Analysis of killer cell immunoglobulin-like receptors and their human leukocyte antigen-ligands gene polymorphisms in Iranian patients with systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease. Natural killer (NK) cells play a critical role in the pathogenesis of autoimmune disorders that mainly express killer cell immunoglobulin-like receptors (KIRs). The present study was undertaken to determine the association of the KIR alleles, genotypes, and KIR-human leukocyte antigen (HLA) ligand gene combinations with the susceptibility to SLE. METHODS: The genotyping of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method. The study population consisted of 230 SLE patients and 273 ethnical-, age-, and sex-matched healthy controls. The association of the polymorphisms with the prevalence of 11 clinical criteria in patients was analyzed. RESULTS: The carrier frequency of HLA-A-Bw4 was modestly decreased in the SLE patients. The prevalence of hematological and renal disorders was significantly increased in patients with combination of KIR3DL1(+); HLA-B-Bw4(Thr80+) and KIR2DS1(+); HLA-C2(+) genes, respectively. Female patients with combination of KIR2DL2(+); HLA-C1(-) genes were more likely to develop serositis. In addition the prevalence of renal disorders, oral ulcer and serositis was significantly increased in male patients with KIR3DP1(+), KIR2DS1(+), and KIR2DS3(+) genotypes respectively. CONCLUSION: Our results showed that the presence of activating KIR receptors alone or in combination with their HLA ligands and the absence of inhibitory KIRs in combination with their HLA ligands may activate NK cells and are significantly correlated with the prevalence of renal disease, hematologic disorders, serositis, and oral ulcer in SLE patients.

Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient.

We present a case of severe Clostridium difficile infection (CDI) in a non-neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso-jejunal instillation of donor stool, the patient's symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

Variable anisotropic brain electrical conductivities in epileptogenic foci.

Source localization models assume brain electrical conductivities are isotropic at about 0.33 S/m. These assumptions have not been confirmed ex vivo in humans. This study determined bidirectional electrical conductivities from pediatric epilepsy surgery patients. Electrical conductivities perpendicular and parallel to the pial surface of neocortex and subcortical white matter (n = 15) were measured using the 4-electrode technique and compared with clinical variables. Mean (+/-SD) electrical conductivities were 0.10 +/- 0.01 S/m, and varied by 243% from patient to patient. Perpendicular and parallel conductivities differed by 45%, and the larger values were perpendicular to the pial surface in 47% and parallel in 40% of patients. A perpendicular principal axis was associated with normal, while isotropy and parallel principal axes were linked with epileptogenic lesions by MRI. Electrical conductivities were decreased in patients with cortical dysplasia compared with non-dysplasia etiologies. The electrical conductivity values of freshly excised human brain tissues were approximately 30% of assumed values, varied by over 200% from patient to patient, and had erratic anisotropic and isotropic shapes if the MRI showed a lesion. Understanding brain electrical conductivity and ways to non-invasively measure them are probably necessary to enhance the ability to localize EEG sources from epilepsy surgery patients.

Eosinophilic pulmonary syndrome as a manifestation of GVHD following hematopoietic stem cell transplantation in three patients.

Eosinophilic pulmonary syndrome is an uncommon problem in SCT recipients that can mimic an infectious process. We report the occurrence of eosinophilic pulmonary syndrome in three patients following allogeneic hematopoietic stem cell transplantation (HSCT), and postulate that this entity is part of the clinicopathologic spectrum of pulmonary GVHD. In all three cases, active chronic GVHD of the skin preceded or coincided with the development of pulmonary involvement. Other common features included peripheral blood eosinophilia, diffuse bilateral pulmonary infiltrates and lung biopsies showing pronounced infiltrates of eosinophils involving the small bronchioles. All patients responded promptly to systemic steroid therapy, with improvement of their pulmonary symptoms and the resolution of peripheral blood eosinophilia. Clinicians should be aware that eosinophilic pulmonary syndrome can occur following HSCT, may be associated with other manifestations of chronic GVHD, and generally responds well to corticosteroid therapy.

Electrical conductivities of the freshly excised cerebral cortex in epilepsy surgery patients; correlation with pathology, seizure duration, and diffusion tensor imaging.

