Multiple spin-echo magnetic resonance imaging

Spin-echo magnetic resonance (MR) imaging detects a variety of pathologic states with great sensitivity. A technique for producing multiple spin-echo images in multisection operation is presented. This method of intensity-image acquisition is compared with retrospective intensity-image synthesis from routine data sets. Both yield long echo time (TE) images with similar image contrast and comparable and often increased diagnostic utility. Technical and clinical considerations are addressed, including signal-to-noise levels, flow effects, and patient throughput.     

Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells

TLR7 and TLR8 are intracellular sensors activated by single-stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 or TLR8 or both through an unknown mechanism. Notably, direct interaction between small molecules and TLR7 or TLR8 has never been shown. To shed light on how small molecule agonists target TLRs, we labeled 2 imidazoquinolines, resiquimod and imiquimod, and one adenine-based compound, SM360320, with 2 different fluorophores [5(6) carboxytetramethylrhodamine and Alexa Fluor 488] and monitored their intracellular localization in human plasmacytoid dendritic cells (pDCs). All fluorescent compounds induced the production of IFN-α, TNF-α, and IL-6 and the up-regulation of CD80 and CD86 by pDCs showing they retained TLR7-stimulating activity. Confocal imaging of pDCs showed that, similar to CpG-B, all compounds concentrated in the MHC class II loading compartment (MIIC), identified as lysosome-associated membrane protein 1(+), CD63, and HLA-DR(+) endosomes. Treatment of pDCs with bafilomycin A, an antagonist of the vacuolar-type proton ATPase controlling endosomal acidification, prevented the accumulation of small molecule TLR7 agonists, but not of CpG-B, in the MIIC. These results indicate that a pH-driven concentration of small molecule TLR7 agonists in the MIIC is required for pDC activation.     

Influenza A (H1N1) virus-associated pneumonia: high-resolution computed tomography-pathologic correlation

Objective

The purpose of this study was to describe the high-resolution computed tomography (HRCT) features of fatal cases of Influenza A (H1N1) virus-associated pneumonia and to correlate them with pathologic findings.

Methods

The study included six adult patients who died following Influenza A (H1N1) virus-associated pneumonia. All patients had undergone HRCT, and the images were retrospectively analyzed by two chest radiologists, who reached decisions by consensus. Two experienced lung pathologists reviewed all pathological specimens. The HRCT findings were correlated with the histopathologic data.

Results

The predominant HRCT findings included areas of airspace consolidation (n = 6) and ground-glass opacities (n = 3). The main pathological features consisted of diffuse alveolar damage with hyaline membrane formation (n = 5), associated with various degrees of pulmonary congestion, edema, hemorrhage, inflammatory infiltration and bronchiolitis. A patient who survived longer showed findings of organizing pneumonia.

Conclusion

Fatal cases of Influenza A (H1N1) virus-associated pneumonia can present as areas of consolidation on CT, with or without ground-glass opacities. These abnormalities can be pathologically correlated with diffuse alveolar damage. Patients with longer survival may present with findings of organizing pneumonia.     

Hypergammaglobulinemia can be associated with a positive direct antiglobulin test, a nonreactive eluate, and no evidence of hemolysis

To determine the cause of a positive direct antiglobulin test (DAT), blood banks routinely perform serologic tests on eluates prepared from DAT-positive red cells. Negative eluates traditionally have been suspected to be associated with drug reactions. This report confirms that the most frequent cause of a positive DAT and a nonreactive eluate is hypergammaglobulinemia. The results of 74 patient samples with positive DATs were analyzed retrospectively. Eluates prepared from the red cells of 54 patients (72.9%) reacted; eluates from 20 patients (27.1%) did not react. This latter group had identical serologic and clinical findings, suggesting that they made up a homogeneous group. In particular, the patients had a positive DAT, a negative indirect antiglobulin test, and a negative eluate; an increased serum concentration of IgG; and no evidence of hemolysis. In a subsequent study, DATs were performed prospectively on red cells from 44 consecutive patients with elevated serum IgG levels. The serum IgG concentration was highest in the three patients whose red cells had a positive DAT. The DAT also became positive in two patients treated with high-dose intravenous gammaglobulin (IV IgG). These studies indicate that a negative eluate from red cells with a positive DAT, a common serologic finding, is often caused by hypergammaglobulinemia. The authors postulate that IgG binds nonspecifically to the red cells because of the hypergammaglobulinemia.     

Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C

Summary: The healthy liver of adult humans has little or no lymphocyte component and the histological finding of intrahepatic lymphocytes (IHL) is evidence of liver pathology. In a liver injured by chronic hepatitis C, the most common chronic liver disease, most IHL are activated/pro-inflammatory cells, which are particularly enriched for effectors of innate immunity (natural killer (NK), natural T, and other NK-like T cells). IHL do not undergo clonal expansion in the liver but migrate from extrahepatic sites to the chronically infected liver, where they display effector function and subsequently die, suggesting that maintenance of the IHL pool depends on continuous lymphocyte migration. The cytotoxic and inflammatory functions of these IHL have three potential outcomes: 1) they could be helpful in clearing the virus (a rare case in hepatitis C virus (HCV) infection);    2) they could be useless and have no effect on the infection; or 3) they could be harmful, whereby overaggressive lymphocyte responses destroy the liver in a continuous and unsuccessful attempt to clear the virus. Unfortunately, we do not know as of yet which of these possibilities is the case and, therefore, a more complete picture of the intrahepatic immune response will be relevant to the development of new therapeutic strategies against HCV. Additionally and from a more general perspective, due to the availability of biopsied material and the high prevalence (~3%) of HCV infection worldwide, studying the chronically inflamed liver of hepatitis C patients is an ideal model to investigate the poorly understood processes of lymphocyte trafficking, activation and death to non-lymphoid sites of chronic inflammation in man.     

Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Vα24+ T cells and rapid elimination of effector cells by apoptosis

Chronic viral hepatitis is characterized by a dramatic lymphocyte infiltrate in the liver. Although it is one of the most common chronic inflammatory diseases in humans, little information is available on the functional state of these intra-hepatic lymphocytes (IHL). To address this issue, we have optimized cytofluorimetric techniques to assess directly ex vivo the functions, dynamics and repertoires of IHL isolated from biopsies of patients with chronic hepatitis C. We estimate that 1 % of the total body lymphocytes infiltrate the inflamed liver and find that, at variance with peripheral blood lymphocytes (PBL) isolated from the same patients, most IHL display an activated phenotype and produce Th1 type lymphokines when stimulated in vitro. Virtually all IHL are found in the G0/G1 state of the cell cycle, while a sizeable percentage of them is undergoing programmed cell death in vivo, as detected by the TUNEL assay performed on freshly isolated cells. In contrast again to PBL from the same patients, IHL show a preferential compartmentalization of NK and TCRγ / δ⁺ cells, and a remarkable (up to 20-fold) enrichment for Vα24⁺ T cells. Together our data suggest that in a liver injured by chronic hepatitis C, most IHL are pro-inflammatory activated cells which are highly enriched for effectors of innate resistance. These IHL do not undergoclonal expansion in the liver but rather display effector function and die in situ at a high rate, suggesting that maintenance of the IHL pool is dependent on continuous migration from extra-hepatic sites.     

Transition to seizure: from "macro"- to "micro"-mysteries

One of the most terrifying aspects of epilepsy is the sudden and apparently unpredictable transition of the brain into the pathological state of an epileptic seizure. The pathophysiology of the transition to seizure still remains mysterious. Herein we review some of the key concepts and relevant literatures dealing with this enigmatic transitioning of brain states. At the "MACRO" level, electroencephalographic (EEG) recordings at time display preictal phenomena followed by pathological high-frequency oscillations at the seizure onset. Numerous seizure prediction algorithms predicated on identifying changes prior to seizure onset have met with little success, underscoring our lack of understanding of the dynamics of transition to seizure, amongst other inherent limitation. We then discuss the concept of synchronized hyperexcited oscillatory networks underlying seizure generation. We consider these networks as weakly coupled oscillators, a concept which forms the basis of some relevant mathematical modeling of seizure transitions. Next, the underlying "MICRO" processes involved in seizure generation are discussed. The depolarization of the GABA(A) chloride reversal potential is a major concept, facilitating epileptogenesis, particularly in immature brain. Also the balance of inhibitory and excitatory local neuronal networks plays an important role in the process of transitioning to seizure. Gap junctional communication, including that which occurs between glia, as well as ephaptic interactions are increasingly recognized as critical for seizure generation. In brief, this review examines the evidence regarding the characterization of the transition to seizure at both the "MACRO" and "MICRO" levels, trying to characterize this mysterious yet critical problem of the brain state transitioning into a seizure.