BACKGROUND

Even hydrolysed cow's milk formulae may retain residual allergens and there are few nutritional options for children with cow's milk allergy (CMA) who also react to soy.

OBJECTIVE

To assess clinical tolerance to a rice-based hydrolysate in children with such a clinical presentation.

METHODS

Eighteen children (six girls and 12 boys; median age 5 years; range 1-9 years) with CMA, who developed clinical reactions to a soy-based formula after 2-18 months' treatment, were recruited between January 1998 and June 1999. Clinical evaluation was by skin prick test (SPT) with cow's milk, casein, lactalbumin, soy and rice allergen extracts, fresh cow's milk, soy and hydrolysated rice formula (HRF). Serology was investigated by CAP system technology and immunoblotting. Assessment of the rice formula was carried out by double-blind, placebo-controlled food challenge with rice hydrolysate.

RESULTS

Thirteen children had positive SPT to casein, 10 to lactalbumin, eight to rice and two to rice hydrolysate. Positive serology was found in all patients' sera tested with cow's milk, with soy in 13 sera and with rice in seven. Double-blinded, placebo-controlled challenge with an HRF was negative in all cases.

CONCLUSIONS

Children allergic to cow's milk and soy tolerate an HRF clinically. This suggests that rice hydrolysate may be used as a protein source for children with multiple food-induced reactions.

OBJECTIVE

Electroencephalography and functional magnetic resonance imaging (fMRI) can be combined to noninvasively map abnormal brain activation elicited by epileptic processes. A major aim was to investigate the impact of a subject-specific hemodynamic response function (HRF) to describe the differences across patients versus the use of a standard model.

METHODS

We developed and applied on simulated and real data a method designed to choose optimum HRF model for identifying fMRI activation maps. In simulation, the ability of five models to reproduce data was assessed: four standard and an individual-based HRF model (ibHRF). In clinical data, drug-resistant epileptic patients underwent fMRI to investigate hemodynamic responses evoked by interictal activity.

RESULTS

When data are simulated with models different from the standard ones, the results obtained with ibHRF are superior to those obtained with the standard HRFs. Results on real data indicate an increase in extent and degree of activation with the ibHRF in comparison of the results obtainable using standard HRFs.

CONCLUSIONS

The use of the same HRF in all patients is inappropriate and resolves in biased extension of the activation maps.

CONCLUSIONS

The new method could represent an useful diagnostic tool for other clinical studies that may be biased because of misspecification of HRF.

Research groups who study epileptic spikes with simultaneous EEG-fMRI have used mostly the general linear model (GLM). A shortcoming of the GLM is that the specification of a simple hemodynamic response function (HRF) may lead to biased results. Other methods, which predict the hemodynamic response from the measured data, have been termed "recognition models". The merit of recognition models lies in the power of estimating the region-specific or voxel-specific HRF. We propose an approach that merges these two models in a general framework: estimate the HRF on the training data sets, and applying the estimated HRF on the other part of the data sets. The merit of this framework is that it can utilize the advantages of both models. A comparison of performance is made between the GLM with three fixed HRFs and the new model with voxel-specific HRFs. The main results are as follows: (1) in 18 of the 21 patients, the new model has a higher adjusted coefficient of multiple determination than the GLM with fixed HRF; (2) in some subjects, with the new model, we found areas of activation that had not been detected with the three fixed HRFs at our threshold of significance. The results suggest that the new model can do better than the fixed HRF GLM for the analysis of epileptic activity with EEG-fMRI.

The hypothesis-driven fMRI data analysis methods, represented by the conventional general linear model (GLM), have a strictly defined statistical framework for assessing regionally specific activations but require prior brain response modeling that is usually hard to be accurate. On the contrary, exploratory methods, like the support vector machine (SVM), are independent of prior hemodynamic response function (HRF), but generally lack a statistical inference framework. To take the advantages of both kinds of methods, this paper presents a composite approach through combining conventional GLM with SVM. This hybrid SVM-GLM concept is to use the power of SVM to obtain a data-derived reference function and enter it into the conventional GLM for statistical inference. The data-derived reference function was extracted from the SVM classifier using a new temporal profile extraction method. In simulations with synthetic fMRI data, SVM-GLM demonstrated a better sensitivity and specificity performance for detecting the synthetic activations, as compared to the conventional GLM. With real fMRI data, SVM-GLM showed better sensitivity than regular GLM for detecting the sensorimotor activations.

