recurrent stroke (OR = 0.1, 95% CI = 0.0-1.0, p = 0.053). CONCLUSIONS: The results of this observational, nonrandomized study suggest that PFO closure might be superior to medical therapy for the prevention of recurrent stroke. Periprocedural complications were the trade-off for this clinical benefit. Controlled randomized clinical trials comparing percutaneous closure with medical management are required.

Physical methods for preventing deep vein thrombosis in stroke.

BACKGROUND: Deep vein thrombosis (DVT) and resulting pulmonary embolism (PE) are important complications of stroke. Physical methods to reduce the risk of DVT and PE, such as graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) applied to the legs, do not appear to be associated with any bleeding risk and reduce the risk of DVT in some categories of surgical patients. We sought to assess their effects in stroke patients. OBJECTIVES: To assess the effectiveness and safety of physical methods of reducing the risk of DVT, fatal or non-fatal PE and death in patients with recent stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE (1966 to November 2009), EMBASE (1980 to November 2009), CINAHL (1982 to November 2009) and The British Nursing Index (1985 to November 2009). We screened reference lists of all relevant papers, searched ongoing trials registers (November 2009) and contacted experts in the field. SELECTION CRITERIA: Unconfounded randomised controlled trials comparing physical methods for reducing the risk of DVT with control and in which prophylaxis was started within seven days of the onset of stroke. DATA COLLECTION AND ANALYSIS: Two review authors searched for trials and extracted data. MAIN RESULTS: We identified two trials of GCS that included 2615 patients and two small studies of IPC that included 177 patients. Overall, physical methods were not associated with a significant reduction in DVTs during the treatment period (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.70 to 1.04) or deaths (OR 1.12, 95% CI 0.87 to 1.45). Use of GCS was not associated with any significant reduction in risk of DVT (OR 0.88, 95% CI 0.72 to 1.08) or death (OR 1.13, 95% CI 0.87 to 1.47) at the end of follow up. IPC was associated with a non-significant trend towards a lower risk of DVTs (OR 0.45, 95% CI 0.19 to 1.10) with no evidence of an effect on deaths (OR 1.04, 95% CI 0.37 to 2.89). AUTHORS' CONCLUSIONS: Evidence from randomised trials does not support the routine use of GCS to reduce the risk of DVT after acute stroke. There is insufficient evidence to support the routine use of IPC to reduce the risk of DVT in acute stroke and further larger randomised studies of IPC are needed to reliably assess the balance of risks and benefits of this intervention.

Possible Anandamide and Palmitoylethanolamide involvement in human stroke.

BACKGROUND: Endocannabinoids (eCBs) are ubiquitous lipid mediators that act on specific (CB1, CB2) and non-specific (TRPV1, PPAR) receptors. Despite many experimental animal studies proved eCB involvement in the pathogenesis of stroke, such evidence is still lacking in human patients. Our aim was to determine eCB peripheral levels in acute stroke patients and evaluate their relationship with clinical disability and stroke volume. METHODS: A cohort of ten patients with a first acute (within six hours since symptoms onset) ischemic stroke and a group of eight age- and sex-matched normal subjects were included. Groups were also matched for metabolic profile. All subjects underwent a blood sample collection for anandamide (AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA) measurement; blood sampling was repeated in patients on admission (T0), at 6 (T1) and 18 hours (T2) thereafter. Patients neurological impairment was assessed using NIHSS and Fugl-Meyer Scale arm subitem (FMSa); stroke volume was determined on 48 h follow-up brain CT scans. Blood samples were analyzed by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. RESULTS: 1)T0 AEA levels were significantly higher in stroke patients compared to controls. 2)A significant inverse correlation between T0 AEA levels and FMSa score was found. Moreover a positive correlation between T0 AEA levels and stroke volume were found in stroke patients. T0 PEA levels in stroke patients were not significantly different from the control group, but showed a significant correlation with the NIHSS scores. T0 2-AG levels were lower in stroke patients compared to controls, but such difference did not reach the significance threshold. CONCLUSIONS: This is the first demonstration of elevated peripheral AEA levels in acute stroke patients. In agreement with previous murine studies, we found a significant relationship between AEA or PEA levels and neurological involvement, such that the greater the neurological impairment, the higher were these levels.

