Analysis of dynamical interactions between distributed brain areas is of fundamental importance for understanding cognitive information processing. However, estimating dynamic causal interactions between brain regions using functional magnetic resonance imaging (fMRI) poses several unique challenges. For one, fMRI measures Blood Oxygenation Level Dependent (BOLD) signals, rather than the underlying latent neuronal activity. Second, regional variations in the hemodynamic response function (HRF) can significantly influence estimation of causal interactions between them. Third, causal interactions between brain regions can change with experimental context over time. To overcome these problems, we developed a novel state-space Multivariate Dynamical Systems (MDS) model to estimate intrinsic and experimentally-induced modulatory causal interactions between multiple brain regions. A probabilistic graphical framework is then used to estimate the parameters of MDS as applied to fMRI data. We show that MDS accurately takes into account regional variations in the HRF and estimates dynamic causal interactions at the level of latent signals. We develop and compare two estimation procedures using maximum likelihood estimation (MLE) and variational Bayesian (VB) approaches for inferring model parameters. Using extensive computer simulations, we demonstrate that, compared to Granger causal analysis (GCA), MDS exhibits superior performance for a wide range of signal to noise ratios (SNRs), sample length and network size. Our simulations also suggest that GCA fails to uncover causal interactions when there is a conflict between the direction of intrinsic and modulatory influences. Furthermore, we show that MDS estimation using VB methods is more robust and performs significantly better at low SNRs and shorter time series than MDS with MLE. Our study suggests that VB estimation of MDS provides a robust method for estimating and interpreting causal network interactions in fMRI data.

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

BACKGROUND

The number of resected lymph-nodes (#RNs) has proven prognostic in breast and colorectal cancer. Here we evaluated its prognostic impact in a series of resected NSCLC patients.

METHODS

A panel of established prognostic factors plus (1) #RNs or (2) the ratio between the number of metastatic nodes and #RNs (NR) were correlated to overall- (OS), cancer-specific- (CSS), and disease-free-survival (DFS), using the Cox-model. Risk-classes according to hazard ratios (HR) were generated. Internal and external validation was accomplished.

RESULTS

A dataset of 415 resected NSCLC patients was retrieved. At multivariate analysis, #RNs and NR were independent factor for longer OS, CSS and DFS (p<0.0001). Patients with a #RNs>10 (identified optimal cut-off) had a statistically significant OS (p=0.02) and DFS (p=0.0005) benefit. In node-positive patients, a NR<9% significantly correlated with better outcome. Stratification into High-, Medium-, and Low-Risk classes, based on High- (HRFs: stage, N-status, age, #RNs) and Intermediate-Risk Factors (IRFs: sex, grading, histology), efficiently predicted outcomes (p<0.0001). The risk class model performance was externally validated in and independent dataset of 297 patients.

CONCLUSIONS

These results contribute to complete the panel of prognostic factors for resected NSCLC. A prospective larger validation and comparison with molecular prognostic tools is warranted.

Histamine-releasing factors (HRFs) have been shown to be released from a variety of human cells, including T lymphocytes and alveolar macrophages. We considered the possibility that known cytokines might possess such activity on human basophils and/or mast cells and therefore tested preparations of human recombinant IL 3, IL 4, IL 5, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) upon a panel of basophil donors. IL 3 and GM-CSF possessed significant histamine-releasing activity in 8 of 10 and 12 of 14 subjects, respectively. In each instance, a dose response could be demonstrated. IL 4 and G-CSF had no such activity, whereas IL 5 had activity in only 2 of 14 donors tested. We conclude that IL 3 and GM-CSF represent two effective HRFs, and suggest that HRF, as isolated based upon histamine-releasing activity, is likely to be heterogeneous in terms of molecular identity. Whether previously described HRFs relate specifically to IL 3 or GM-CSF must await primary sequence analysis of HRF and/or studies with monospecific antisera.

Monocyte chemotactic and activating factor (MCAF) is a recently cloned cytokine that causes chemotaxis of basophils. In our pursuit of cytokines affecting basophil function, we studied the effect of MCAF on histamine secretion from basophils. Leukocytes from 20 donors, 10 allergic and 10 normal subjects, were studied. MCAF caused dose-dependent release of histamine at concentrations of 10(-8) and 10(-7) M, and the mean release was 31.25 +/- 2.9% at the highest concentration. In the same experiments the mean histamine release by anti-IgE and histamine releasing factor (HRF) was 27.05 +/- 4% and 32.70 +/- 2.7%, respectively. All 20 subjects responded to MCAF with significant histamine release. Allergic subjects released significantly more histamine than normals in response to anti-IgE (P less than 0.01) but not to MCAF (P = 0.2) and HRF (P = 0.1). The histamine release was significantly correlated between MCAF and HRF (P less than 0.01), but not between MCAF and anti-IgE (P greater than 0.05). The histamine release by MCAF was complete within the first 3 min. MCAF-induced degranulation was a calcium-dependent process. Leukocytes depleted of monocytes responded equally well to MCAF. Using an anti-MCAF affinity column we determined that greater than 50% of HRF activity of crude PBMC supernatant could be attributed to MCAF. Thus, we established that MCAF is a potent secretagogue for basophils.

Identification and characterization of patients with diabetic macular edema (DME) are important for individualizing treatment and optimizing outcome. We investigated OCT biomarkers for DME treated by intravitreal dexamethasone (DEX) implant.

Multicenter, retrospective, observational cohort study.

A total of 299 eyes from 284 patients treated with DEX implant for DME (naïve, n = 209; refractory, n = 90). Baseline best-corrected visual acuity (BCVA) was between 0.3 and 1.0 on a logarithm of minimum angle of resolution visual chart.

The OCT scans previous to DEX implants were evaluated for submacular fluid, size and location of cystoid changes, inner segment-outer segment (IS-OS) continuity, quantity and location of hyperreflective foci (HRF), vitreomacular interface abnormalities, and epiretinal membrane. The BCVA and central macular thickness were recorded at baseline and at 1, 2, and 4 months after treatment with DEX implants. Correlations between OCT measures and visual outcome were analyzed using the generalized estimating equations procedure.

The correlation between spectral-domain (SD) OCT measures at baseline and BCVA response (mean change from baseline; categorized improvement [<5, 5-9, or ≥10; Early Treatment Diabetic Retinopathy Study letters] in BCVA) after treatment with a DEX implant.

The presence of subretinal fluid (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.23-3.20; P = 0.01), absence of HRF (OR, 3.66; 95% CI, 1.40-9.62; P = 0.01), and integrity of the IS-OS layer (OR, 2.09; 95% CI, 1.30-3.37; P = 0.003) were all predictive of better visual outcome after treatment with DEX implants. Although eyes with naïve DME gained more vision than refractory eyes (P < 0.001), the predictive value of OCT findings did not differ according to this classification.

Spectral-domain OCT is useful in identifying various imaging findings in DME. Among eyes with DME, those with submacular fluid, no HRF, and a continuous IS-OS layer responded better to DEX implants than those without these features. These findings call for further study of combinations of OCT and metabolic biomarkers.

We propose a fast, efficient, general, simple, valid, and robust method of estimating and making inference about the delay of the fMRI response modeled as a temporal shift of the hemodynamic response function (HRF). We estimate the shift unbiasedly using two optimally chosen basis functions for a spectrum of time shifted HRFs. This is done at every voxel, to create an image of estimated delays and their standard deviations. This can be used to compare delays for the same stimulus at different voxels, or for different stimuli at the same voxel. Our method is compared to other alternatives and validated on an fMRI data set from an experiment in pain perception.

Experimental designs for functional magnetic resonance imaging (fMRI) experiments can be characterized by their estimation efficiency, which is a measure of the variance in the estimate of the hemodynamic response function (HRF), and their detection power, which is a measure of the variance in the estimate of the amplitude of functional activity. Previous studies have shown that there exists a fundamental trade-off between efficiency and power for experiments with a single trial type of interest. This paper extends the prior work by presenting a theoretical model for the relation between detection power and estimation efficiency in experiments with multiple trial types. It is shown that the trade-off between efficiency and power present in multiple-trial-type experiments is identical in form to that observed for single-trial-type experiments. Departures from the predicted trade-off due to the inclusion of basis function expansions and the assumption of correlated noise are examined. Finally, conditional entropy is introduced as measure for the randomness of a design, and an empirical relation between entropy and estimation efficiency is presented.