Voluntary locomotion is accompanied by large increases in cortical activity and localized increases in cerebral blood volume (CBV). We sought to quantitatively determine the spatial and temporal dynamics of voluntary locomotion-evoked cerebral hemodynamic changes. We measured single vessel dilations using two-photon microscopy and cortex-wide changes in CBV-related signal using intrinsic optical signal (IOS) imaging in head-fixed mice freely locomoting on a spherical treadmill. During bouts of locomotion, arteries dilated rapidly, while veins distended slightly and recovered slowly. The dynamics of diameter changes of both vessel types could be captured using a simple linear convolution model. Using these single vessel measurements, we developed a novel analysis approach to separate out spatially and temporally distinct arterial and venous components of the location-specific hemodynamic response functions (HRF) for IOS. The HRF of each pixel of was well fit by a sum of a fast arterial and a slow venous component. The HRFs of pixels in the limb representations of somatosensory cortex had a large arterial contribution, while in the frontal cortex the arterial contribution to the HRF was negligible. The venous contribution was much less localized, and was substantial in the frontal cortex. The spatial pattern and amplitude of these HRFs in response to locomotion in the cortex were robust across imaging sessions. Separating the more localized arterial component from the diffuse venous signals will be useful for dealing with the dynamic signals generated by naturalistic stimuli.

Hypercapnia has been accepted during nasal intermittent positive pressure ventilation (nIPPV) and during subsequent spontaneous breathing in patients with chronic hypercapnic respiratory failure (HRF) due to COPD. We tested the hypothesis that nIPPV aimed at normalizing PaCO2 will reduce PaCO2 during subsequent spontaneous breathing. For that purpose 14 consecutive inpatients (age 61.4 +/- 9.9 years) with chronic HRF due to COPD were established on passive pressure-controlled nIPPV in a stepwise approach. Assisted ventilation with supplemental oxygen to reach normoxemia was started followed by passive ventilation with a stepwise increment in the inspiratory pressure and finally by a stepwise increase in the respiratory rate to establish normocapnia. Baseline pulmonary function parameters were: FEV1 0.97 +/- 0.43 l, PaCO2 59.5 +/- 8.4 mmHg, PaO2 49.9 +/- 7.8 mmHg, HCO3- 35.6 +/- 5.2 mmol/l, pH 7.39 +/- 0.04. Normoxemia as well as normocapnia was thus established by decreasing PaCO2 by 19.5 +/- 7.0 mmHg during nIPPV within 8.8 +/- 3.8 days (P < 0.001) (inspiratory pressure 29.8 +/- 3.8 mmHg, respiratory rate 22.9 +/- 1.9 BPM). Spontaneous PaCO2 measured 4 h after cessation of nIPPV decreased to 46.0 +/- 5.5 mmHg (P < 0.001), and HCO3- decreased to 27.2 +/- 3.0 mmol/l (P < 0.001). At 6 months of follow-up, II patients continued nIPPV with stable blood gases and with a decrease of P0.1/Plmax from 9.4 +/- 4.3% to 5.9 +/- 2.0% (P < 0.005). In conclusion, normalization of PaCO2 by passive nIPPV in patients with HRF due to COPD is possible and leads to a significant reduction of PaCO2 during subsequent spontaneous breathing and is associated with improved parameters of respiratory muscle function.

In acute hypoxaemic respiratory failure (HRF), oxygenation, reduction in the work of breathing and in dyspnoea may be achieved by delivering noninvasive mechanical ventilation (NIMV). Several uncontrolled and 13 randomized controlled studies (RCS) were reviewed. Uncontrolled studies confirmed the feasibility and the possibility to improve arterial blood oxygenation with NIMV. The 13 RCS compared NIMV versus a conventional approach in a total of 720 patients with HRF. Endotracheal intubation was required in 186 of the 358 patients (median (95% confidence interval (CI)) 51%, (40-63%)) assigned to a conventional approach and in 107 of the 362 patients (29% (20-39%)) assigned to NIMV. Eleven of the 13 RCS found a reduction in the rate of endotracheal intubation with NIMV with an absolute risk reduction of 31% (30-33%). Ten of the 13 RCS found a reduction in the mortality rate which was 30% (19-40%) in the control group and 19% (13-26%) in the NIMV group. The mean absolute risk reduction was 15% (10-20%). In conclusion, noninvasive ventilation appears to be a useful method in avoiding endotracheal intubation and probably in reducing the morbidity of patients with hypoxaemic respiratory failure.