Model-based analysis of potassium removal during hemodialysis.

Potassium ion (K(+)) kinetics in intra- and extracellular compartments during dialysis was studied by means of a double-pool computer model, which included potassium-dependent active transport (Na-K-ATPase pump) in 38 patients undergoing chronic hemodialysis. Each patient was treated for 2 weeks with a constant K(+) dialysate concentration (K(+)(CONST) therapy) and afterward for 2 weeks with a time-varying (profiled) K(+) dialysate concentration (K(+)(PROF) therapy). The two therapies induced different levels of K(+) plasma concentration (K(+)(CONST): 3.71 +/- 0.88 mmol/L vs. K(+)(PROF): 3.97 +/- 0.64 mmol/L, time-averaged values, P < 0.01). The computer model was tuned to accurately fit plasmatic K(+) measured in the course and 1 h after K(+)(CONST) and K(+)(PROF) therapies and was then used to simulate the kinetics of intra- and extracellular K(+). Model-based analysis showed that almost all the K(+) removal in the first 90 min of dialysis was derived from the extracellular compartment. The different K(+) time course in the dialysate and the consequently different Na-K pump activity resulted in a different sharing of removed potassium mass at the end of dialysis: 56% +/- 17% from the extracellular compartment in K(+)(PROF) versus 41% +/- 14% in K(+)(CONST). At the end of both therapies, the K(+) distribution was largely unbalanced, and, in the next 3 h, K(+) continued to flow in the extracellular space (about 24 mmol). After rebalancing, about 80% of the K(+) mass that was removed derived from the intracellular compartment. In conclusion, the Na-K pump plays a major role in K(+) apportionment between extracellular and intracellular compartments, and potassium dialysate concentration strongly influences pump activity.

Acute hemorrhagic leukoencephalitis with atypical features.

Acute hemorrhagic leukoencephalitis (AHL) is a rare demyelinating disease mainly affecting children, characterized by acute onset, progressive course and high mortality. A 62-year-old man was admitted to our Unit for diplopia and ataxia ensuing 2 weeks after the onset of pneumonia. MRI T2-weighted images showed signal hyperintensities in the brainstem. Antibodies against Mycoplasma Pneumoniae and cold agglutinins were found. Two weeks later the patient had a worsening of his conditions: he developed left hemiplegia with motor focal seizures and the day after he was deeply comatose (GCS = 4). A second MRI scan showed extensive hyperintensities involving the whole right hemisphere white matter with a small parietal hemorrhagic area. The clinical and neuroimaging features suggested the diagnosis of AHL, Aciclovir in association with steroid therapy were administered and then plasmapheresis was started. After 30 days of coma, the patient gradually reacquired consciousness and motor functions; anyway a left hemiplegia persisted.

Simple model of intra-extracellular potassium kinetics and removal applied to constant and potassium-profiled dialysis.

AIM: The incidence rate for sudden death in hemodialysis patients ranges between 2% and 7%. This phenomenon is frequently due to cardiac arrhythmias. In particular, the process of potassium (K(+)) depuration performed during hemodialysis has been found to be related to arrhythmia onset. The main aim of this study was to introduce a simple double-pool mathematical model of K(+) kinetics to investigate the effects of dialysate K(+) concentration on intracellular and extracellular K(+) removal. The secondary aim was to evaluate the K(+) removed from the different body pools in 2 different types of K(+) dialysate: constant and profiled. METHODS: Our model evaluated K(+) removal and body water in the intracellular and extracellular spaces using plasma, erythrocytes and spent dialysate K(+) concentration, and intracellular and extracellular volume (t=0) in 6 patients (4 females and 2 males). All patients were treated with acetate-free biofiltration with a constant K(+) dialysate concentration (AFB) and with a profiled one (AFB-K). Moreover, the electrolyte concentration (sodium, calcium and bicarbonate) and pH were analyzed in all sessions. RESULTS: A similar total potassium removal was evaluated by the model, starting from a similar final K(+) plasma reduction. At 10 minutes, the model assessed a higher K(+) removal in the extracellular space during AFB (26.6% vs. 7.7%, p<0.001) involving a lower K(+) concentration (5.0 +/- 0.5 in AFB and 5.2 +/- 0.6 in AFB-K, p<0.05) and consequently a higher cell hyperpolarization (-73.4 +/- 3.9 mV vs. -72.1 +/- 2.4 mV, p=0.05). No differences in pH, intracellular and extracellular Na+ or plasma Ca(2+) were highlighted between AFB and AFB-K. CONCLUSIONS: The model we developed allows us to evaluate K(+) removal and body water in the intracellular and extracellular spaces during treatment. The assessment of this information may have a relevant role toward an understanding of the causes of the Nernst potential changes during hemodialysis that are often related to the onset of arrhythmias.

Calcium and potassium changes during haemodialysis alter ventricular repolarization duration: in vivo and in silico analysis.

BACKGROUND: Alterations of ventricular repolarization duration, as measured by the QT interval, are frequently observed in haemodialysis (HD) patients. The nature and the sign of these changes are not yet fully understood. METHODS: Different dialysate K(+) and Ca(2+) levels, leading to different end-HD plasma concentrations in the patient, have been tested in the present study in terms of their impact on QTc. A model of the human cardiomyocyte action potential (AP) has been used to assess in silico whether the changes in Ca(2+) and K(+) were able to justify at the cellular level the observed alterations of QTc. RESULTS: QTc was prolonged in HDs with low (1.25 mM) versus high (2 mM) Ca(2+) (424 +/- 33 versus 400 +/- 28 ms, P < 0.05) and in HDs with low (2 mM) versus high (3 mM) K(+) (420 +/- 35 versus 399 +/- 36 ms, P < 0.05). These alterations were confirmed at the cellular level by computational analysis showing prolongation of ventricular AP at low K(+) and low Ca(2+) at the same extent of the measured QTc variations. Numerical simulation predicted a critically long AP (and QT) when considering low K(+) and Ca(2+) simultaneously, suggesting the concurrent lowering of Ca(2+) and K(+) as a potential arrhythmogenic factor. CONCLUSIONS: Numerical simulations of the ventricular AP may be useful to quantitatively predict the complex dependence of AP duration on simultaneous changes in Ca(2+) and K(+). Moreover, Ca(2+) content in the dialysate should be designed not to critically lower serum Ca(2+), especially in sessions at risk of end-dialysis hypokalaemia.

Acetate-free biofiltration.

Acetate-free biofiltration (AFB) is a hemodiafiltration technique that, technically as well as biologically speaking, has all the premises for being a perfectly biocompatible technique capable of satisfying even the demands of critical patients laden with comorbidities. Important clinical benefits to patients have been reported, such as a better correction of acid-base balance, an improved nutritional status and a better hemodynamic stability. In particular, as far as the cardiovascular instability is concerned, several studies have shown that the rationale behind a better hemodynamic stability is the overall absence of acetate usually present in the dialysis bath, which often leads to an impaired vascular tone and a reduced cardiac contractility. One of the powerful features of AFB is its adaptability to new devices and tools which can be easily and safely used. In AFB, potassium modulation in the dialysate is easily achieved. Thus, patients with elevated levels of predialysis potassium and a tendency to develop both intra- and interdialysis arrhythmias benefit most. Lastly, the possibility to associate AFB with devices like Hemocontrol (which allows for a feedback conditioning of blood volume) broadens its practical scope, not only for use with hypotension-prone patients, but also with hypertensive patients with massive increases in their interdialysis body weight. In this category of patients, avoiding the risk of dangerous hypovolemias allows for the achievement of dry body weight, thereby facilitating the control of arterial blood pressure and minimizing the clinical consequences of a chronic fluid overload.