The electrical conductivities (sigma) of freshly excised neocortex and subcortical white matter were studied in the frequency range of physiological relevance for EEG (5-1005 Hz) in 21 patients (ages 0.67 to 55 years) undergoing epilepsy neurosurgery. Surgical patients were classified as having cortical dysplasia (CD) or non-CD pathologies. Diffusion tensor imaging (DTI) for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) was obtained in 9 patients. Results found that electrical conductivities in freshly excised neocortex vary significantly from patient to patient (sigma = 0.0660-0.156 S/m). Cerebral cortex from CD patients had increased conductivities compared with non-CD cases. In addition, longer seizure durations positively correlated with conductivities for CD tissue, while they negatively correlated for non-CD tissue. DTI ADC eigenvalues inversely correlated with electrical conductivity in CD and non-CD tissue. These results in a small initial cohort indicate that electrical conductivity of freshly excised neocortex from epilepsy surgery patients varies as a consequence of clinical variables, such as underlying pathology and seizure duration, and inversely correlates with DTI ADC values. Understanding how disease affects cortical electrical conductivity and ways to non-invasively measure it, perhaps through DTI, could enhance the ability to localize EEG dipoles and other relevant information in the treatment of epilepsy surgery patients.

A model for frequency dependence of conductivities of the live human skull.

A mathematical model (sigma(omega) approximately equal to A omega alpha, where, sigma is identical with conductivity, omega = 2 pi f is identical with applied frequency (Hz), A (amplitude) and alpha (unit less) is identical with search parameters) was used to fit the frequency dependence of electrical conductivities of compact, spongiosum, and bulk layers of the live and, subsequently, dead human skull samples. The results indicate that the fit of this model to the experimental data is excellent. The ranges of values of A and alpha were, spongiform (12.0-36.5, 0.0083-0.0549), the top compact (5.02-7.76, -0.137-0.0144), the lower compact (2.31-10.6, 0.0267-0.0452), and the bulk (7.46-10.6, 0.0133-0.0239). The respective values A and alpha for the respective layers of the dead skull samples were (40.1-89.7, -0.0017-0.0287), (5.53-14.5, -0.0296 - -0.0061), (4.58-15.9, -0.0226-0.0268), and (12.7-25.3, -0.0158-0.0132).

Conductivities of three-layer live human skull.

Electrical conductivities of compact, spongiosum, and bulk layers of the live human skull were determined at varying frequencies and electric fields at room temperature using the four-electrode method. Current, at higher densities that occur in human cranium, was applied and withdrawn over the top and bottom surfaces of each sample and potential drop across different layers was measured. We used a model that considers variations in skull thicknesses to determine the conductivity of the tri-layer skull and its individual anatomical structures. The results indicate that the conductivities of the spongiform (16.2-41.1 milliS/m), the top compact (5.4-7.2 milliS/m) and lower compact (2.8-10.2 milliS/m) layers of the skull have significantly different and inhomogeneous conductivities. The conductivities of the skull layers are frequency dependent in the 10-90 Hz region and are non-ohmic in the 0.45-2.07 A/m2 region. These current densities are much higher than those occurring in human brain.

Dipole localization of human induced focal afterdischarge seizure in simultaneous magnetoencephalography and electrocorticography.

Localizations were compared for the same human seizure between simultaneously measured MEG and iEEG, which were both co-registered to MRI. The whole-cortex neuromagnetometer localized a dipole in a sphere phantom, co-registered to the MEG sensor array, with an error of 1.4 mm. A focal afterdischarge seizure was induced in a patient with partial epilepsy, by stimulation at a subdural electrocorticography (ECoG) electrode with a known location, which was co-registered to the MRI and to the MEG sensor array. The simultaneous MEG and ECoG during the 30-second seizure was measured and analyzed using the single, moving dipole model, which is the localization model used clinically. The dipole localizations from simultaneous whole cortex 68-channel MEG and 64-channel ECoG were then compared for the repetitive spiking at six different times during the seizure. There were two main regions of MEG and ECoG activity. The locations of these regions were confirmed by determining the location clusters of 8,000 dipoles on ECoG at consecutive time points during the seizure. The mean distances between the stimulated electrode location versus the dipole location of the MEG and versus the dipole location of the ECoG were each about one (1) centimeter. The mean distance between the dipole locations of the MEG versus the dipole locations of the ECoG was about 2 cm. These errors were compared to errors of MEG and ECoG reported previously for phantoms and for somatosensory evoked responses (SER) in patients. Comparing the findings from the present study to those from prior studies, there appeared to be the expected stepwise increase in mean localization error progressing from the phantom, to the SER, to the seizure.

Conductivities of three-layer human skull.