Subject-specific hemodynamic response functions (HRFs) have been recommended to capture variation in the form of the hemodynamic response between subjects (Aguirre et al., [ 1998]: Neuroimage 8:360-369). The purpose of this article is to find optimal designs for estimation of subject-specific parameters for the double gamma HRF. As the double gamma function is a nonlinear function of its parameters, optimal design theory for nonlinear models is employed in this article. The double gamma function is linearized by a Taylor approximation and the maximin criterion is used to handle dependency of the D-optimal design on the expansion point of the Taylor approximation. A realistic range of double gamma HRF parameters is used for the expansion point of the Taylor approximation. Furthermore, a genetic algorithm (GA) (Kao et al., [ 2009]: Neuroimage 44:849-856) is applied to find locally optimal designs for the different expansion points and the maximin design chosen from the locally optimal designs is compared to maximin designs obtained by m-sequences, blocked designs, designs with constant interstimulus interval (ISI) and random event-related designs. The maximin design obtained by the GA is most efficient. Random event-related designs chosen from several generated designs and m-sequences have a high efficiency, while blocked designs and designs with a constant ISI have a low efficiency compared to the maximin GA design.

The autonomic information flow (AIF) represents the complex communication within the Autonomic Nervous System (ANS). It can be assessed by the mutual information function (MIF) of heart rate fluctuations (HRF). The complexity of HRF is based on several interacting physiological mechanisms operating at different time scales. Therefore one prominent time scale for HRF complexity analysis is not given a priori. The MIF reflects the information flow at different time scales. This approach is defined and evaluated in the present paper. In order to aggregate relevant physiological time scales, the MIF of HRF obtained from eight adult Lewis rats during the awake state, under general anesthesia, with additional vagotomy, and additional betal-adrenergic blockade are investigated. Physiologically relevant measures of the MIF were assessed with regard to the discrimination of these states. A simulation study of a periodically excited pendulum is performed to clarify the influence of the time scale of MIF in comparison to the Kolmogorov Sinai entropy (KSE) of that well defined system. The general relevance of the presented AIF approach was confirmed by comparing mutual information, approximate entropy, and sample entropy at their respective time scales.

In this article, we propose an efficient approach to find optimal experimental designs for event-related functional magnetic resonance imaging (ER-fMRI). We consider multiple objectives, including estimating the hemodynamic response function (HRF), detecting activation, circumventing psychological confounds and fulfilling customized requirements. Taking into account these goals, we formulate a family of multi-objective design criteria and develop a genetic-algorithm-based technique to search for optimal designs. Our proposed technique incorporates existing knowledge about the performance of fMRI designs, and its usefulness is shown through simulations. Although our approach also works for other linear combinations of parameters, we primarily focus on the case when the interest lies either in the individual stimulus effects or in pairwise contrasts between stimulus types. Under either of these popular cases, our algorithm outperforms the previous approaches. We also find designs yielding higher estimation efficiencies than m-sequences. When the underlying model is with white noise and a constant nuisance parameter, the stimulus frequencies of the designs we obtained are in good agreement with the optimal stimulus frequencies derived by Liu and Frank, 2004, NeuroImage 21: 387-400. In addition, our approach is built upon a rigorous model formulation.

Infecting the insect cell line IPLB-Ld652Y with the baculovirus Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) results in global translation arrest, which correlates with the presence of the AcMNPV apoptotic suppressor, p35. In this study, we investigated the role of apoptotic suppression on AcMNPV-induced translation arrest. Infecting cells with AcMNPV bearing nonfunctional mutant p35 did not result in global translation arrest. In contrast, global translation arrest was observed in cells infected with AcMNPV in which p35 was replaced with Opiap, Cpiap, or p49, baculovirus apoptotic suppressors that block apoptosis by different mechanisms than p35. These results indicated that suppressing apoptosis triggered translation arrest in AcMNPV-infected Ld652Y cells. Experiments using the DNA synthesis inhibitor aphidicolin and temperature shift experiments, using the AcMNPV replication mutants ts8 and ts8deltap35, indicated that translation arrest initiated during the early phase of infection, but events during the late phase were required for global translation arrest. Peptide caspase inhibitors could not substitute for baculovirus apoptotic suppressors to induce translation arrest in Ld652Y cells infected with a p35-null virus. However, if the p35-null-AcMNPV also carried hrf-1, a novel baculovirus host range gene, progeny virus was produced and treatment with peptide caspase inhibitors enhanced translation of a late viral gene transcript. Together, these results indicate that translation arrest in AcMNPV-infected Ld652Y cells is due to the anti-apoptotic function of p35, but suggests that rather than simply preventing caspase activation, its activity enhances signaling to a separate translation arrest pathway, possibly by stimulating the late stages of the baculovirus infection cycle.

The Heidelberg Retina Flowmeter (HRF) is intended to assess ocular blood flow by scanning laser doppler flowmetry. In the retina and possibly in the optic nerve head, carbogen increases blood flow, whereas pure oxygen or high intraocular pressure (IOP) decrease it. This study addresses whether at the papilla of healthy volunteers, the HRF parameter flow, is modulated by breathing 5% carbogen (5% carbon dioxide + 95% oxygen) for 7 minutes, breathing 100% oxygen for 7 minutes, increasing IOP to 50 mm Hg with a suction cup, or decreasing IOP with a single topical ocular instillation of the beta-blockers 0.5% betaxolol (betoptic) or 0.5% timolol (timoptic). At the papilla (20 degrees x 5 degrees, 256 X 64 pixels), values of HRF parameter, flow (50 X 50) pixels, increased after carbogen (N = 5, P < 0.05), but decreased after oxygen (N = 5, P < 0.05) or IOP increase (N = 5, P < 0.01). Although IOP values were significantly reduced by betaxolol (N = 9, P < 0.05) and timolol (N = 9, P < 0.01), HRF values were only significantly decreased (N = 9, P < 0.05) after timolol. In conclusion, at the papilla of healthy volunteers, a positive correlation exists between changes in values of the HRF-parameter, flow, and stimuli considered to modulate retinal and ONH blood flow. Furthermore, although of unkown clinical relevance, it appears that in contrast to betaxolol, values of the HRF parameter, flow, at the papilla of healthy volunteers are significantly decreased after a single instillation of timolol.

BACKGROUND

Although multiple studies of demographic variables have been associated with allograft thrombosis, these results are not routinely reproducible. Are ESRD patients with hypercoagulable states (HCS) (antithrombin III deficiency, protein S or C deficiency, activated protein C resistance, and anticardiolipin antibodies) at predictably greater risk for allograft thrombosis?

METHODS

Between 1996 and 1999, all renal transplant candidates were screened for hypercoagulability risk factors [HRF] (multiple arteriovenous access thromboses, prior deep vein thrombosis, prior allograft thrombosis, collagen vascular disease, multiple miscarriages, diabetes, autoimmune disease, and Fabry's disease). HRF(+) candidates were then tested for HCS status. We administered preemptive posttransplant i.v. Heparin in HCS(+) patients and observed the impact of this intervention upon the incidence of allograft thrombosis. We compared demographic data and incidence of allograft thrombosis in an historic control (346 patients transplanted between June 31, 1992, and March 5, 1996) not tested for HCS and a study cohort (502 patients transplanted between March 6, 1996, and June 31, 1999) prospectively screened for HRF. HRF(+) patients who were HCS(+) in the study cohort received i.v. heparin immediately after transplant and p.o. warfarin as outpatients.

RESULTS

Demographic characteristics previously implicated in allograft thrombosis were equivalently distributed in both cohorts with the exceptions that more living-donor transplants (33.1% vs. 15.3%) were performed in study cohort, CIT>24 hr occurred in more control patients (37.3% vs. 22.1%) and more study patients (16.7% vs. 0%) received tacrolimus. Hypercoagulable states were found upon reevaluating five of seven controls (71.4%), who lost prior allografts to thrombosis. Hypercoagulable states were prospectively detected in 10 study patients with hypercoagulability risk factors. Most (9 of 10) study patients receiving anticoagulation have achieved long-term allograft function. Study group allograft thrombosis incidence was reduced (1.59% vs. 4.05%). Hypercoagulable states were demonstrated in most episodes of allograft thrombosis. Control patients who lost prior allografts to thrombosis were anticoagulated after retransplantation and 100% achieved long-term allograft function.

