MRzero - Automated discovery of MRI sequences using supervised learning.

PURPOSE: A supervised learning framework is proposed to automatically generate MR sequences and corresponding reconstruction based on the target contrast of interest. Combined with a flexible, task-driven cost function this allows for an efficient exploration of novel MR sequence strategies. METHODS: The scanning and reconstruction process is simulated end-to-end in terms of RF events, gradient moment events in x and y, and delay times, acting on the input model spin system given in terms of proton density, T1 and T2 , and ΔB0 . As a proof of concept, we use both conventional MR images and T1 maps as targets and optimize from scratch using the loss defined by data fidelity, SAR penalty, and scan time. RESULTS: In a first attempt, MRzero learns gradient and RF events from zero, and is able to generate a target image produced by a conventional gradient echo sequence. Using a neural network within the reconstruction module allows arbitrary targets to be learned successfully. Experiments could be translated to image acquisition at the real system (3T Siemens, PRISMA) and could be verified in the measurements of phantoms and a human brain in vivo. CONCLUSIONS: Automated MR sequence generation is possible based on differentiable Bloch equation simulations and a supervised learning approach.

Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study.

BACKGROUND: Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. PATIENT AND METHODS: One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS: Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS: This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23.

Combined PET/MRI: Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tübingen, Germany.

The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.

An overview of CEST MRI for non-MR physicists.

The search for novel image contrasts has been a major driving force in the magnetic resonance (MR) research community, in order to gain further information on the body's physiological and pathological conditions.Chemical exchange saturation transfer (CEST) is a novel MR technique that enables imaging certain compounds at concentrations that are too low to impact the contrast of standard MR imaging and too low to directly be detected in MRS at typical water imaging resolution. For this to be possible, the target compound must be capable of exchanging protons with the surrounding water molecules. This property can be exploited to cause a continuous buildup of magnetic saturation of water, leading to greatly enhanced sensitivity.The goal of the present review is to introduce the basic principles of CEST imaging to the general molecular imaging community. Special focus has been given to the comparison of state-of-the-art CEST methods reported in the literature with their positron emission tomography (PET) counterparts.

Interactions between the intestinal microbiome and helminth parasites.

Throughout evolution, both helminths and bacteria have inhabited our intestines. As intestinal helminths and bacteria inhabit the same environmental niche, it is likely that these organisms interact with, and impact on, each other. In addition, intestinal helminths are well known to alter intestinal physiology, permeability, mucous secretion and the production of antimicrobial peptides - all of which may impact on bacterial survival and spatial organization. Yet despite rapid advances in our understanding of host-intestinal bacteria interactions, the impact of helminths on this relationship has remained largely unexplored. Moreover, although intestinal helminths are generally accepted to possess potent immuno-modulatory activity, it is unknown whether this capacity requires interactions with intestinal bacteria. We propose that this 'ménage à trois' situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Whilst such pressures remain in developing countries, the eradication of helminths in industrialized countries has shifted this evolutionary balance, possibly underlying the increased development of chronic inflammatory diseases. Thus, helminth-bacteria interactions may represent a key determinant of healthy homoeostasis.

Intestinal bacteria induce TSLP to promote mutualistic T-cell responses.

Thymic stromal lymphopoietin (TSLP) is constitutively expressed in the intestine and is known to regulate inflammation in models of colitis. We show that steady-state TSLP expression requires intestinal bacteria and has an important role in limiting the expansion of colonic T helper type 17 (Th17) cells. Inappropriate expansion of the colonic Th17 cells occurred in response to an entirely benign intestinal microbiota, as determined following the colonization of germ-free C57BL/6 or TSLPR(-/-) mice with the altered Schaedler flora (ASF). TSLP-TSLPR (TSLP receptor) interactions also promoted the expansion of colonic Helios(-)Foxp3(+) regulatory T cells, necessary for the control of inappropriate Th17 responses following ASF bacterial colonization. In summary, these data reveal an important role for TSLP-TSLPR signaling in promoting steady-state mutualistic T-cell responses following intestinal bacterial colonization.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

A new contrast in MR mammography by means of chemical exchange saturation transfer (CEST) imaging at 3 Tesla: preliminary results.

