Generative Adversarial Network-Enhanced Ultra-Low-Dose [18F]-PI-2620 τ PET/MRI in Aging and Neurodegenerative Populations.

BACKGROUND AND PURPOSE: With the utility of hybrid τ PET/MR imaging in the screening, diagnosis, and follow-up of individuals with neurodegenerative diseases, we investigated whether deep learning techniques can be used in enhancing ultra-low-dose [18F]-PI-2620 τ PET/MR images to produce diagnostic-quality images. MATERIALS AND METHODS: Forty-four healthy aging participants and patients with neurodegenerative diseases were recruited for this study, and [18F]-PI-2620 τ PET/MR data were simultaneously acquired. A generative adversarial network was trained to enhance ultra-low-dose τ images, which were reconstructed from a random sampling of 1/20 (approximately 5% of original count level) of the original full-dose data. MR images were also used as additional input channels. Region-based analyses as well as a reader study were conducted to assess the image quality of the enhanced images compared with their full-dose counterparts. RESULTS: The enhanced ultra-low-dose τ images showed apparent noise reduction compared with the ultra-low-dose images. The regional standard uptake value ratios showed that while, in general, there is an underestimation for both image types, especially in regions with higher uptake, when focusing on the healthy-but-amyloid-positive population (with relatively lower τ uptake), this bias was reduced in the enhanced ultra-low-dose images. The radiotracer uptake patterns in the enhanced images were read accurately compared with their full-dose counterparts. CONCLUSIONS: The clinical readings of deep learning-enhanced ultra-low-dose τ PET images were consistent with those performed with full-dose imaging, suggesting the possibility of reducing the dose and enabling more frequent examinations for dementia monitoring.

Investigating Simultaneity for Deep Learning-Enhanced Actual Ultra-Low-Dose Amyloid PET/MR Imaging.

BACKGROUND AND PURPOSE: Diagnostic-quality amyloid PET images can be created with deep learning using actual ultra-low-dose PET images and simultaneous structural MR imaging. Here, we investigated whether simultaneity is required; if not, MR imaging-assisted ultra-low-dose PET imaging could be performed with separate PET/CT and MR imaging acquisitions. MATERIALS AND METHODS: We recruited 48 participants: Thirty-two (20 women; mean, 67.7 [SD, 7.9] years) were used for pretraining; 328 (SD, 32) MBq of [18F] florbetaben was injected. Sixteen participants (6 women; mean, 71.4 [SD. 8.7] years of age) were scanned in 2 sessions, with 6.5 (SD, 3.8) and 300 (SD, 14) MBq of [18F] florbetaben injected, respectively. Structural MR imaging was acquired simultaneously with PET (90-110 minutes postinjection) on integrated PET/MR imaging in 2 sessions. Multiple U-Net-based deep networks were trained to create diagnostic PET images. For each method, training was done with the ultra-low-dose PET as input combined with MR imaging from either the ultra-low-dose session (simultaneous) or from the standard-dose PET session (nonsimultaneous). Image quality of the enhanced and ultra-low-dose PET images was evaluated using quantitative signal-processing methods, standardized uptake value ratio correlation, and clinical reads. RESULTS: Qualitatively, the enhanced images resembled the standard-dose image for both simultaneous and nonsimultaneous conditions. Three quantitative metrics showed significant improvement for all networks and no differences due to simultaneity. Standardized uptake value ratio correlation was high across different image types and network training methods, and 31/32 enhanced image pairs were read similarly. CONCLUSIONS: This work suggests that accurate amyloid PET images can be generated using enhanced ultra-low-dose PET and either nonsimultaneous or simultaneous MR imaging, broadening the utility of ultra-low-dose amyloid PET imaging.

Hippocampal subfield imaging and fractional anisotropy show parallel changes in Alzheimer's disease tau progression using simultaneous tau-PET/MRI at 3T.

INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by abnormal aggregation of two proteins, tau and amyloid beta. We assessed tau pathology and white matter connectivity changes in subfields of the hippocampus simultaneously in vivo in AD. METHODS: Twenty-four subjects were scanned using simultaneous time-of-flight 18F-PI-2620 tau positron emission tomography/3-Tesla magnetic resonance imaging and automated segmentation. RESULTS: We observed extensive tau elevation in the entorhinal/perirhinal regions, intermediate tau elevation in cornu ammonis 1/subiculum, and an absence of tau elevation in the dentate gyrus, relative to controls. Diffusion tensor imaging showed parahippocampal gyral fractional anisotropy was lower in AD and mild cognitive impairment compared to controls and strongly correlated with early tau accumulation in the entorhinal and perirhinal cortices. DISCUSSION: This study demonstrates the potential for quantifiable patterns of 18F-PI2620 binding in hippocampus subfields, accompanied by diffusion and volume metrics, to be valuable markers of AD.

A floating wide-band current source for electrical impedance tomography.

The quality of reconstructed images in Electrical Impedance Tomography (EIT) depends on two essential factors: first, precision of the EIT hardware in current injection and voltage measurement and second, efficiency of its image reconstruction algorithm. Therefore the current source plays an important and a vital role in EIT instruments. Floating-load current sources constructed using sink and source drivers have better performance and higher output impedance than grounded-load (single-ended) current sources. In addition, a main feature of this kind is that the current source is not connected to the ground potential directly but via a large impedance. In this paper, we first focus on recent studies on designed EIT current sources, and after that, a practical design of a floating-load high output impedance current source-operating over a wide frequency band-will be proposed in detail. Simulation results of the proposed voltage-controlled current source (VCCS), along with some other models, will be shown and compared. At the end, the results of practical tests on the VCCS and a few EIT images, taken using our prototype EIT system coupled with the mentioned VCCS, will be illustrated which proves the quality of the proposed current source.

Memory effects on epidemic evolution: The susceptible-infected-recovered epidemic model.

Memory has a great impact on the evolution of every process related to human societies. Among them, the evolution of an epidemic is directly related to the individuals' experiences. Indeed, any real epidemic process is clearly sustained by a non-Markovian dynamics: memory effects play an essential role in the spreading of diseases. Including memory effects in the susceptible-infected-recovered (SIR) epidemic model seems very appropriate for such an investigation. Thus, the memory prone SIR model dynamics is investigated using fractional derivatives. The decay of long-range memory, taken as a power-law function, is directly controlled by the order of the fractional derivatives in the corresponding nonlinear fractional differential evolution equations. Here we assume "fully mixed" approximation and show that the epidemic threshold is shifted to higher values than those for the memoryless system, depending on this memory "length" decay exponent. We also consider the SIR model on structured networks and study the effect of topology on threshold points in a non-Markovian dynamics. Furthermore, the lack of access to the precise information about the initial conditions or the past events plays a very relevant role in the correct estimation or prediction of the epidemic evolution. Such a "constraint" is analyzed and discussed.

Clinical evaluation of TOF versus non-TOF on PET artifacts in simultaneous PET/MR: a dual centre experience.

PURPOSE: Our objective was to determine clinically the value of time-of-flight (TOF) information in reducing PET artifacts and improving PET image quality and accuracy in simultaneous TOF PET/MR scanning. METHODS: A total 65 patients who underwent a comparative scan in a simultaneous TOF PET/MR scanner were included. TOF and non-TOF PET images were reconstructed, clinically examined, compared and scored. PET imaging artifacts were categorized as large or small implant-related artifacts, as dental implant-related artifacts, and as implant-unrelated artifacts. Differences in image quality, especially those related to (implant) artifacts, were assessed using a scale ranging from 0 (no artifact) to 4 (severe artifact). RESULTS: A total of 87 image artifacts were found and evaluated. Four patients had large and eight patients small implant-related artifacts, 27 patients had dental implants/fillings, and 48 patients had implant-unrelated artifacts. The average score was 1.14 ± 0.82 for non-TOF PET images and 0.53 ± 0.66 for TOF images (p < 0.01) indicating that artifacts were less noticeable when TOF information was included. CONCLUSION: Our study indicates that PET image artifacts are significantly mitigated with integration of TOF information in simultaneous PET/MR. The impact is predominantly seen in patients with significant artifacts due to metal implants.

Light Chain Podocytopathy Mimicking Recurrent Focal Segmental Glomerulosclerosis.