CONCLUSIONS

Long-term allograft function has been achieved in 90% of study patients when prophylactically anticoagulating study patients with hypercoagulable states. A 2.6-fold reduction in the expected incidence of allograft thrombosis was observed in anticoagulated patients with hypercoagulable states.

Abstract Although several functional magnetic resonance imaging (fMRI) studies have been conducted in human models of mild traumatic brain injury (mTBI), to date no studies have explicitly examined how injury may differentially affect both the positive phase of the hemodynamic response function (HRF) as well as the post-stimulus undershoot (PSU). Animal models suggest that the acute and semi-acute stages of mTBI are associated with significant disruptions in metabolism and to the microvasculature, both of which could impact on the HRF. Therefore, fMRI data were collected on a cohort of 30 semi-acute patients with mTBI (16 males; 27.83±9.97 years old; 13.00±2.18 years of education) and 30 carefully matched healthy controls (HC; 16 males; 27.17±10.08 years old; 13.37±2.31 years of education) during a simple sensory-motor task. Patients reported increased cognitive, somatic, and emotional symptoms relative to controls, although no group differences were detected on traditional neuropsychological examination. There were also no differences between patients with mTBI and controls on fMRI data using standard analytic techniques, although mTBI exhibited a greater volume of activation during the task qualitatively. A significant Group×Time interaction was observed in the right supramarginal gyrus, bilateral primary and secondary visual cortex, and the right parahippocampal gyrus. The interaction was the result of an earlier time-to-peak and positive magnitude shift throughout the estimated HRF in patients with mTBI relative to HC. This difference in HRF shape combined with the greater volume of activated tissue may be indicative of a potential compensatory mechanism to injury. The current study demonstrates that direct examination and modeling of HRF characteristics beyond magnitude may provide additional information about underlying neuropathology that is not available with more standard fMRI analyses.

Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes (HRFs).

OBJECTIVE

The aims of the study were to determine the incidence of FMF in Germany and to describe the spectrum of pyrin mutations and the clinical characteristics in children. A prospective surveillance of children with HRF including FMF was conducted in Germany during a time period of 3 years by the German paediatric surveillance unit for rare paediatric diseases (ESPED). Monthly inquiries were sent to 370 children's hospitals (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated pyrin mutations, and more than three self-limiting episodes of fever >38.5 °C with increased inflammation markers. In n1, 122 patients with FMF and 225 pyrin mutations were identified. Ninety-two of 122 (75 %) children were of Turkish origin. The minimum incidence of FMF was estimated to be 3 (95 % CI: 2.48-3.54) per 10(6) person-years in the whole children population and 55 (95 % CI: 46-66) per 10(6) person-years in Turkish children living in Germany. N1 U n2 amounted to 593 asymptomatic and symptomatic carriers of 895 mutations (overlap of 73 cases with 134 mutations). p.Met694Val (45 %), p.Met680Ile (14 %), p.Val726Ala (12 %), and p.Glu148Gln (11.5 %) were the most common pyrin mutations.

CONCLUSIONS

Despite FMF being the most frequent of the HRFs, its incidence in Germany is low. Twenty-five to 50 FMF patients ≤ 16 years are newly diagnosed per year. The disease is most commonly observed in individuals of Turkish ancestry.

Risk assessment policies and practice place increasing reliance on mode of action (MOA) data to inform conclusions about the human relevance of animal tumors. In June 2001, the Risk Science Institute of the International Life Sciences Institute formed a workgroup to study this issue. The workgroup divided into two subgroups, one developing and testing a "framework" for MOA relevance analysis and the other conducting an in-depth analysis of peroxisome proliferation-activated receptor (PPAR)alpha activation as the MOA for some animal carcinogens. This special issue of Critical Reviews in Toxicology presents the scientific reports emerging from this activity. These reports serve several purposes. For risk assessors in and out of government, they offer a new human relevance framework (HRF) that complements and extends existing guidance from other organizations. Regarding the specific MOA for peroxisome proliferating chemicals, these reports offer a state-of-the-science review of this important MOA and its role in tumorigenesis in three different tissues (liver, testis, and pancreas). The case studies in these reports present models for using MOA information to evaluate the hazard potential for humans. The cases also illustrate the substantial impact of a complete human relevance analysis, as distinct from an animal MOA analysis alone, on the nature and scope of risk assessment.