The affected E of two patients with paroxysmal nocturnal hemoglobinuria (PNH) were enriched by lysing the unaffected, normal E with anti-human decay-accelerating factor (DAF) and guinea pig serum. The membranes of the unlysed, DAF-deficient cells (PNH-E) were dissolved and examined by SDS-PAGE and immunoblotting using an antiserum to homologous restriction factor (HRF). Whereas the 65 kD complement regulatory protein was readily detectable in the normal controls, it was completely lacking in both samples of PNH-E membranes. Functional studies likewise indicated the absence of HRF activity from PNH-E. When radiolabeled, isolated HRF protein was offered to PNH-E, it became firmly attached to the cell. Approximately 1,000 molecules of HRF per cell reduced the characteristic susceptibility of these cells to reactive lysis by C5b-9 to nearly normal levels. The results suggest that HRF, which is known to control the action of C8 and C9 on normal human E membranes, is deficient in PNH, as well as acetylcholinesterase and DAF.

Evolutionary conserved and pleiotropic, the TPT1/TCTP gene (translationally controlled tumor protein, also called HRF, fortilin), encodes a highly structured mRNA shielded by ribonucleoproteins and closely resembling viral particles. This mRNA activates, as do viruses, protein kinase R (PKR). The TPT1/TCTP protein is structurally similar to mRNA-helicases and MSS4. TPT1/TCTP has recently been identified as a prognostic factor in breast cancer and a critical regulator of the tumor suppressor p53 and of the cancer stem cell (SC) compartment. Emerging evidence indicates that TPT1/TCTP is key to phenotypic reprogramming, as shown in the process of tumor reversion and possibly in pluripotency. We provide here an overview of these diverse functions of TPT1/TCTP.

OBJECTIVE

Neoadjuvant chemotherapy (NACT) for cervical cancer still remains controversial. NACT was evaluated to establish selection criteria.

METHODS

A matched-case comparison was designed for the NACT group (n=707) and primary surgery treatment (PST; n=707) group to investigate short-term responses and high/intermediate risk factors (HRFs/IRFs). The 5-year disease-free survival (DFS) and overall survival (OS) rates were stratified by NACT response, HRFs/IRFs, International Federation of Gynecology and Obstetrics (FIGO) stage and tumour size, respectively.

RESULTS

The clinical and pathological response rates were 79.3% and 14.9% in the NACT group. In comparison to the PST group, IRFs but not HRFs were significantly decreased (P<0.05), and the 5-year DFS rate was significantly improved in the NACT group (88.4% versus 83.1%, P=0.021). Moreover, the 5-year DFS and OS rates were favourably increased in the clinical responders in comparison to the PST group and the clinical non-responders (P<0.05). Compared to those of clinical non-responders, the 5-year DFS and OS rates of clinical responders, with or without HRFs, were also significantly increased (P<0.01). In stage IB2, the 5-year DFS and OS rates were significantly increased, whereas operation duration declined in the NACT group (P<0.05). For patients with stage IB tumours of 2-5 cm, the 5-year DFS and OS rates of clinical responders were significantly improved (P<0.05).

CONCLUSIONS

NACT is a suitable option for patients with cervical cancer, especially for NACT responders and patients with stage IB, which provides a new concept of fertility preservation for young patients.

OBJECTIVE

To evaluate factors affecting Heidelberg retinal flowmeter (HRF) measurements of retinal and optic nerve head blood flow in human subjects.

METHODS

The angle of incidence between laser beam and fundus, and camera distance from the eye, were evaluated for their effect upon measures of blood volume, velocity, and flow in a single 100 x 100 x 400 microns volume of temporal peripapillary retinal tissue in normal volunteers. Both intra and intersession reproducibility of these measures were studied. Intersession data were obtained by taking one image per week for 4 weeks. Finally, the intersession haemodynamic data were examined in the entire image (640 x 2560 x 400 microns), using histograms of pixel by pixel blood flow.

RESULTS

Measures of blood volume, velocity, and flow from a single anatomical site were unaffected by laser beam to fundus angle of incidence (n = 12). As camera distance from the eye was increased (from 2 to 5 to 7 cm), flow measurements showed increasing individual changes, despite unaltered measured vessel lengths and constant overall mean flow (n = 14). The coefficient of variation for two intersession images of optic nerve head blood flow averaged 7% (n = 20); in contrast, the 4 week intersession coefficient of variation averaged 30% (n = 15). Intersession reproducibility was increased by using flow histograms from the entire image: the coefficients of variation averaged 16% for total flow and 17% for flow in the pixel of median flow.

CONCLUSIONS

HRF measures of flow are independent of the laser beam to fundus angle of the incidence and dependent upon camera distance from the eye. Intersession reproducibility is best using pixel by pixel analysis of the entire image.

OBJECTIVE

To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS).

METHODS

In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient's disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis.

RESULTS

Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0-175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%).

CONCLUSIONS

The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.

Although, on average, the magnitude of alpha oscillations (8 to 12 Hz) is decreased in task-relevant cortices during externally oriented attention, its fluctuations have significant consequences, with increased level of alpha associated with decreased level of visual processing and poorer behavioral performance. Functional MRI signals exhibit similar fluctuations. The default mode network (DMN) is on average deactivated in cognitive tasks requiring externally oriented attention. Momentarily insufficient deactivation of DMN, however, is often accompanied by decreased efficiency in stimulus processing, leading to attentional lapses. These observations appear to suggest that visual alpha power and DMN activity may be positively correlated. To what extent such correlation is preserved in the resting state is unclear. We addressed this problem by recording simultaneous EEG-fMRI from healthy human participants under two resting-state conditions: eyes-closed and eyes-open. Short-time visual alpha power was extracted as time series, which was then convolved with a canonical hemodynamic response function (HRF), and correlated with blood-oxygen-level-dependent (BOLD) signals. It was found that visual alpha power was positively correlated with DMN BOLD activity only when the eyes were open; no such correlation existed when the eyes were closed. Functionally, this could be interpreted as indicating that (1) under the eyes-open condition, strong DMN activity is associated with reduced visual cortical excitability, which serves to block external visual input from interfering with introspective mental processing mediated by DMN, while weak DMN activity is associated with increased visual cortical excitability, which helps to facilitate stimulus processing, and (2) under the eyes-closed condition, the lack of external visual input renders such a gating mechanism unnecessary.

OBJECTIVE

To report the outcome of patients with autologous peripheral blood stem cell transplantation (PBSCT) receiving mechanical ventilation.

METHODS

Retrospective observational study.

METHODS

Active hematopoietic stem cell transplantation center and a university hospital medical ICU.

METHODS

Patients with autologous PBSCT receiving mechanical ventilation.

METHODS

A review of the medical records of patients with autologous PBSCT receiving mechanical ventilation. Data collection was restricted to the first episode of mechanical ventilation.

RESULTS

A total of 78 autologous PBSCT patients received mechanical ventilation for>> 24 h. Twenty patients (26%) were extubated and discharged alive from the hospital. Thirteen hospital survivors (60%) were alive at 6 months. Lung injury (LI), vasopressor use, and hepatic and renal failure (HRF) were used to predict survival after mechanical ventilation. Sixty patients (76%) had no organ failure, or had isolated LI or only required treatment with vasopressors. Their hospital survival and 6-month survival were 32% and 20%, respectively. Hospital and 6-month survival for the patients with HRF or LI and vasopressor use was 6% and 0%, respectively.

CONCLUSIONS

Prolonged mechanical ventilation and aggressive ICU support is justified for autologous PBSCT patients receiving mechanical ventilation with no organ failure, or who have only isolated LI, or who only require treatment with vasopressors.

Hypoxia is a common environmental stress that regulates gene expression and cell function. A number of hypoxia-regulated transcription factors have been identified and have been shown to play critical roles in mediating cellular responses to hypoxia. One of these is the endothelial PAS-domain protein 1 (EPAS1/HIF2-alpha/HLF/HRF). This protein is 48% homologous to hypoxia-inducible factor 1-alpha (HIF1-alpha). To date, virtually nothing is known about the signaling pathways that lead to either EPAS1 or HIF1-alpha activation. Here we show that EPAS1 is phosphorylated when PC12 cells are exposed to hypoxia and that p42/p44 MAPK is a critical mediator of EPAS1 activation. Pretreatment of PC12 cells with the MEK inhibitor, PD98059, completely blocked hypoxia-induced trans-activation of a hypoxia response element (HRE) reporter gene by transfected EPAS1. Likewise, expression of a constitutively active MEK1 mimicked the effects of hypoxia on HRE reporter gene expression. However, pretreatment with PD98059 had no effect on EPAS1 phosphorylation during hypoxia, suggesting that MAPK targets other proteins that are critical for the trans-activation of EPAS1. We further show that hypoxia-induced trans-activation of EPAS1 is independent of Ras. Finally, pretreatment with calmodulin antagonists nearly completely blocked both the hypoxia-induced phosphorylation of MAPK and the EPAS1 trans-activation of HRE-Luc. These results demonstrate that the MAPK pathway is a critical mediator of EPAS1 activation and that activation of MAPK and EPAS1 occurs through a calmodulin-sensitive pathway and not through the GTPase, Ras. These results are the first to identify a specific signaling pathway involved in EPAS1 activation.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