PURPOSE: To evaluate the feasibility to detect and delineate malignant breast lesions in human patients by chemical exchange saturation transfer (CEST) as an MR imaging technique without the need for contrast agent administration. MATERIALS AND METHODS: Six female patients referred for pre-surgical staging due to histologically confirmed breast cancer were examined with MR at 3 T. The routine breast protocol included T (2w), STIR, T (1w)-DCE and contrast-enhanced T (1w) imaging with SPAIR fat suppression. For CEST imaging, a 3D RF-spoiled gradient echo (GRE) sequence with an optimized saturation pulse train was applied. To assess the diagnostic value of the technique, CEST effects observed between frequency offsets of 1.2 to 1.8 ppm from the bulk water resonance were compared to pharmacokinetic parameter maps (k (ep)) obtained by DCE-MRI. RESULTS: In 3 of 6 patients, regions with high CEST signal intensity correlated well with tumor areas as determined by DCE-MRI. Analysis of signal intensities from ROIs in tumor, fibroglandular, adipose, and muscle tissue revealed significantly higher CEST values in tumor tissue compared to fibroglandular tissue. The detection of lesions was equally well possible with DCE-MRI and CEST-MRI. In the three other patients, the tumor regions could not be delineated based on the CEST image due to artifacts, which were most likely caused by a high content of fat tissue within the ROIs. CONCLUSION: The results of this initial feasibility study indicate a significant potential of CEST-MRI to discriminate cancer from fibroglandular tissue in the human breast by a CEST contrast generated by endogenous solute molecules.

Whole body low dose irradiation improves the course of beginning polyarthritis in human TNF-transgenic mice.

Rheumatoid arthritis (RA) displays a chronic inflammatory joint disease, accompanied by symmetric polyarthritis (PA) which evokes synovial inflammation, cartilage damage, and bone erosion. Patients with RA are routinely treated by immunosuppressive drugs. The therapy of inflammatory diseases and degenerative disorders with Low-dose radiotherapy (LD-RT) (single doses from 0.3 to 1.0 Gy) represents a low cost therapy with low toxicity, and is able to substitute at least in part treatment with drugs. The efficiency of LD-RT has already been proven in several animal models of inducible arthritis. In the present study we used a human TNF transgenic mouse model to examine the effects of LD-RT on PA. We observed a significant temporal improvement of the clinical progression of disease when mice were irradiated at the beginning of the disease. These data emphasize the role of LD-RT in clinical settings to treat patients with chronic and degenerative disorders and diseases.

CTLA-4 directly inhibits osteoclast formation.

CTLA-4 is a regulator of co-stimulation and inhibits the activation of T cells through interfering with the interaction of CD80/86 on antigen-presenting cells with CD28 on T cells. CTLA-4 binds to the surface of antigen-presenting cells, such as dendritic cells and monocytes through CD80/86. Monocytes can differentiate in osteoclasts, the primary bone resorbing cells. Herein, we investigated whether the binding of CTLA-4 affects the differentiation of monocytes into osteoclasts in vitro and vivo. We show that CTLA-4 dose-dependently inhibits RANKL- as well as tumour necrosis factor (TNF)-mediated osteoclastogenesis in vitro without the presence of T cells. Furthermore, CTLA-4 was effective in inhibiting TNF-induced osteoclast formation in a non-T cell dependent TNF-induced model of arthritis as well as the formation of inflammatory bone erosion in vivo. These data suggest that CTLA-4 is an anti-osteoclastogenic molecule that directly binds osteoclast precursor cells and inhibits their differentiation. These findings are an attractive explanation for the anti-erosive effect of abatacept, a CTLA-4 immunoglobulin fusion protein used for the treatment of rheumatoid arthritis.

A multimodal treatment approach including high-dose chemotherapy in very advanced gastric cancer: evidence for control of metastatic disease.