Hierarchical mechanochemical switches in angiostatin.

We wish to propose a novel mechanism by which the triggering of a biochemical signal can be controlled by the hierarchical coupling between a protein redox equilibrium and an external mechanical force. We have characterized this mechanochemical mechanism in angiostatin, and we have evidence that it can switch the access to partially unfolded structures of this protein. We have identified a metastable intermediate that is specifically accessible under thioredoxin-rich reducing conditions, like those met by angiostatin on the surface of a tumor cell. The structure of the same intermediate accounts for the unexplained antiangiogenic activity of angiostatin. These findings demonstrate a new link between redox biology and mechanically regulated processes.

Renal osteodystrophy: alpha-Heremans Schmid glycoprotein/fetuin-A, matrix GLA protein serum levels, and bone histomorphometry.

BACKGROUND: Fetuin-A of hepatic origin circulates in large amounts in serum, but also is expressed in bone, where it is an inhibitor of transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) proteins. Together with matrix GLA protein (MGP), fetuin-A is able to make up a complex with calcium and phosphate that is more soluble than calcium and phosphate alone, preventing its deposition in extraskeletal tissues. Experimental results suggested that this complex is made at bone tissue level. The aim of this study is to evaluate whether serum fetuin-A and MGP are influenced by type of renal osteodystrophy, they correlate with bone histomorphometric and histodynamic parameters, and/or serum levels may influence bone turnover. METHODS: Thirty-eight hemodialysis patients who volunteered to undergo a bone biopsy were studied. Patients (27 men, 11 women) had a mean age of 55.2 +/- 11.8 years and dialysis vintage of 75.7 +/- 57.4 months. They were not administered vitamin D or drugs connected with mineral metabolism. They underwent transiliac bone biopsy after tetracycline labeling. Biopsies were performed for histological, histomorphometric, and histodynamic evaluation and aluminum histochemistry. Serum fetuin-A and MGP were measured by using enzyme-linked immunosorbent assay kits. RESULTS: Serum fetuin-A levels were significantly less than normal, whereas MGP levels were less than the normal average. Fetuin-A levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were 0.219 +/- 0.1, 0.27 +/- 0.1, and 0.197 +/- 0.1 ng/mL, respectively (P = not significant). Fetuin-A level significantly correlated inversely with values for several histomorphometric parameters, such as osteoid volume (OV/BV), osteoblastic surface (Ob.S/BS), osteoid surface (OS/BS), and osteoclastic surface (Oc.S/BS). Logistic regression showed odds ratios of 5.3 and 4.9 for the association of high fetuin-A levels with low values for OS/BS and Ob.S/BS, respectively. Results of multiple regression analysis with intact parathyroid hormone and fetuin-A levels as independent variables and OV/BV and Ob.S/BS as dependent variables showed that independent variables correlated significantly with dependent variables, positively for intact parathyroid hormone levels and inversely for fetuin-A levels. MGP levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were not significantly different (3.94 +/- 0.86, 3.40 +/- 0.99, and 5.64 +/- 2.4 nmol/L, respectively). By dividing MGP serum values into tertiles, mean values for OV/BV were different (analysis of variance, P < 0.04), with a greater value in the higher MGP tertile. By exclusion of 3 extravariant cases (>3 SDs greater than the mean), 1 case for each type of osteodystrophy, a significant correlation between bone formation rate and MGP serum level was found (P < 0.05). In addition, a significant correlation was found between MGP level and trabecular thickness. CONCLUSION: Fetuin-A and MGP levels correlated with bone formation parameters. This association could be caused by an effect of these proteins on bone formation, presumably mediated by the TGF-beta/BMP system. Fetuin-A, as opposed to MGP, is known to inhibit the TGF-beta/BMP complex, a protein-cytokine system that appears to be an important regulator of bone formation and probably a factor with an important role in renal osteodystrophy.