The exact relationship between neural activity and BOLD fMRI is unknown. However, several recent findings, recorded invasively in both humans and monkeys, show a positive correlation of BOLD to high-frequency (30-150 Hz) oscillatory power changes and a negative correlation to low-frequency (8-30 Hz) power changes arising from cortical areas. In this study, we computed the time series correlation between BOLD GE-EPI fMRI at 7 T and neural activity measures from noninvasive MEG, using a time-frequency beam former for source localisation. A sinusoidal drifting grating was presented visually for 4 s followed by a 20 s rest period in both recording modalities. The MEG time series were convolved with either a measured or canonical haemodynamic response function (HRF) for comparison with the measured BOLD data, and the BOLD data were deconvolved with either a measured or a canonical HRF for comparison with the measured MEG. In the visual cortex, the higher frequencies (mid-gamma=52-75 Hz and high-gamma=75-98 Hz) were positively correlated with BOLD whilst the lower frequencies (alpha=8-12 Hz and beta=12-25 Hz) were negatively correlated with BOLD. Furthermore, regression including all frequency bands predicted BOLD better than stimulus timing alone, although no individual frequency band predicted BOLD as well as stimulus timing. For this paradigm, there was, in general, no difference between using the SPM canonical HRF compared to the subject-specific measured HRF. In conclusion, MEG replicates findings from invasive recordings with regard to time series correlations with BOLD data. Conversely, deconvolution of BOLD data provides a neural estimate which correlates well with measured neural effects as a function of neural oscillation frequency.

Till now, most studies of the Blood Oxygen Level-Dependent (BOLD) response to interictal epileptic discharges (IED) have assumed that its time course matches closely to that of brief physiological stimuli, commonly called the canonical event-related haemodynamic response function (canonical HRF). Analyses based on that assumption have produced significant response patterns that are generally concordant with prior electroclinical data. In this work, we used a more flexible model of the event-related response, a Fourier basis set, to investigate the presence of other responses in relation to individual IED in 30 experiments in patients with focal epilepsy. We found significant responses that had a noncanonical time course in 37% of cases, compared with 40% for the conventional, canonical HRF-based approach. In two cases, the Fourier analysis suggested activations where the conventional model did not. The noncanonical activations were almost always remote from the presumed generator of epileptiform activity. In the majority of cases with noncanonical responses, the noncanonical responses in single-voxel clusters were suggestive of artifacts. We did not find evidence for IED-related noncanonical HRFs arising from areas of pathology, suggesting that the BOLD response to IED is primarily canonical. Noncanonical responses may represent a number of phenomena, including artefacts and propagated epileptiform activity.

OBJECTIVE

Simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) (EEG-fMRI) recording is a noninvasive tool for investigating epileptogenic networks. Most EEG-fMRI studies in epilepsy have been performed in adults. Childhood epilepsies, however, differ from those in adults due to interactions between epileptogenic and developmental processes. The purpose of this study was to investigate EEG-fMRI in children with lesional epilepsies.

METHODS

Thirteen children with symptomatic epilepsy underwent a 20-min EEG-fMRI acquisition at 3 T under sedation-induced sleep. Statistical analysis was performed using the timing of spikes as events, modelled with hemodynamic response functions (HRFs) that peaked at 3, 5, 7, and 9 s after the spike.

RESULTS

Each spike type was analyzed separately, resulting in 25 studies. In 84% of the studies, blood oxygenation level-dependent (BOLD) responses were localized in the lesion or brain area presumably generating spikes. Activation (positive BOLD) corresponding with the lesion was seen in 20% and deactivation (negative BOLD) in 52% of the studies. In the area of spike generation, activation was found in 48% of studies and deactivation in 36%.

CONCLUSIONS

Despite the necessarily short recording times (20 min), good results could be obtained from the EEG-fMRI recordings, performed in sedated children using a high field scanner and individual HRFs. In contrast to studies in adults, deactivations in the lesion and the irritative zone were more common than activations. The impact of age, sleep, and sedation on the BOLD response might explain these findings, but future studies in children should not disregard the importance of deactivations in relation to the epileptogenic network.