Factors such as strabismus or anisometropia during infancy can disrupt normal visual development and result in amblyopia, characterized by reduced visual function in an otherwise healthy eye and often associated with persistent suppression of inputs from the amblyopic eye by those from the dominant eye. It has become evident from fMRI studies that the cortical response to stimulation of the amblyopic eye is also affected. We were interested to compare the hemodynamic response function (HRF) of early visual cortex to amblyopic vs. dominant eye stimulation. In the first experiment, we found that stimulation of the amblyopic eye resulted in a signal that was both attenuated and delayed in its time to peak. We postulated that this delay may be due to suppressive effects of the dominant eye and, in our second experiment, measured the cortical response of amblyopic eye stimulation under two conditions--where the dominant eye was open and seeing a static pattern (high suppression) or where the dominant eye was patched and closed (low suppression). We found that the HRF in response to amblyopic eye stimulation depended on whether the dominant eye was open. This effect was manifested as both a delayed HRF under the suppressed condition and an amplitude reduction.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is the most toxic man-made member of the class of environmental pollutants represented by polychlorinated dibenzo-p-dioxins and dibenzofurans. TCDD produces a wide variety of toxic effects. However, the downstream genes targeted by TCDD and their relation to the diversity of dioxin toxicity symptoms are poorly understood. To identify the target genes of TCDD, we used a cDNA representational difference analysis (RDA) to compare the mRNA patterns of mouse embryonic stem (ES) cells that had and had not been exposed to TCDD. Here we show that TCDD stimulated the expression of IgE-dependent histamine-releasing factor (HRF) mRNA via an aryl hydrocarbon receptor (AhR)-dependent pathway. TCDD also induced the synthesis and secretion of HRF. To our knowledge, this is the first example of HRF being a direct transcriptional target of a toxic agent. HRF has previously been shown to induce histamine release in a dose-dependent manner, at least in vitro. Thus, our data suggest that "endocrine-disrupting" agents may have the potential to influence allergic disorders in the human body.

Human thyroid cells are resistant to lysis by the homologous membrane attack complex. By immunohistochemical staining we here show that normal thyroid cells and those in Graves' disease and Hashimoto's thyroiditis express two membrane attack complex-inhibiting proteins, CD59 antigen and membrane attack complex-inhibiting protein/homologous restriction factor (MIP/HRF). In vitro, the expression of both molecules was enhanced by interleukin-1 (IL-1), tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) and cytokine-treated thyroid cells were more resistant to lysis by homologous complement. Blocking experiments with monoclonal antibodies against CD59 antigen and MIP/HRF showed that both molecules contributed but CD59 antigen was the more important in mediating resistance to complement attack. Expression of these proteins may be an important determinant of the severity of tissue injury produced by complement-fixing thyroid peroxidase antibodies in autoimmune thyroid disease.

BACKGROUND

Hyperoxaluria is a major risk factor of calcium oxalate stone disease and renal injury is thought to be a significant initiating event. However, the relationship among oxidative stress, renal tubule injury and hyperoxaluria in the progression of nephrolithiasis is unclear, especially in animal models. In the current study, we assess the role of oxidative stress in renal tubular damage in a rat model of chronic hyperoxaluria (HYP) and chronic renal failure induced by hyperoxaluria (HRF) compared to control rats.

METHODS

Urinary excretion of renal tubular enzymes, including lactate dehydrogenase (LDH), alkaline phosphatase (AP), N-acetyl-beta-D-glucosaminidase (NAG), and alpha- and mu-glutathione-S-transferase (alpha-GST and mu-GST, respectively) was quantified in four groups of Sprague-Dawley rats. The study included normal controls, those made hyperoxaluric with ethylene glycol administration (HYP), unilateral nephrectomized controls, and unilateral nephrectomized rats administered ethylene glycol (HRF). Levels of catalase, superoxide dismutase (SOD), glutathione peroxidase (GP), and glutathione transferase (GST) in the renal cortex were measured after 4 weeks and lipid peroxidation was assessed by measuring 8-isoprostane in the urine and lipid hydroperoxide in the renal cortex.

RESULTS

Urinary excretion of NAG, AP, and LDH was elevated after 2 and 4 weeks in the HYP and HRF groups. Urinary levels of mu-GST, a marker of distal tubule damage, were elevated in HRF rats after 4 weeks. alpha-GST levels were similar between control and HYP rats but were lower in HRF rats. Levels of catalase, SOD, GP, and GST in the renal cortex were similar among control, HYP, and unilateral nephrectomized control rats, but were attenuated in the HRF rats after 4 weeks. Renal cortical content of lipid hydroperoxide and urinary 8-isoprostane levels were similar among all groups after 4 weeks.

CONCLUSIONS

Ethylene glycol-induced hyperoxaluria in Sprague-Dawley rats is accompanied by enzymuria, which is suggestive of renal tubular damage. The antioxidant capacity of the renal cortex in HYP rats is similar to that of control rats after 4 weeks of treatment; however, this capacity is significantly attenuated in rats that are in renal failure induced by hyperoxaluria, although significant lipid peroxidation is not evident. These results suggest that lipid peroxidation is not the underlying cause of renal injury in hyperoxaluric rats.

The objective of this study was to investigate the effect of interleukin-8 (IL-8) and RANTES on basophil histamine release induced with monocyte chemoattractant peptide-1 (MCP-1) and crude histamine releasing factor (HRF). IL-8 induced low levels of histamine release (8.5 +/- 0.5%) from basophils obtained from only six of 20 donors at high concentrations (10(-6) M). RANTES induced histamine release (16 +/- 2%) from basophils of four of 15 donors at 10(-7) M concentration. However, both IL-8 and RANTES inhibited MCP-1 and HRF-induced histamine release from basophils dose-dependently at concentrations of 10(-9) to 10(-7) M. Basophils from all donors showed a significant inhibitory response (greater than 15%). The maximal inhibition of MCP-1 and HRF by IL-8 was 28 +/- 4% and 48 +/- 8%, respectively. The maximal inhibition of MCP-1 and HRF by RANTES was 26 +/- 4% and 43 +/- 6%, respectively. Peripheral blood mononuclear cell-derived HRF was purified into three distinct peaks by reverse-phase high performance liquid chromatography. Peak I contained MCP-1 as judged by binding to an immunoaffinity column that was prepared with anti-MCP-1 antibody. IL-8 inhibited histamine release induced with all three peaks of HRF. The inhibition of histamine release by IL-8 was significantly higher in normal subjects than in allergic patients (59 +/- 9% versus 31 +/- 7%, P less than 0.05). Both IL-8 and RANTES inhibited cytokine-induced histamine release only and did not affect histamine release by anti-IgE, FMLP, and C5a.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

In simultaneous scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), blood oxygen level dependent (BOLD) changes occurring before the spike have been sometimes described but could not be explained. To characterize the origin of this prespike BOLD signal change, we looked for electrographic changes in stereo-EEG (SEEG) possibly preceding the scalp spike in patients that showed early BOLD response in EEG/fMRI.

METHODS

We studied four patients with drug-resistant focal epilepsy who underwent EEG/fMRI, showed a prespike BOLD response, and were then studied with depth electrodes for presurgical localization of the epileptic generator. Early BOLD responses in the region of the spike field were analyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. SEEG recordings in the period and location corresponding to the early HRF responses were analyzed to detect if electrographic changes were present in the SEEG before the scalp abnormality.

RESULTS

One of the four patients presented a SEEG interictal discharge in the period corresponding to the early BOLD response. In the other three, no electrographic changes were detected in the SEEG in the period corresponding to early BOLD changes.

CONCLUSIONS

Although the early BOLD activity may sometimes be explained by a synchronized neural discharge detectable with SEEG but not visible on the scalp EEG, in most cases the early BOLD response reflects a metabolic phenomenon that does not appear to result from a synchronized neuronal discharge. Prespike metabolic responses can result from synchronized or nonsynchronized neuronal activity, or from nonneuronal mechanisms including glia.

