Basophils initiate IL-4 production during a memory T-dependent response

Experiments were performed to characterize and identify the cellular sources of the secondary interleukin (IL)-4 response to a T cell-dependent antigen. Mice were primed by immunization with goat anti-mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4+ T cells to secrete IL-4 in 3-4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by approximately 100-fold, started in <2 h, and lasted for 4 d. Studies with 4get mice, in which cells with an accessible Il4 gene express a green fluorescent protein (GFP), revealed CD4+ memory T cells, natural killer T cells, basophils, mast cells, and eosinophils as possible rapid producers of IL-4. GFP(+)CD4+ T cells and basophils expanded more in the spleen than the other cell types during the primary response to GaMD. Quantitation of in vivo IL-4 production by the in vivo cytokine capture assay after individual cell types were selectively stimulated or deleted demonstrated that basophils and memory CD4+ T cells account for most of the secondary IL-4 response, with basophils initiating that response through IgE/FcepsilonRI-mediated signaling but secreting IL-4 for <4 h and memory T cells secreting IL-4 within 4 h and continuing to secrete this cytokine for 4 d.     

Distribution of pulmonary blood flow in the perfluorocarbon-filled lung

Objective: Partial liquid ventilation (PLV) improves gas exchange in animal studies of lung injury. Perfluorocarbons (PFCs) are heavy liquids and are therefore preferentially delivered to the most dependent areas of lung. We hypothesised that improved oxygenation during PLV might be the consequence of a redistribution of pulmonary blood flow away from poorly ventilated, dependent alveoli, leading to improved ventilation/perfusion (V/Q) matching. This study investigated whether partially filling the lung with PFC would result in a redistribution of pulmonary blood flow.¶Design: Prospective experimental study.¶Setting: Hospital research institute laboratory.¶Participants: Six anaesthetised pigs without lung injury.¶Interventions: Animals were anaesthetised and ventilated (gas tidal volume 12 ml/kg, PEEP 5, FIO₂ 1.0, rate 16). Whilst the pigs were maintained in the supine position, regional pulmonary blood flow was measured during conventional gas ventilation and repeated during PLV. Flow to regions of lung was determined by injection of radioactive microspheres (Co⁵⁷, Sn¹¹³, Sc⁴⁶). Measurements were performed with ventilation held at end-expiratory pressure and, in two PLV animals only, repeated with ventilation held at peak inspiratory pressure.¶Results: During conventional gas ventilation, blood flow followed a linear distribution with the highest flow to the most dependent lung. In the lung partially filled with PFC a diversion of blood flow away from the most dependent lung was seen (p = 0.007), resulting in a more uniform distribution of flow down the lung (p = 0.006). Linear regression analysis (r ² = 0.75) also confirmed a difference in distribution pattern. On applying an inspiratory hold to the liquid-containing lung, blood flow was redistributed back towards the dependent lung.¶Conclusions: Partially filling the lung with PFC results in a redistribution of pulmonary blood flow away from the dependent region of the lung. During PLV a different blood flow distribution may be seen between inspiration and expiration. The clinical significance of these findings has yet to be determined.     

The PKC inhibitor AEB071 may be a therapeutic option for psoriasis

PKC isoforms tau, alpha, and beta play fundamental roles in the activation of T cells and other immune cell functions. Here we show that the PKC inhibitor AEB071 both abolishes the production of several cytokines by activated human T cells, keratinocytes, and macrophages in vitro and inhibits an acute allergic contact dermatitis response in rats. To translate these findings into humans, single and multiple ascending oral doses of AEB071 were administered to healthy volunteers and patients with psoriasis, respectively. AEB071 was well tolerated with no clinically relevant laboratory abnormalities. Ex vivo stimulation of lymphocytes from subjects exposed to single doses of AEB071 resulted in a dose-dependent inhibition of both lymphocyte proliferation and IL2 mRNA expression. Clinical severity of psoriasis was reduced up to 69% compared with baseline after 2 weeks of treatment, as measured by the Psoriasis Area Severity Index (PASI) score. The improvement in psoriasis patients was accompanied by histological improvement of skin lesions and may be partially explained by a substantial reduction of p40+ dermal cells, which are known to mediate psoriasis. These data suggest that AEB071 could be an effective novel treatment regimen for psoriasis and other autoimmune diseases, and that AEB071 warrants long-term studies to establish safety and efficacy.     

Utility of [<Superscript>18</Superscript>F]FSPG PET to Image Hepatocellular Carcinoma: First Clinical Evaluation in a US Population

Purpose

Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[¹⁸F]fluoropropyl)-L-glutamic acid ([¹⁸F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [¹⁸F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [¹¹C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [¹⁸F]FSPG PET/CT and present the first comparison to [¹¹C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations.

Procedures

x_C? transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [¹⁸F]FSPG PET/CT, with seven patients also imaged with [¹¹C]acetate PET/CT.

Results

x_C? transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [¹⁸F]FSPG PET/CT demonstrated a detection rate of 75 %. [¹⁸F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [¹⁸F]FSPG and [¹¹C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [¹⁸F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [¹¹C]acetate PET/CT.

Conclusions

[¹⁸F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [¹⁸F]FSPG PET/CT impact on diagnosis and management of HCC. [¹⁸F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.

     

A systematic review of the utility of 1.5 versus 3 Tesla magnetic resonance brain imaging in clinical practice and research

Objective

MRI at 3?T is said to be more accurate than 1.5?T MR, but costs and other practical differences mean that it is unclear which to use.

Methods

We systematically reviewed studies comparing diagnostic accuracy at 3?T with 1.5?T. We searched MEDLINE, EMBASE and other sources from 1 January 2000 to 22 October 2010 for studies comparing diagnostic accuracy at 1.5 and 3?T in human neuroimaging. We extracted data on methodology, quality criteria, technical factors, subjects, signal-to-noise, diagnostic accuracy and errors according to QUADAS and STARD criteria.