Activation of coagulation during hemodialysis: effect of blood lines alone and whole extracorporeal circuit.

Activation of coagulation during hemodialysis (HD) is a relevant clinical problem, especially when patients at risk of bleeding are treated. However, little is known about the relative contribution of the various components of the circuit to the thrombotic process. Thus, an experimental model was developed that is aimed at evaluating biochemical markers of coagulation activation at different times and sites throughout the HD circuit. A HD blood-tubing set with integrated arterial and venous chambers (cartridge-line set) was used, which was added with the following sampling points: at the beginning of the arterial line (P1), before the blood pump (P2), after the blood pump (P3), and at the end of the venous line (P4). A bypass system allowed us to circulate the blood only into the blood lines for the first 20 min of the extracorporeal circulation. The extracorporeal circuit was rinsed with 1.7 L of heparinized saline (2,500 IU/L) that was completely discarded before patient connection. A continuous administration of unfractionated heparin (500-800 IU/h) without a starting bolus was adopted as a low heparin extracorporeal treatment. Samples were collected before the start of the extracorporeal circulation from the fistula needle (T0P0), after 5 (T1), 10 (T2), and 20 min (T3) from P1, P2, P3, and P4. After 20 min, the blood was returned to the patient using only saline and HD was then started, circulating the blood through the dialyzer. Further samples were obtained from P1 and P4 after 5 (T4) and 210 min (T5). Plasma levels of coagulation activation markers-thrombin-antithrombin complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2)-were evaluated in all the samples in 12 stable HD patients. In each patient, the activated partial thromboplastin time (APTT) was measured at T0P0 and T1-T5 from P1. No significant changes were found at any time as far as F1 + 2 is concerned. However, TAT levels increased over time only after the start of HD, suggesting that the latter test could be more useful in order to detect coagulation activation during HD. The same experiments performed with nonheparin-primed extracorporeal circuit showed similar results. The blood lines used did not significantly activate coagulation during the first 20 min, whereas only 5 min of blood circulation throughout the whole circuit increased TAT values, which still remained lower than previous reports, even after 210 min of treatment.

In vivo assessment of intact parathyroid hormone adsorption by different dialysis membranes during hemodialysis.

BACKGROUND: Different parathyroid hormone (PTH) behavior during hemodialysis with different types of dialysis membranes has been reported. The behavior of intact parathyroid hormone (iPTH) adsorption using different dialysis membranes was assessed in 12 dialysis patients with secondary hyperparathyroidism. METHODS: The study was performed according to a longitudinal scheme comprising three treatment modalities, each lasting 2 weeks, for 6 weeks altogether. The first treatment consisted of standard bicarbonate dialysis with low-flux polysulfone, followed by acetate-free biofiltration with high-flux-polysulfone or with polyacrylonitrile-AN69. In the first week of each period, dialysis was delivered by using a 1.3 m(2) surface area and subsequently, a 1.8 m(2) surface area. Intact parathyroid hormone was assayed on the blood and dialysate samples to calculate iPTH adsorption. RESULTS: The results showed that polyacrylonitrile-AN69 and high-flux polysulfone induce a significantly larger drop in PTH serum levels as compared with low-flux-polysulfone, particularly in the first half of the dialysis session, while the ionized calcium increase is comparable in all different hemodialysis treatments. The measurement of iPTH in the dialysate showed lower values than those disappearing on the blood side, thus suggesting the presence of an adsorptive mechanism in the different dialysis membranes. CONCLUSION: High-flux polysulfone is endowed with a comparable adsorptive capacity per surface unit compared to polyacrylonitrile-AN69, although it seems to show a different behavior, as polyacrylonitrile-AN69 saturates early in the first hour of dialysis corresponding to its maximum adsorption power, while high-flux-polysulfone displays a more lasting adsorptive capacity. Thus, iPTH changes during hemodialysis also depend on dialyzer characteristics and the dialysis membrane adsorption.