Functional MRI (fMRI) signals are robustly detectable in white matter (WM) but they have been largely ignored in the fMRI literature. Their nature, interpretation, and relevance as potential indicators of brain function remain under explored and even controversial. Blood oxygenation level dependent (BOLD) contrast has for over 25 years been exploited for detecting localized neural activity in the cortex using fMRI. While BOLD signals have been reliably detected in grey matter (GM) in a very large number of studies, such signals have rarely been reported from WM. However, it is clear from our own and other studies that although BOLD effects are weaker in WM, using appropriate detection and analysis methods they are robustly detectable both in response to stimuli and in a resting state. BOLD fluctuations in a resting state exhibit similar temporal and spectral profiles in both GM and WM, and their relative low frequency (0.01-0.1 Hz) signal powers are comparable. They also vary with baseline neural activity e.g. as induced by different levels of anesthesia, and alter in response to a stimulus. In previous work we reported that BOLD signals in WM in a resting state exhibit anisotropic temporal correlations with neighboring voxels. On the basis of these findings, we derived functional correlation tensors that quantify the correlational anisotropy in WM BOLD signals. We found that, along many WM tracts, the directional preferences of these functional correlation tensors in a resting state are grossly consistent with those revealed by diffusion tensors, and that external stimuli tend to enhance visualization of specific and relevant fiber pathways. These findings support the proposition that variations in WM BOLD signals represent tract-specific responses to neural activity. We have more recently shown that sensory stimulations induce explicit BOLD responses along parts of the projection fiber pathways, and that task-related BOLD changes in WM occur synchronously with the temporal pattern of stimuli. WM tracts also show a transient signal response following short stimuli analogous to but different from the hemodynamic response function (HRF) characteristic of GM. Thus there is converging and compelling evidence that WM exhibits both resting state fluctuations and stimulus-evoked BOLD signals very similar (albeit weaker) to those in GM. A number of studies from other laboratories have also reported reliable observations of WM activations. Detection of BOLD signals in WM has been enhanced by using specialized tasks or modified data analysis methods. In this mini-review we report summaries of some of our recent studies that provide evidence that BOLD signals in WM are related to brain functional activity and deserve greater attention by the neuroimaging community.

OBJECTIVE

to image functionally perfused retinal vessels and to assess quantitatively the intercapillary space of the retinal microvasculature.

METHODS

The base of functional imaging and the quantitative assessment of the retinal vasculature is the two-dimensional map of the retina encoded by the laser Doppler frequency shift. By Scanning Laser Doppler Flowmetry (HRF. Heidelberg Engineering) the laser Doppler frequency shift of 16.384 retinal sites (256 pixels x 64 lines, spatial resolution 10 mum) of a retinal area of 2.7 x 0.7 mm was gained. The image processing was performed by a recently described algorithm (AFFPIA). Using the data of the laser Doppler frequency shift of every retinal site, a color-coded retinal image was established showing perfused vessels and capillaries. By automatic pattern analysis of this image vessels and capillaries were identified and segmented. Based on this image the distances in [microm] of every retinal site to the next vessel or capillary were calculated ("distance to next capillary"). The functional imaging of the retinal perfusion was demonstrated in (1) normal retina, (2) retinal arterial occlusion, and (3) proliferative retinopathy. Intraobserver reliability of the quantitative assessment of the parameter "distance to next capillary" was estimated by measuring 10 eyes of 10 subjects at 5 different days by one observer. Interobserver reliability of the quantitative assessment was evaluated by analysing 10 perfusion maps by 5 different operators. In 93 eyes of 71 normal subjects (mean age 40.4 mu 15 years) the juxtapapillary retina was quantitatively evaluated.

RESULTS

QUALITATIVE EVALUATION: The functional images of the retinal perfusion of eyes with normal retina, with retinal arterial occlusion, and with proliferative retinopathy corresponded well with the fluorescein angiography. Perfused vessels and capillaries became visible in a high local resolution. QUANTITITATIVE ASSESSMENT: The coefficient of reliability of the introobserver and interobserver reproducibility of the parameter 'mean distance to next capillary" was 0.74, and 0.95, respectively. The quantitative assessment of the perfusion showed that the major part of the retinal sites (>700%) had distances to the next capillary lower than 30 microm 46% of the retinal area had distances to the next capillary from 0-20 microm 26% of the retina had distances from 20-30 microm, 12% of the retina had distances from 30-40 microm 7% of the retina had distances from 40-50 microm, 4% of the retina had distances from 50-60 microm, and 4% of the retinal sites showed distances to the next capillary greater than 60 mum. The mean distance to the next capillary or vessel was calculated with 21 +/- 6.5 microm.

CONCLUSIONS

By non-invasive Scanning Laser Doppler Flowmetry in combination with adequate software it is possible to perform a functional imaging of the retinal vasculature and to measure all index for the functional density of retinal capillaries and vessels.