In this study, electrical conductivities of compact, spongiosum, and bulk layers of cadaver skull were determined at varying electric fields at room temperature. Current was applied and withdrawn over the top and bottom surfaces of each sample and potential drop across different layers was measured using the four-electrode method. We developed a model, which considers of variations in skull thicknesses, to determine the conductivity of the tri-layer skull and its individual anatomical structures. The results indicate that the spongiform and the two compact layers of the skull have significantly different and inhomogeneous conductivities ranging from 0.76 +/- .14 to 11.5 +/- 1.8 milliS/m.

The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103.

Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factor V and coagulation factor VIII are diminished. In order to map and subsequently clone the gene responsible for this phenotype, DNAs from 19 families (16 from Iran, 2 from Pakistan, and 1 from Algeria) with a total of 32 affected individuals were collected for a genomewide linkage search using genotypes of highly informative DNA polymorphisms. All pedigrees except two contained at least one consanguineous marriage. A maximum LOD score (Zmax) of 14.82 for theta = .02 was generated with marker D18S1129 in 18q21; LOD scores > 9 were obtained for several other markers-D18S849, D18S1103, D18S64, and D18S862. Multipoint analysis resulted in Zmax = 18.91 for the interval between D18S1129 and D18S64. Informative recombinants placed the locus for F5F8D between D18S849 and D18S1103, in an interval of approximately 1 cM. These results are similar to the recently reported linkage of this disease to chromosome 18q in Jewish families (Nichols et al. 1997) and provide evidence that the same gene is responsible for all F5F8D among human populations. The difference in clinical severity of the phenotype in unrelated families, as well as the failure to detect a specific haplotype of DNA polymorphisms in the consanguineous Iranian families, suggests the existence of different molecular defects in the F5F8D gene. There exists an apparently gap-free contig with CEPH YACs linking the two markers on either side of the critical region. Positional cloning efforts are now in progress to clone the F5F8D gene.

Multiple source localization using genetic algorithms.

We present a new procedure for localizing simultaneously active multiple brain sources that overlap in both space and time on EEG recordings. The source localization technique was based on a spatio-temporal model and a genetic algorithm search routine. The method was successfully applied to the localization of two dipole sources from several sets of simulated potentials with various signal-to-noise ratios (SNR). The different SNR values resembled evoked responses and epileptic spikes as commonly seen in the laboratory. Results of the simulation studies yielded localization accuracy ranging from 0.01 to 0.07 cm with an SNR of 10; from 0.02 to 0.26 cm with an SNR of 5; and from 0.06 to 0.73 cm when the SNR was equal to 2. Additionally, two sets of simulations were based on the dipole arrangements and time activities of data obtained during electrical stimulation of the median nerve in human subjects. These studies yielded localization accuracy within 0.1 cm. We also studied the localization accuracy of the algorithm using a physical model incorporating potential measurements of two current dipoles embedded in a sphere. In this situation the algorithm was successful in localizing the two simultaneously active sources to within 0.07-0.15 cm.

Somatosensory evoked response source localization using actual cortical surface as the spatial constraint.

We localized right median nerve somatosensory evoked responses in a normal human subject using an equivalent dipole method applied to magnetic field recordings. High resolution, 3-dimensional MRI data were used to confine source locations to the cortical surface. Results localized in Brodmann area 3b corresponding to location of hand somatosensory cortex derived from direct brain stimulation studies. The solution was unique and total computational time for an exhaustive, brute-force search was small and the results realistic due to applied anatomical constraints. This study demonstrates feasibility of accurate, non-invasive, realistic localization of dynamic human cortical function using spatial constraints provided by MRI images.

Assessment of lung water distribution by nuclear magnetic resonance. A new method for quantifying and monitoring experimental lung injury.

We have developed a new analytical method that uses nuclear magnetic resonance (NMR) imaging data to quantify lung water content and distribution. This new method generates a distribution of lung water density in which the fraction of voxels corresponding to a given water density is plotted on the vertical axis as a function of water density on the horizontal axis, thereby complementing the spatial information provided by the NMR image. We obtained reproducible lung water distribution data at comparable lung volumes in normal excised lungs and in intact living rats. In normal excised unperfused rat lungs, the distribution varied with the degree of inflation, but the changes were small compared with those associated with lung edema. The lung water density distribution changed markedly after induction of lung edema by intrabronchial saline instillation, intravenous oleic acid injection, and rapid intravenous saline infusion. Lung water density distribution data were well correlated (correlation coefficient = 0.948 for the excised lungs and 0.823 for the intact living rats) with gravimetric lung water measurements. The new analytical method is noninvasive, provides easily repeatable measurements, and is as sensitive as the gravimetric technique to lung water changes.