OBJECTIVE

Early detection of local recurrences following stereotactic ablative radiotherapy (SABR) for lung cancer may allow for curative salvage treatment, but recurrence can be difficult to distinguish from fibrosis. We studied the clinical performance of CT imaging high-risk features (HRFs) for detecting local recurrence.

METHODS

Patients treated with SABR for early stage lung cancer between 2003 and 2012 who developed pathology-proven local recurrence (n=12) were matched 1:2 to patients without recurrences (n=24), based on baseline factors. Serial CT images were assessed by blinded radiation oncologists. Previously reported HRFs were (1) enlarging opacity at primary site; (2) sequential enlarging opacity; (3) enlarging opacity after 12-months; (4) bulging margin; (5) loss of linear margin and (6) air bronchogram loss.

RESULTS

All HRFs were significantly associated with local recurrence (p<0.01), and one new HRF was identified: cranio-caudal growth (p<0.001). The best individual predictor of local recurrence was opacity enlargement after 12-months (100% sensitivity, 83% specificity, p<0.001). The odds of recurrence increased 4-fold for each additional HRF detected. The presence of ≥3 HRFs was highly sensitive and specific for recurrence (both >90%).

CONCLUSIONS

The systematic assessment of post-SABR CT images for HRFs enables the accurate prediction of local recurrence.

Ethylene glycol (EG) consumption is commonly employed as an experimental regimen to induce hyperoxaluria in animal models of calcium oxalate nephrolithiasis. This approach has, however, been criticized because EG overdose induces metabolic acidosis in humans. We tested the hypothesis that EG consumption (0.75% in drinking water for 4 wk) induces metabolic acidosis by comparing arterial blood gases, serum electrolytes, and urinary chemistries in five groups of Sprague-Dawley rats: normal controls (CON), those made hyperoxaluric (HYP) with EG administration, unilaterally nephrectomized controls (UNI), unilaterally nephrectomized rats fed EG (HRF), and a metabolic acidosis (MA) reference group imbibing sweetened drinking water (5% sucrose) containing 0.28 M NH4Cl. Arterial pH, plasma bicarbonate concentrations, anion gap, urinary pH, and the excretion of titratable acid, ammonium, phosphate, citrate, and calcium in HYP rats were not significantly different from CON rats, indicating that metabolic acidosis did not develop in HYP rats with two kidneys. Unilateral nephrectomy alone (UNI group) did not significantly affect arterial pH, plasma bicarbonate, anion gap, or urinary pH compared with CON rats; however, HRF rats exhibited some signs of a nascent acidosis in having an elevated anion gap, higher phosphate excretion, lower urinary pH, and an increase in titratable acid. Frank metabolic acidosis was observed in the MA rats: decreased arterial pH and plasma HCO3(-) concentration with lower urinary pH and citrate excretion with elevated excretion of ammonium, phosphate and, hence, titratable acid. We conclude that metabolic acidosis does not develop in conventional EG treatments but may ensue with renal insufficiency resulting from an oxalate load.

The culture supernatants of LK1 cells, murine erythroleukemia cells, showed B cell-stimulating activity. Purification and NH(2)-terminal sequence analysis revealed that one of the candidates was murine IgE-dependent histamine-releasing factor (IgE-HRF), which is known to induce histamine from basophils. Recombinant IgE-HRF (rHRF) obtained from Escherichia coli- or 293-transformed embryonal kidney cells was tested for B cell-stimulating activity. Both rHRFs stimulated B cell proliferation in a dose-dependent manner. However, boiling or anti-HRF Ab abolished the B cell stimulatory effects of rHRF. Recombinant HRF showed strong synergistic effects with IL-2, IL-4, and IL-5 for B cell activation, with maximal activity in the presence of anti-CD40 AB: Recombinant HRF increased MHC class II expression of B cells. It also increased Ig production from B cells. Treatment with polymyxin B, a neutralizing peptide antibiotic of LPS, did not reduce the activity of rHRF. In addition, FACS analysis using PE-conjugated rHRF showed that HRF bound to B cells. Recombinant HRF up-regulated the expression of IL-1 and IL-6 in B cells. In vivo administration of rHRF or the cDNA for rHRF increased total and Ag-specific Ig synthesis. Taken together, these results indicate that HRF stimulates B cell activation and function.