Results

Amongst 150 studies (4,500 subjects), most were tiny, compared old 1.5?T with new 3?T technology, and only 22 (15?%) described diagnostic accuracy. The 3?T images were often described as “crisper”, but we found little evidence of improved diagnosis. Improvements were limited to research applications [functional MRI (fMRI), spectroscopy, automated lesion detection]. Theoretical doubling of the signal-to-noise ratio was not confirmed, mostly being 25?%. Artefacts were worse and acquisitions took slightly longer at 3?T.

Conclusion

Objective evidence to guide MRI purchasing decisions and routine diagnostic use is lacking. Rigorous evaluation accuracy and practicalities of diagnostic imaging technologies should be the routine, as for pharmacological interventions, to improve effectiveness of healthcare.

Key Points

? Higher field strength MRI may improve image quality and diagnostic accuracy. ? There are few direct comparisons of 1.5 and 3?T MRI. ? Theoretical doubling of the signal-to-noise ratio in practice was only 25?%. ? Objective evidence of improved routine clinical diagnosis is lacking. ? Other aspects of technology improved images more than field strength.     

A comparison of hip joint centre localisation techniques with 3-DUS for clinical gait analysis in children with cerebral palsy

Little is known about dynamic balance control under dual-task conditions in older adults with fear of falling (FoF). The purpose of this study was to examine the effect of FoF on anticipatory postural adjustment (APA) during gait initiation under dual-task conditions in older adults. Fifty-seven elderly volunteers (age, 79.2 [6.8] years) from the community participated in this study. Each participant was categorised into either the Fear (n=24) or No-fear (n=33) group on the basis of the presence or absence of FoF. Under single- and dual-task conditions, centre of pressure (COP) data were collected while the participants performed gait initiation trials from a starting position on a force platform. We also performed a 10-m walking test (WT), a timed up & go test (TUG), and a functional reach test (FR). The reaction and APA phases were measured from the COP data. The results showed that under the dual-task condition, the Fear group had significantly longer APA phases than the No-fear group, although no significant differences were observed between the 2 groups in the reaction and APA phases under the single-task condition and in any clinical measurements (WT, TUG, and FR). Our findings suggest that specific deficits in balance control occur in subjects with FoF during gait initiation while dual tasking, even if their physical functions are comparable to subjects without FoF.     

Telomeric IGH losses detectable by fluorescence in situ hybridization in chronic lymphocytic leukemia reflect somatic VH recombination events

Routine interphase fluorescence in situ hybridization (FISH) analysis of chronic lymphocytic leukemia (CLL) with LSI IGH/CCND1 assay, applied to differentiate CLL from leukemic mantle cell lymphoma, identified a subset of cases (42/174) with translocation-like IGH signal pattern. To unravel the underlying 14q32/IGH aberrations, 14 of these cases were subjected to cytogenetic, detailed FISH, and V(H) mutation analyses. FISH identified cryptic losses of various portions of the IGHV region in all 14 cases. Fine mapping of these V(H) deletions revealed a strict correlation between their distal border and localization of the used VH gene, suggesting that they are not oncogenic but reflect physiological events accompanying somatic V-D-J assembly. This hypothesis was further supported by FISH analysis of 20 CLL and hairy cell leukemia cases with the known V(H) usage showing a constant loss of sequences proximal to the used gene, identification of V(H) deletions in normal B cells, and their exclusive demonstration in B cell malignancies, but not of T cell and myeloid linage. Given that these cryptic physiological VH losses in B cells may seriously complicate analysis of B cell leukemia/lymphoma and lead to false conclusions, FISH users should take them into consideration when interpreting IGH aberrations in these malignancies.     

Electrocardiogram in Pneumocystis carinii pneumonia: can it be used as a prognostic variable?

OBJECTIVE: Many prognostic variables have been studied in patients with Pneumocystis carinii pneumonia and acquired immunodeficiency syndrome (AIDS). The role of the electrocardiogram in this setting has not been previously evaluated. We analyzed the admission electrocardiogram in patients with Pneumocystis carinii pneumonia and AIDS in an attempt to identify electrocardiogram findings that could be associated with adverse clinical outcomes and worse prognostic variables. DESIGN: A retrospective medical chart review. SETTING: All confirmed cases of Pneumocystis carinii pneumonia in patients positive for human immunodeficiency virus admitted to Albert Einstein Medical Center from 1994 to 2000. METHODS: Patients were assigned increasing severity ranks based on the findings on the admission electrocardiogram (normal sinus rhythm, sinus tachycardia, and right ventricular strain pattern). Data were extracted regarding study outcomes (admission to intensive care unit, mechanical ventilation, and hospital mortality) and prognostic variables. MAIN RESULTS: Of the 40 study patients, 14 (35%) had normal sinus rhythm, 15 (37.5%) had sinus tachycardia, and 11 (27.5%) presented with signs of right ventricular strain. The number of admissions to the intensive care unit, use of mechanical ventilation, and hospital mortality rate all increased with the severity of the electrocardiogram findings (p < or =.03). The serum lactate dehydrogenase concentrations and the alveolar-arterial oxygen gradient both increased with the severity of the electrocardiogram findings (p < or =.02). CONCLUSION: Electrocardiogram findings of sinus tachycardia and right heart strain are common in Pneumocystis carinii pneumonia. These findings are associated with adverse clinical outcomes as well as worsening of prognostic variables. The electrocardiogram may be useful in predicting outcome in patients with Pneumocystis carinii pneumonia.     

Lipid phosphate phosphatase 3 enables efficient thymic egress

The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance.