Meta-analysis assessing the sensitivity and specificity of 18F-FDG PET/CT for the diagnosis of prosthetic valve endocarditis (PVE) using individual patient data (IPD).

IMPORTANCE: The use of 18F-FDG PET/CT in diagnostic algorithms for PVE has increased since publication of studies and guidelines advocating its use. The assessment of test accuracy has been limited by small study sizes. We undertook a systematic review using individual patient data (IPD) meta-analysis techniques. OBJECTIVE: To estimate the summary sensitivity and specificity of 18F-FDG PET/CT in diagnosing PVE. We also assessed the effect of patient factors on test accuracy as defined by changes in the odds ratios associated with each factor. The effect of the PET/CT study on the final diagnosis was also assessed when compared to the preliminary Duke classification to determine in which patient group 18F-FDG PET/CT had the greatest utility. STUDY SELECTION: Studies were included if PET/CT was performed for suspicion of PVE and IPD of both the PET/CT result and final diagnosis defined by a gold-standard assessment was available. There were 3 possible final diagnoses ("definite PVE," "possible PVE," and "rejected PVE"). RESULTS: Seventeen studies were included with IPD available for 537 patients (from 538 scans). The summary sensitivity and specificity were 85% (95% CI 74.2%-91.8%) and 86.5% (95% CI 75.8%-92.9%) respectively when patients with final diagnosis of "possible PVE" were classified as positive for PVE. When this group was classified as negative for PVE, sensitivity was 87.4% (95% CI 80.4%-92.1%) and specificity was 84.9% (95% CI 71.5%-92.6%). Patients with a known pathogen (especially coagulase negative staphylococcal species), elevated CRP, a biological or aortic valve infection appeared more likely to have an accurate PET/CT diagnosis. Those with a mechanical valve, prior antibiotic treatment or a transcatheter aortic valve replacement valve were less likely to have an accurate test. Time since valve implantation and the presence of surgical adhesive did not appear to affect test accuracy. Of the patients with a preliminary Duke classification of "possible PVE," 84% received a more conclusive final diagnosis of "definite" or "rejected" PVE after the PET/CT study. CONCLUSIONS AND RELEVANCE: 18F-FDG PET/CT has high sensitivity and specificity in diagnosing PVE and the diagnostic utility is greatest in patients with a preliminary Duke classification of "possible PVE." Some patient factors appear to affect test accuracy, though these results should be interpreted with caution given low patient numbers for subgroup analyses.

Fluid shear stress promotes embryonic stem cell pluripotency via interplay between ß-catenin and vinculin in bioreactor culture.

The expansion of pluripotent stem cells (PSCs) as aggregates in stirred suspension bioreactors is garnering attention as an alternative to adherent culture. However, the hydrodynamic environment in the bioreactor can modulate PSC behavior, pluripotency and differentiation potential in ways that need to be well understood. In this study, we investigated how murine embryonic stem cells (mESCs) sense fluid shear stress and modulate a noncanonical Wnt signaling response to promote pluripotency. mESCs showed higher expression of pluripotency marker genes, Oct4, Sox2, and Nanog in the absence of leukemia inhibitory factor (LIF) in stirred suspension bioreactors compared to adherent culture, a phenomenon we have termed mechanopluripotency. In bioreactor culture, fluid shear promoted the nuclear translocation of the less well-known pluripotency regulator ß-catenin and concomitant increase of c-Myc expression, an upstream regulator of Oct4, Sox2, and Nanog. We also observed similar ß-catenin nuclear translocation in LIF-free mESCs cultured on E-cadherin substrate under defined fluid shear stress conditions in flow chamber plates. mESCs showed lower shear-induced expression of pluripotency marker genes when ß-catenin was inhibited, suggesting that ß-catenin signaling is crucial to mESC mechanopluripotency. Key to this process is vinculin, which is known to rearrange and associate more strongly with adherens junctions in response to fluid shear. When the vinculin gene is disrupted, we observe that nuclear ß-catenin translocation and mechanopluripotency are abrogated. Our results indicate that mechanotransduction through the adherens junction complex is important for mESC pluripotency maintenance.

Quantitative Susceptibility Mapping for Characterization of Intraplaque Hemorrhage and Calcification in Carotid Atherosclerotic Disease.

BACKGROUND: Carotid artery intraplaque hemorrhage (IPH), an unstable component of atherosclerosis, is associated with an increased risk of stroke. PURPOSE: To investigate quantitative susceptibility mapping (QSM) as a tool for the evaluation of IPH and calcification in vivo. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers and 15 patients. FIELD STRENGTH/SEQUENCE: 3.0T Susceptibility-weighted imaging (SWI), magnetization-prepared rapid acquisition with gradient echo (MP-RAGE), T1 -weighted sampling perfection with application of optimized contrasts using different flip angle evolution (T1 -SPACE), T2 -weighted turbo spin-echo (T2 WI), and time-of-flight (TOF) sequences. ASSESSMENT: The vessel wall area of the carotid artery was measured with QSM and compared with T1 -SPACE on healthy volunteers. Four radiologists, blinded to clinical history and patient identity, determined the presence and area of IPH on MP-RAGE and QSM, as well as the area of calcification on T1 -SPACE and QSM. STATISTICAL TESTS: Bland-Altman analysis, Pearson correlation coefficients, linear regression analyses were performed to evaluate the concordance of area measurements. Cohen's kappa (κ) was analyzed to determine the agreement between IPH detections. The paired t-test was used to compare the group differences. RESULTS: In 423 matched slices, 20.1% (85/423) and 19.6% (83/423) were detected to have IPH on MP-RAGE and QSM, respectively. IPH detection by QSM and MP-RAGE showed good agreement (κ = 0.822, P < 0.001) between the two methods. There was no significant difference in IPH area measurements between QSM and MP-RAGE (7.28 mm2 ± 6.41 vs. 7.16 mm2 ± 5.99, P = 0.575). There was no significant difference in calcification area measurement between QSM and T1 -SPACE (3.51 mm2 ± 1.78 vs. 3.41 mm2 ± 2.02, P = 0.783). DATA CONCLUSION: QSM is a novel imaging tool for the identification of IPH in patients with carotid atherosclerosis and enables differentiation of IPH and calcification. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1 J. Magn. Reson. Imaging 2020;52:534-541.

Obstructive Lymphangitis Precedes Colitis in Murine Norovirus-Infected Stat1-Deficient Mice.

Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1-/- mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1-/- mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti-IFN-γ and anti-tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαßγr-/- mice suggested that canonical signaling via interferon receptors did not cause MNV-4-induced disease. Infected Stat1-/- mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1-/- mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4-infected Stat1-/- mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host.

Embolisation for pulmonary arteriovenous malformation.

BACKGROUND: Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. This is an update of a previously published review. OBJECTIVES: To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 10 April 2017.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 27 August 2017). to be updatedWe checked cross-references and searched references from review articles. SELECTION CRITERIA: Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. DATA COLLECTION AND ANALYSIS: Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. MAIN RESULTS: There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation is a safe procedure which reduces morbidity and mortality. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.

Angioplasty versus stenting for infrapopliteal arterial lesions in chronic limb-threatening ischaemia.

BACKGROUND: Chronic limb-threatening ischaemia (CLTI) is a manifestation of peripheral arterial disease (PAD) that includes chronic ischaemic rest pain or ischaemic skin lesions, ulcers, or gangrene for longer than two weeks. The severity of the disease depends on the extent of arterial stenosis and the availability of collateral circulation. Treatment for CLTI aims to relieve ischaemic pain, heal ischaemic ulcers, prevent limb loss, improve quality of life, and prolong survival. CLTI due to occlusive disease in the infrapopliteal arterial circulation (below-knee circulation) can be treated via an endovascular technique by a balloon opening the narrowed vessel, so called angioplasty, with or without the additional deployment of a scaffold made of metal alloy or other material, so called stenting. Endovascular interventions in the infrapopliteal vasculature may improve symptoms in patients with CLTI by re-establishing in-line blood flow to the foot. Controversy remains as to whether a balloon should be used alone to open the vessel, or whether a stent should also be deployed. OBJECTIVES: To determine the efficacy and safety of percutaneous transluminal angioplasty (PTA) alone versus PTA with stenting of infrapopliteal arterial lesions (anterior tibial artery, posterior tibial artery, fibular artery (formerly known as peroneal artery), and common tibioperoneal trunk) for patients with chronic limb-threatening ischaemia (CLTI). SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, as well as World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 25 June 2018. We applied no language restrictions. SELECTION CRITERIA: We planned to include randomised or quasi-randomised controlled trials comparing PTA versus PTA with a stent and including patients aged 18 years or over with CLTI. We defined CLTI as Fontaine stage III (ischaemic rest pain) and IV (ischaemic ulcers or gangrene) or consistent with Rutherford category 4 (ischaemic rest pain), 5 (minor tissue loss), and 6 (major tissue loss), with stenotic (> 50% luminal loss) or occluded infrapopliteal artery, including tibiofibular trunk, anterior tibial artery, posterior tibial artery, and fibular artery. We included all types of stents irrespective of design (e.g. bare-metal, drug-eluting, bio-absorbable). DATA COLLECTION AND ANALYSIS: Two review authors (CC-TH and GNCK) independently selected suitable trials, assessed trial quality, and extracted data. An additional third review author (MLvD) assessed trial quality and, when necessary, acted as arbiter for study selection and data extraction. Outcomes included technical success of the procedure, procedural complications, patency, major amputation, and mortality. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included in the review seven trials with 542 participants. One trial randomised limbs to undergo PTA alone or PTA with stent placement, and the remaining studies randomised participants. Five trials with 476 participants show that the technical success rate was greater in the stent group than in the angioplasty group (odds ratio (OR) 3.00, 95% confidence interval (CI) 1.14 to 7.93; 476 lesions; 5 studies; I² = 23%). Meta-analysis of three eligible trials with 456 participants did not show a clear difference in short-term (within six months) patency between infrapopliteal arterial lesions treated with PTA and those treated with PTA and stenting (OR 0.88, 95% CI 0.37 to 2.11; 456 lesions; 3 studies; I² = 77%). Results also did not show clear differences between treatment groups in procedure complication rate (OR 0.87, 95% CI 0.01 to 53.60; 360 participants; 5 studies; I² = 85%), rate of major amputations at 12 months (OR 1.34, 95% CI 0.56 to 3.22; 306 participants; 4 studies; I² = 0%), and rate of mortality at 12 months (OR 0.71, 95% CI 0.43 to 1.17; 497 participants; 6 studies; I² = 0%). Heterogeneity between studies was high for the outcomes procedure complications and primary patency. The overall methodological quality of the trials included in this review was moderate due to selection and performance bias. Studies used different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication. We downgraded the certainty of the overall evidence for all outcomes by one level to moderate due to inconsistency of results across studies and large confidence intervals (small numbers of trials and participants). AUTHORS' CONCLUSIONS: Trials show that the immediate technical success rate of restoring luminal patency is higher in the stent group but reveal no clear differences in short-term patency at six months between infrapopliteal arterial lesions treated with PTA with stenting versus those treated with PTA without stenting. We ascertained no clear differences between groups in periprocedural complications, major amputation, and mortality. However, use of different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication and the duration of its use within and between trials may have influenced the outcomes. Limited currently available data suggest that high-quality evidence is insufficient to show that PTA with stent insertion is superior to use of standard PTA alone without stenting for treatment of infrapopliteal arterial lesions. Further studies should standardise the use of antiplatelets/anticoagulants before and after the intervention to improve the comparability of the two treatments.

Venous cutdown versus the Seldinger technique for placement of totally implantable venous access ports.

BACKGROUND: Totally implantable venous access ports (TIVAPs) provide patients with a safe and permanent venous access, for instance in the administration of chemotherapy for oncology patients. There are several methods for TIVAP placement, and the optimal evidence-based method is unclear. OBJECTIVES: To compare the efficacy and safety of three commonly used techniques for implanting TIVAPs: the venous cutdown technique, the Seldinger technique, and the modified Seldinger technique. This review includes studies that use Doppler or real-time two-dimensional ultrasonography for locating the vein in the Seldinger technique. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Cochrane Vascular Specialised Register (last searched August 2015) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 7), as well as clinical trials registers. SELECTION CRITERIA: We included randomised or quasi-randomised controlled clinical trials that randomly allocated people requiring TIVAP to the venous cutdown, Seldinger, or modified Seldinger technique. Two review authors independently assessed studies for inclusion eligibility, with a third review author checking excluded studies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We assessed all studies for risk of bias. We assessed heterogeneity using Chi(2) statistic and variance (I(2)statistic) methods. Dichotomous outcomes, summarised as odds ratio (OR) with 95% confidence interval (CI), were: primary implantation success, complications (in particular infection), pneumothorax, and catheter complications. We conducted separate analyses to assess the two access veins, subclavian and internal jugular (IJ) vein, in the Seldinger technique versus the venous cutdown technique. We used both intention-to-treat (ITT) and on-treatment analyses and pooled data using a fixed-effect model. MAIN RESULTS: We included nine studies with a total of 1253 participants in the review. Five studies compared Seldinger technique (subclavian vein access) with venous cutdown technique (cephalic vein access). Two studies compared Seldinger (IJ vein) versus venous cutdown (cephalic vein). One study compared the modified Seldinger technique (cephalic vein) with the venous cutdown (cephalic vein), and one study compared the Seldinger (subclavian vein) versus the Seldinger (IJ vein) technique.Seldinger technique (subclavian or IJ vein access) versus venous cutdown (cephalic vein): We included seven trials with 1006 participants for analysis. Both ITT (OR 0.40; 95% CI 0.25 to 0.65) and on-treatment analysis (OR 0.59; 95% CI 0.36 to 0.98) showed that the Seldinger technique for implantation of TIVAP had a higher success rate compared with the venous cutdown technique. We found no difference between overall peri- and postoperative complication rates: ITT (OR 1.16; 95% CI 0.76 to 1.75) and on-treatment analysis (OR 0.93; 95% CI 0.62 to 1.40). In the Seldinger group, the majority of the trials reported use of the subclavian vein for venous access, with only a limited number of trials utilising the IJ vein for access. When individual complication rates of infection, pneumothorax, and catheter complications were analysed, the Seldinger technique (subclavian vein access) was associated with a higher rate of catheter complications compared to the venous cutdown technique: ITT (OR 6.77; 95% CI 2.31 to 19.79) and on-treatment analysis (OR 6.62; 95% CI 2.24 to 19.58). There was no difference in incidence of infections, pneumothorax, and other complications between the groups.Modified Seldinger technique (cephalic vein) versus venous cutdown (cephalic vein): We identified one trial with 164 participants. ITT analysis showed no difference in primary implantation success rate between the modified Seldinger technique (69/82, 84%) and the venous cutdown technique (66/82, 80%), P = 0.686. We observed no differences in the peri- or postoperative complication rates.Seldinger (subclavian vein access) versus Seldinger (IJ vein access): We identified one trial with 83 participants. The primary success rate was 84% (37/44) for Seldinger (subclavian vein) versus 74% (29/39) for the Seldinger (IJ vein). There was a higher overall complication rate in the subclavian group (48%) compared to the jugular group (23%), P = 0.02. However, when specific complications were compared individually, we found no differences between the groups.The overall quality of the trials included in this review was moderate. The methods used for randomisation were inadequate in four of the nine included studies, but sensitivity analysis excluding these trials did not alter the outcome. The nature of the interventions, either venous cutdown or Seldinger techniques, meant that it was not feasible to blind the participant or personnel, therefore we judged this to be at low risk of bias. The majority of participants in the included trials were oncology patients at tertiary centres, and the outcomes were applicable to the typical clinical scenario. For all outcomes, when comparing venous cutdown and Seldinger technique, serious imprecision was evident by wide confidence intervals in the included trials. The quality of the overall evidence was therefore downgraded from high to moderate. Due to the limited number of included studies we were unable to assess publication bias. AUTHORS' CONCLUSIONS: Moderate-quality evidence showed that the Seldinger technique has a higher primary implantation success rate compared with the venous cutdown technique. The majority of trials using the Seldinger technique used the subclavian vein for venous access, and only a few trials reported the use of the internal jugular vein for venous access. Moderate-quality evidence showed no difference in the overall complication rate between the Seldinger and venous cutdown techniques. However, when the Seldinger technique with subclavian vein access was compared with the venous cutdown group, there was a higher reported incidence of catheter complications. The rates of pneumothorax and infection did not differ between the Seldinger and venous cutdown group. We identified only one trial for each of the comparisons modified Seldinger technique (cephalic vein) versus venous cutdown (cephalic vein) and Seldinger (subclavian vein access) versus Seldinger (IJ vein access), thus a definitive conclusion cannot be drawn for these comparisons and further research is recommended.

Embolisation for pulmonary arteriovenous malformation.

BACKGROUND: Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. OBJECTIVES: To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 31 March 2014.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 1 July 2014).We checked cross-references and searched references from review articles. SELECTION CRITERIA: Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. DATA COLLECTION AND ANALYSIS: Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. MAIN RESULTS: There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation reduces morbidity. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.

Neurocognitive impairment in Susac syndrome: Magnetic resonance imaging and Tc-99m hexamethylpropyleneamine oxime single photon emission computed tomography correlation.

Susac syndrome is a clinical triad of branch retinal artery occlusions, sensorineural hearing loss, and encephalopathy. The characteristic central corpus callosum involvement in Susac syndrome is readily recognizable on conventional magnetic resonance imaging (MRI); however, the neurocognitive effect of these lesions is not well-understood. We present a case of Susac syndrome with typical MRI findings of central callosal lesions at diagnosis. The patient had a protracted clinical course and did not respond well to immunosuppression therapy. Follow-up brain single photon emission computed tomography with Tc-99m hexamethylpropyleneamine oxime revealed marked unilateral frontoparietal and temporal lobe hypoperfusion. Our case highlights the utility of functional neuroimaging to uncover the possible underlying white matter dysfunction, which is not otherwise detectable with conventional MRI techniques.

A retinoid analogue, TTNPB, promotes clonal expansion of human pluripotent stem cells by upregulating CLDN2 and HoxA1.

Enzymatic dissociation of human pluripotent stem cells (hPSCs) into single cells during routine passage leads to massive cell death. Although the Rho-associated protein kinase inhibitor, Y-27632 can enhance hPSC survival and proliferation at high seeding density, dissociated single cells undergo apoptosis at clonal density. This presents a major hurdle when deriving genetically modified hPSC lines since transfection and genome editing efficiencies are not satisfactory. As a result, colonies tend to contain heterogeneous mixtures of both modified and unmodified cells, making it difficult to isolate the desired clone buried within the colony. In this study, we report improved clonal expansion of hPSCs using a retinoic acid analogue, TTNPB. When combined with Y-27632, TTNPB synergistically increased hPSC cloning efficiency by more than 2 orders of magnitude (0.2% to 20%), whereas TTNPB itself increased more than double cell number expansion compared to Y-27632. Furthermore, TTNPB-treated cells showed two times higher aggregate formation and cell proliferation compared to Y-27632 in suspension culture. TTNPB-treated cells displayed a normal karyotype, pluripotency and were able to stochastically differentiate into all three germ layers both in vitro and in vivo. TTNBP acts, in part, by promoting cellular adhesion and self-renewal through the upregulation of Claudin 2 and HoxA1. By promoting clonal expansion, TTNPB provides a new approach for isolating and expanding pure hPSCs for future cell therapy applications.

Modification of human BMSC with nanoparticles of polymeric biomaterials and plasmid DNA for BMP-2 secretion.

BACKGROUND: Genetic modification of human bone marrow stem cells (hBMSCs) before administration to a patient is emerging as a viable approach to creating tailored cells that perform effectively in a clinical setting. To this end, safe delivery systems are needed that can package therapeutic genes into nanoparticles for cellular delivery. METHODS: We evaluated different plasmids on gene expression and compared the effective plasmids directly in hBMSCs. Then, we evaluated the transfection efficiencies of the polymeric carriers linoleic acid-substituted polyethylenimine (PEI-LA), polyethylenimine (PEI)-25, and PEI-2 using flow cytometry. We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to compare the toxicity of PEI-LA and PEI-25 on hBMSCs. We further assessed bone morphogenetic protein-2 (BMP-2) secretion and the osteogenic activity of hBMSCs transfected with the polymeric (PEI-LA and PEI-25) gWIZ-BMP-2 complex. RESULTS: Unlike the transformed cells that gave robust (>50%) transfection, only a few percent (<10%) of hBMSCs was transfected by the developed nanoparticles in culture. The plasmid DNA design was critical for expression of the transgene product, with the choice of the right promoter clearly enhancing the efficiency of transgene expression. Using the in-house designed PEI-LA, hBMSCs secreted BMP-2 in culture (~4 ng BMP-2/10(6) cells/d), which indicates the feasibility of using PEI-LA as a delivery system. Furthermore, we demonstrated an increased osteogenic activity in vitro for hBMSCs transfected with the PEI-LA containing the BMP-2 expression system. CONCLUSIONS: These results provide encouraging evidence for the potential use of a low toxic PEI-LA to genetically modify hBMSC.

The Current State of Susceptibility-Weighted Imaging and Quantitative Susceptibility Mapping in Head Trauma.

Susceptibility-weighted imaging (SWI) is a MR imaging technique suited to detect structural and microstructural abnormalities in traumatic brain injury (TBI). This review article provide an insight in to the physics principles of SWI and its clinical application in unraveling the complex interaction of the biophysical mechanisms of head injury. Literature evidences support SWI as the most ideal sequence in detection of microbleeds, which is the "tip of the iceberg" biomarker of microvascular injuries. The review also detailed the emerging advance techniques of Quantitative susceptibility mapping (QSM) and artificial intelligence offer the ability to detect and follow the evolution of microbleeds in patient with chronic TBI. These new techniques offers a unique insight into the acute and chronic state of TBI.

ALDH1A Inhibition Suppresses Colitis and Alters α4ß7 Integrin Expression on Activated T Cells in Mdr1a-/- Mice.

There are limited pharmacological treatment options for inflammatory bowel disease (IBD), and some of these options are expensive and administered by injection or infusion. Thus, new cheaper and easier (oral) treatment options are needed. ALDH1A enzymes produce retinoic acid that can affect intestinal diseases such as IBD by regulating immune cells in the gut. We previously demonstrated that an orally deliverable ALDH1A inhibitor, WIN 18,466, can suppress colitis in an acute mouse model of IBD. Here, we tested the efficacy of ALDH1A inhibition in a chronic mouse model of IBD. Mdr1a-/- mice were treated with a diet containing WIN 18,446 starting 1 week prior to inducing colitis by H. bilis inoculation. Treatment was continued until the study end point and colitis was monitored based on clinical symptoms and confirmed by histological analysis. Immune cell phenotypes in colon-draining lymph nodes (cMLN) were analyzed. WIN 18,446 treatment reduced clinical symptoms and improved histopathologic colitis scores. This was associated with decreased expression of the gut homing integrin, α4ß7, on T cells in cMLN; increased expression of CD103, a protein associated with tissue-resident memory T cells; and changes in dendritic cells, plasmacytoid dendritic cells and B cells in inhibitor-treated mice. ALDH1A inhibition broadly influences immune cells during colitis and is a potential new target for IBD treatment. Future studies will be needed to determine the efficacy of ALDH1A inhibition on active colitis and to evaluate its relative efficacy in comparison to approved drugs.

Yellow droopy eyes: A case of obstructive jaundice from Burkitt's lymphoma with involvement of bilateral cavernous sinus.

Burkitt's lymphoma follows a lymphogenous spread early in the disease. The central nervous system can be involved via a hematogenous route but involvement of the cavernous sinus (CS) is rare and can be misdiagnosed as other pathology of primary neoplastic, infective, or vascular origin. We present a case of a 73-year-old gentleman with painless jaundice and subjective heaviness to his eyes that progressed to partial ptosis of the left eye, complete ptosis of the right eye with diplopia, found to have disseminated Burkitt's lymphoma with bilateral deposits to the CS. Early recognition of Burkitt's lymphoma with CS involvement is important as it often signifies disseminated disease with implications on chemotherapy regimen, treatment outcomes, and survival.

Susceptibility weighted imaging for qualitative grading of persistent arteriovenous shunting in deep-seated arteriovenous malformations after stereotactic radiation surgery.

BACKGROUND AND PURPOSE: To investigate Susceptibility Weighted Imaging (SWI) signal changes in the draining vein of deep-seated arterio-venous malformations (AVMs) following stereotactic radiosurgery (SRS). METHODS AND MATERIALS: This is a retrospective study of 32 patients with deep-seated AVMs who were treated with SRS. Pre-SRS treatment and post-SRS treatment MRI were performed at 6, 12, and 24-month intervals. Deep-seated AVMs were classified based on their anatomical location and venous drainage pattern. AVM nidal volume (cm3) was estimated using the ABC/2 method. AV shunting of the AVM draining veins were graded according to its SWI signal intensity: hyperintense (grade III), mixed signal intensity (grade II), hypointense (grade I) and absent (grade 0). Conventional time-of-flight (TOF)-MRA and contrast enhanced (CE)-MRA sequences were performed to document the patency of the vein. RESULTS: Pre-SRS treatment AVM draining veins were either grade III 18/32 (56%) or grade II 14/32 (44%). Using mixed effects analysis, we demonstrate that each month following the SRS treatment nidal volumes decreased at the rate of 0.51 cm3/per month (CI -0.61 to (-0.40)) p =.00. Following the treatment, there was a clinically significant relationship between the signal and nidal volume: signal 0 corresponded with average nidal volume of 1.81 cm3 (CI 1.40-2.21), signal 1 with nidal volume of 2.06 cm3 (CI 1.69-2.44), signal 2 with nidal volume 2.73 cm3 (CI 2.35-3.11) and signal 3 with nidal volume 3.13 cm3 (CI 2.70-3.56) p = .00. CONCLUSION: Post-SRS AVM draining veins shows a stepwise regression of the SWI signal grades which can be reliably used as a surrogate to monitor the reduction of AV shunting.

Distal aortic perfusion during thoracoabdominal aneurysm repair for prevention of paraplegia.

BACKGROUND: During thoracoabdominal aortic aneurysm (TAAA) surgery, decreased spinal cord perfusion can result in neurological deficits such as paraplegia and paraparesis. Distal aortic perfusion, alone or in combination with other adjuncts, may counter the decrease in spinal cord perfusion and hence reduce the risk of spinal cord injury. OBJECTIVES: To determine the effectiveness of distal aortic perfusion with or without other adjuncts against other adjuncts without use of distal perfusion during TAAA surgery in reducing the risk of developing paraplegia and paraparesis. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Specialised Register (last searched 5 January 2012) and CENTRAL (Issue 4, 2011) were searched for publications describing randomised controlled trials of distal aortic perfusion during thoracoabdominal aortic aneurysm surgery. Reference lists of relevant studies were checked. SELECTION CRITERIA: Randomised or quasi-randomised controlled clinical trials of distal aortic perfusion during TAAA repair. DATA COLLECTION AND ANALYSIS: Studies identified for potential inclusion were independently assessed for inclusion by at least two authors, with excluded trials arbitrated by the third author. MAIN RESULTS: There were no randomised controlled trials identified. AUTHORS' CONCLUSIONS: Currently, there are no randomised controlled trials to support the role of distal aortic perfusion in TAAA surgery for prevention of neurological injury. However, randomised controlled trials are not always feasible based on ethical grounds. Observational studies suggest that distal aortic perfusion alone or in combination with other adjuncts, that is cerebrospinal fluid (CSF) drainage, reduces the rate of neurologic deficit across all types of TAAA; in particular making a striking difference in the rate of neurologic deficit following type II TAAA repair. In the absence of randomised controlled trials, we recommend a standardised approach to reporting through registry studies to strengthen the evidence base for distal aortic perfusion.