The present multimodal treatment approach was designed to achieve prolonged tumor control in advanced gastric cancer. A total of 26 patients with stage IV gastric cancer (metastatic disease n=25), ECOG performance status 0-3 and laparoscopically evaluated peritoneal status received a modified EAP schedule to prove chemosensitivity and to mobilize autologous peripheral blood stem cells (aPBSC). Patients without progressive disease proceeded to tandem high-dose chemotherapy (HD-CT) and aPBSCT. Patients with >50% reduction of the target lesion received a second cycle of HD-CT. Responders were selected for local R0 resections (D2 resection) according clinical criteria. Of 26 patients, 20(77%) achieved partial remission after dose-intensive chemotherapy: local R0 resection was achieved in 12 out of 14 patients selected for surgery (46% of all patients). Eight of these R0-resected patients initially had peritoneal carcinomatosis. With a median follow-up of 3.2 years, four patients are still alive. The median overall survival was 8.4 months (CI 2.5-14.4 months), for histologic regression grade 3 (seven out of 25 patients, 28%) 29 months (CI 12-46 months). The combined treatment approach is tolerable and feasible in advanced disease and opens a therapeutic window for a significant proportion of patients, even in cases with histologically proven peritoneal carcinomatosis.

Autologous tandem transplantation: almost complete reduction of neutropenic fever following the second transplantation by ex vivo expanded autologous myeloid postprogenitor cells.

Reduced post-transplant performance status because of infectious complications is still a problem following autologous peripheral blood stem cell transplantation (aPBSCT). In this study, a tandem transplantation scheme for 15 patients with breast cancer including etoposide (1500 mg/m(2)), ifosfamide (12 g/m(2)) and carboplatin (1500 mg/m(2)) as conditioning regimens, followed by aPBSCT, was used to evaluate the potential clinical benefit of the additional retransfusion of low numbers of ex vivo expanded committed myeloid postprogenitor cells (PPCs) (median 408 x 103 CFU-c/kg BW, range 0.93-1995) following the second transplantation. Following a 7+2 days expansion (using recombinant human SCF, IL-1beta, IL-3, IL-6 + G-CSF), CFU-c generated from CD34-positive cells from leukapheresis products could be expanded by a median factor of 153 (range 5-434). Flow cytometric analysis and morphology of CFUs have shown a nearly exclusive expansion and differentiation of committed myeloid progenitor cells and a significant reduction of CD34-positive cells. In an intra- and interindividual comparison it could be shown that the retransfusion of committed myeloid postprogenitor cells significantly accelerates myeloid recovery. Although retransfusion of PPCs fails to abrogate severe neutropenia following aPBSCT, it significantly ameliorates infectious complications and shortens the duration of hospital stay.

Activation of lymphocytes inhibits human monocyte to macrophage differentiation.

Tissue macrophages (MAC) differentiate from circulating blood monocytes (MO) during a maturation step that is of crucial importance for their functional competence. In vitro a similar process of maturation can be observed, if MO are cultured in the presence of serum. In the work presented here, we show that activated lymphocytes can interfere with MAC differentiation. Resting lymphocytes have only marginal influence upon MO to MAC transition in vitro. However, if cells are activated by the lectins PWM or ConA or by double-stranded RNA (polyinosinic-polycytidylic acid, pI:C), normal MAC maturation is suppressed: MO stay small and do not acquire MAC maturation-associated surface molecules like carboxypeptidase M (CPM, determined by antibody MAX.1) or CD84 (determined by antibody MAX.3). This phenomenon can be induced by small numbers of lymphocytes and can be transmitted by soluble factors in cultures stimulated with ConA or PWM. IFN-gamma is present in these conditioned media and partially suppresses MAC maturation but cannot fully substitute for the conditioned media. On the contrary, in pI:C stimulated cultures, suppression of MAC differentiation is dependent on cell-cell contact. In conclusion, activated lymphocytes are able to suppress the terminal differentiation of MAC by several pathways depending on the mode of lymphocyte stimulation.

The septal mucosa decongests with naphazoline: a study of mucosal dynamics with sonography.

A new method using B-mode and power-Doppler-mode (pD) sonography for the investigation of changes in nasal mucosa swelling and perfusion was developed. The effect of naphazoline (0.25 mg/mL) on the nasal mucosa was visualized and recorded in 1-minute intervals in 40 patients. The effect of normal saline solution was studied in 27 healthy volunteers. The decongestant and normal saline were applied by flooding the anterior nasal cavity. A computer program automatically quantified pD color information. Normal saline solution induced a 4.8 +/- 2.4% increase in perfusion (+/- SEM, n.s.) after 5 minutes. In the naphazoline group, changes in stereometry were measured on B-mode-sequences in 24 (60%) and perfusion changes in 24 participants (60%). In 16 of 40 patients (40%), both stereometry and perfusion were analyzed. After 10 minutes, the septum and inferior turbinate mucosa thickness were reduced by 17 +/- 2.8% (p < 0.001) and 25 +/- 2.6% (p < 0.001). Perfusion of the septum and inferior turbinate mucosa as visualized with pD-sonography decreased by 33 +/- 3.3% (p < 0.001). The reduction of bloodflow induced by naphazoline as visualized with pD-sonography is within the range of perfusion changes found in LDF and Xenon clearance studies. Decongestion of the septum mucosa demonstrates erectile properties of the septum, which may contribute to the increase of nasal patency after nasal decongestion.

Transplant characteristics: minimal residual disease and impaired megakaryocytic colony growth as sensitive parameters for predicting relapse in acute myeloid leukemia.

Dose escalation during consolidation therapy of de novo AML, including myeloablative chemotherapy supported with autologous peripheral blood stem cell transplantation (aPBSCT), continuously improved outcome. Therefore, quality control of transplants is getting increasing interest. We studied leukapheresis products (LPs), consecutively collected during postremission treatment of 20 patients with de novo AML for minimal residual disease (MRD) by 5-parametric flow cytometry and for myelodysplasia (MDS)-associated alterations by paired lineage-selected colony assays for colony-forming units-megakaryocytes (CFU-mega) and burst-granulocytes-monocytes colony-forming units (CFU) to evaluate the predictive value of these transplant-associated parameters on outcome. We defined the leukemia-associated immunophenotype at diagnosis and studied the impact of MRD detection in LPs collected after double induction with TAD (thioguanine, daunorubicin, cytarabine) and HAM (mitoxantrone, high-dose cytarabine, n=18 patients) and TAD consolidation treatment (n=20 patients) on outcome after aPBSCT. The level of MRD in the transplants correlated with the relapse-free survival (RFS) using a cut-off level of 1 x 10(-3) residual leukemic cells. The median RFS was 6 months for the group with > or = 1 x 10(-3) residual leukemic cells and has not been reached in the group with low MRD levels (< 1 x 10(-3)). By using the same cut-off level a weak correlation could also be demonstrated between MRD in the pregraft bone marrow and RFS (P = 0.04). Quantitatively abnormal megakaryocytic colony growth in the back-up LPs collected after double induction and in the transplant LPs was characterized by the ratio CFU-mega/CFU. In the group of relapsing patients the ratio CFU-mega/CFU was significantly lower than in the group of patients with CCR (P = 0.004), both in the back-ups and in the transplants. All patients with CFU-mega/CFU ratios < 0.12 relapsed, five of seven patients developed MDS before progressing to full leukemic relapse. Using the optimized cut-off level for the ratio CFU-mega/CFU (< vs > or = 0.12), seven of 10 relapsing patients (70%) could be identified to be at risk of relapse, whereas MRD in the transplants identified only 50% of the relapses and MRD in the pregraft bone marrow 25%. In conclusion, the study could identify two pretransplant risk factors predicting relapse in patients with AML receiving aPBSCT in first CR: MRD in transplants as well as MDS-like alterations within the transplants. These results may have multifold implications on the design of risk-adapted chemotherapy as well as on purging techniques and may contribute to a better understanding of leukemogenesis.

Whole blood analysis of reticulated platelets: improvements of detection and assay stability.

The flow cytometric analysis of reticulated platelets based on the fluorescent derivatization of their RNA content is increasingly used for the diagnostic classification of patients with thrombocytopenia as well as the monitoring of thrombopoiesis recovering under therapy. Many different modifications of the analytical protocol have been published following the first description in 1990 but consensus on the method has not yet been established. We have now reevaluated the assay's methodology in order to optimize sensitivity and specificity and reduce the time length of incubation and washing procedures. In the modified experimental approach native whole blood is incubated for 15 min with an increased amount of thiazole orange (1 microg/ml) in the presence of phycoerythrin labeled antibodies directed against the constitutively surface expressed antigen GPlb. Data acquisition on the flow cytometer can be started immediately after stopping and stabilization of the reaction by paraformaldehyde fixation. Thiazole orange fluorescence was not significantly changed in thrombin-activated, degranulated platelets compared to resting platelets indicating no significant non-specific staining of platelet granules under the selected test conditions. In addition, experiments employing RNAse digestion demonstrated specificity of thiazole orange staining for platelet RNA.

G-CSF-mobilized peripheral blood progenitor cells: in vitro growth pattern and hematopoietic growth factor receptor profile.

The kinetics of colony formation by granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) were monitored using clone-mapping experiments. Compared with normal resting bone marrow (BM), where the ratio of Day 7:Day 14 granulocyte-macrophage colony-forming cells (GM-CFCs) was 1:0.76-1.9, PB was found to be relatively deficient in progenitor cells with the capacity to form colonies by Day 7 (median ratio Day 7:Day 14 1:21). The most mature Day 7 GM-CFCs, those dispersing or extinguishing before Day 14, were almost absent in PB (< 1% of all GM-CFCs) but comprised 77% of Day 7 GM-CFCs and 32% of all GM-CFCs in BM. The expression patterns of high affinity receptors for G-CSF, GM-CSF, stem cell factor (SCF), and the ligand for flk-2 on CD38hi and CD38-/dim PB CD34+ cells were determined by binding of 125I-labeled ligand and autoradiography. G-CSF receptor (G-CSFR) expression was detected on approximately 25% of CD38-/dim cells (estimated mean 105 receptors per positive cell) and was higher in CD38hi cells (approximately 50% positive, with a mean of 227 receptors per cell). GM-CSFR expression was low (approximately 25% of cells positive, mean of 120 receptor per cell) and did not vary with CD38 expression. c-kit (SCFR) and flk-2 were expressed by > or = 90% and > or = 80% of CD34+ cells, respectively. SCF binding per cell was greater in the CD38hi population, while flk-2 expression did not vary with CD38 expression. These results confirm the heterogeneity of receptor expression by progenitor cells and imply differential regulation of receptor expression during maturation.

Presyncopal sympathetic withdrawal is the same in patients with vasodepressor syncope and controls who faint on head-up tilting.

Head-up tilt provokes vasodepressor syncope in patients with this disorder but may also cause fainting in unaffected subjects. The aims of this study were to examine autonomic function and sequential changes in heart rate variability and plasma catecholamines during graded head-up tilt in patients with vasodepressor syncope compared with healthy subjects. Studies were performed in 10 patients and 15 control subjects. Eight negative controls completed the study; presyncope or syncope developed in seven positive controls and all 10 patients. The negative control group showed a progressive increase in mid-frequency from the supine position to end tilt. Patients and positive controls showed significant and similar falls in mid-frequency in the presyncope period. The rise in plasma norepinephrine was blunted in patients and positive controls, whereas plasma epinephrine increased more in these groups compared with the negative control group. In conclusion, the patterns of heart rate variability and catecholamine changes could not be distinguished in patients and positive control subjects.

Power spectral analysis of heart rate variability during graded head-up tilting in patients with vasodepressor syncope.

1. Two groups of age- and sex-matched subjects, eight healthy controls and 10 patients, suffering from recurrent vasodepressor syncope, participated in a study to examine autonomic function and sequential changes in power distribution of heart rate (HR) variability during graded head-up tilt. 2. The following autonomic function tests were performed: valsalva ratio, HR responses to deep breathing and posture, BP responses to sustained handgrip and postural change. Each subject was tilted at 15 degrees, 30 degrees, 45 degrees, 60 degrees and 80 degrees head-up, each for 15 min, or until symptoms occurred. The eight control subjects completed the tilt study without any symptoms, while all 10 patients developed presyncope and/or syncope at various tilt angles. 3. Resting blood pressure (BP) was lower in the patient group, while resting HR, autonomic function tests and resting HR variability components were similar in the two groups. 4. The control group showed a progressive increase in low frequency power component (LF) from supine to end tilt (delta LF 20.06 +/- 14.50%) and a progressive fall in high frequency (HF) component (delta HF - 24.62 +/- 10.64%). In contrast, in the patient group, LF fell during tilt in the presyncope period (delta LF - 10.57 +/- 12.93%, P < 0.01 vs control group). HF and HF:LF ratio responses did not differ significantly in the two groups. 5. At end tilt, the increase in plasma noradrenaline was significantly greater in the control group than in the patient group (delta NA 0.83 +/- 0.27 vs 0.28 +/- 0.14 pmol/mL, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)