Kidney injury related to paraproteinemia is common and typically occurs after the fourth decade of life in association with an underlying plasma cell dyscrasia or other lymphoproliferative disease. Kidney transplantation in paraprotein-related kidney disease can be successful in conjunction with treatment of the underlying hematopoietic process; however, when hematologic response to therapy is not achieved, recurrent kidney injury is frequently seen. We describe a young male patient who presented at the age of 23 years with end-stage kidney disease thought to be secondary to focal segmental glomerulosclerosis; this patient ultimately received two kidney allografts. He experienced recurrent proteinuria in both kidneys, with a biopsy from his second allograft showing kappa-restricted crystalline light chain podocytopathy, which was identified in both his native and first allograft kidneys upon retrospective review. Recurrent light chain podocytopathy has not been previously reported but poses a diagnostic challenge as it can mimic focal segmental glomerulosclerosis, particularly in young patients in whom paraprotein-related kidney injury is usually not suspected.

Evaluating the efficacy of probiotic on treatment in patients with small intestinal bacterial overgrowth (SIBO)--a pilot study.

BACKGROUND & OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) leads to several gastrointestinal (GI) problems and complications leading to malabsorption. The effectiveness of probiotics in the treatment of SIBO syndrome has not been well studied. This pilot study was aimed to assess the efficacy of a probiotic consisting of lactobacilli in the treatment of SIBO. METHODS: In this study, 30 cases suffering from chronic abdominal pain or diarrhoea and with a positive hydrogen breath test were randomized in a double-blind manner into two groups: probiotic drug user and control group. After an initial 3-week aggressive therapy with broad-spectrum antibiotics, a 15-day maintenance antibiotic therapy with lactol was administered for the study group and the same regimen without lactol for the control group. After six months the HBT result and the GI symptoms were analyzed and compared between the two groups. RESULTS: The result of hydrogen breath test and the clinical symptoms in patients receiving the maintenance regimen with lactol probiotic showed a better response. The hydrogen breath test turned negative in 93.3 per cent of those receiving lactol compared to 66.7 per cent of the controls. In all the cases receiving lactol, the abdominal pain disappeared completely ( p =0.002). In addition, other GI problems including flatulence, belching and diarrhoea significantly improved in the study group ( p < 0.05). INTERPRETATION & CONCLUSIONS: Based on the preliminary data it seems that adding lactol probiotic to the maintenance therapy of small intestinal bacterial overgrowth patients on routine antibiotic therapy will be beneficial in preventing the complications of this syndrome.

Inhibition of human prenatal biosynthesis of all-trans-retinoic acid by ethanol, ethanol metabolites, and products of lipid peroxidation reactions: a possible role for CYP2E1.

Biotransformation of all-trans-retinol (t-ROH) and all-trans-retinal (t-RAL) to all-trans-retinoic acid (t-RA) in human prenatal hepatic tissues (53-84 gestational days) was investigated with HPLC using human adult hepatic tissues as positive controls. Catalysis of the biotransformation of t-ROH by prenatal human cytosolic fractions resulted in accumulation of t-RAL with minimal t-RA. Oxidations of t-ROH catalyzed by prenatal cytosol were supported by both NAD+ and NADP+, although NAD+ was a much better cofactor. In contrast, catalysis of the oxidation of t-RAL to t-RA appeared to be solely NAD+ dependent. Substrate Km values for conversions of t-ROH to t-RAL and of t-RAL to t-RA were 82.4 and 65.8 microM, respectively. At concentrations of 10 and 90 mM, ethanol inhibited the conversion of t-ROH to t-RAL by 25 and 43%, respectively, but did not inhibit the conversion of t-RAL to t-RA significantly. In contrast, acetaldehyde reduced the conversion of t-RAL to t-RA by 25 and 87% at 0.1 and 10 mM respective concentrations. Several alcohols and aldehydes known to be generated from lipid peroxides also exhibited significant inhibition of t-RA biosynthesis in human prenatal hepatic tissues. Among the compounds tested, 4-hydroxy-2-nonenal (4-HNE) was highly effective in inhibiting the conversion of t-RAL to t-RA. A 20% inhibition was observed at a concentration of only 0.001 mM, and nearly complete inhibition was produced at 0.1 mM. Human fetal and embryonic hepatic tissues each exhibited significant CYP2E1 expression as assessed with chlorzoxazone 6-hydroxylation, a highly sensitive western blotting technique, and reverse transcriptase-polymerase chain reaction (PCR) (RT-PCR), suggesting that lipid peroxidation can be initiated via CYP2E1-catalyzed ethanol oxidation in human embryonic hepatic tissues. In summary, these studies suggest that ethanol may affect the biosynthesis of t-RA in human prenatal hepatic tissues directly and indirectly. Ethanol and its major oxidative metabolite, acetaldehyde, both inhibit the generation of t-RA. Concurrently, the CYP2E1-catalyzed oxidation of ethanol can initiate lipid peroxidation via generation of a variety of free radicals. The lipid peroxides thereby generated could then be further converted via CYP2E1-catalyzed reactions to alcohols and aldehydes, including 4-HNE, that act as potent inhibitors of t-RA synthesis.

Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.

Cytochrome P450 3A (CYP3A) metabolizes a diverse array of clinically important drugs. For some of these (e.g., cyclosporine, verapamil, midazolam), CYP3A in the intestinal mucosa contributes to their extensive and variable first-pass extraction. To further characterize this phenomenon, we measured CYP3A content and catalytic activity toward the probe substrate midazolam in mucosa isolated from duodenal, jejunal and ileal sections of 20 human donor intestines. For comparison, the same measurements were performed for 20 human donor livers, eight of which were obtained from the same donors as eight of the intestines. Excellent correlations existed between homogenate and microsomal CYP3A content for the three intestinal regions. Median microsomal CYP3A content was greatest in the duodenum and lowest in the ileum (31 vs. 17 pmol/mg of protein). With respect to midazolam 1'-hydroxylation kinetics, the median Km for each intestinal region was similar to the median hepatic Km, approximately 4 microM. In contrast, the median Vmax decreased from liver to duodenum to jejunum to ileum (850 vs. 644 vs. 426 vs. 68 pmol/min/mg). Intrinsic clearance (Vmax/Km) followed a similar trend for the intestinal regions; median duodenal intrinsic clearance was comparable to hepatic intrinsic clearance (157 and 200 microl/min/mg, respectively). Vmax correlated with CYP3A content for all tissues except the ileum. Duodenal and jejunal Vmax and CYP3A content varied by >30-fold among donors. Microsomes prepared from every other 1-foot section of six intestines were also analyzed for CYP3A as well as for two coenzymes. In general, CYP3A activity, CYP3A content and CYP reductase activity rose slightly from duodenum to middle jejunum and then declined to distal jejunum and ileum. Cytochrome b5 content and cytochrome b5 reductase activity varied little throughout the intestinal tract. Regional intrinsic midazolam 1'-hydroxylation clearance was greatest for the jejunum, followed by the duodenum and ileum (144, 50 and 19 ml/min, respectively). Collectively, these results demonstrate that the upper small intestine serves as the major site for intestinal CYP3A-mediated first-pass metabolism and provides a rationale for interindividual differences in oral bioavailability for some CYP3A substrates.

High-titer bicistronic retroviral vectors employing foot-and-mouth disease virus internal ribosome entry site.

Bicistronic retroviral vectors were constructed containing the foot-and-mouth disease virus (FMDV) internal ribosome entry site (IRES) followed by the coding region of beta-galactosidase (beta-gal) or therapeutic genes, with the selectable neomycin phosphotransferase gene under the control of the viral long terminal repeat (LTR) promoter. LNFX, a vector with a multiple cloning site 3' to foot-and-mouth disease virus IRES, was used to construct vectors encoding rat erythropoietin (EP), rat granulocyte colony-stimulating factor (G-CSF), human adenosine deaminase (ADA) and beta-gal. In transduced primary rat vascular smooth muscle cells the cytokines were expressed at high levels, similar to those obtained from vectors employing the viral LTR promoter. LNFZ, a vector encoding beta-gal, had a 10-fold increase in titer over that of LNPoZ, a comparable vector containing the poliovirus (Po) internal ribosome entry site. Primary canine vascular smooth muscle cells infected with LNFZ and LNPoZ expressed similar activities of beta-gal and neomycin phosphotransferase (NPT). Overall, these vectors had titers between 10(6) and 2 x 10(7) c.f.u./ml, indicating that foot-and-mouth disease virus IRES provides high-titer bicistronic vectors with high-level two gene expression.

Influence of reserpine and guanethidine on the responses of the isolated rat ileum to catecholamines.

The sensitivity of the isolated ileum of the rat to catecholamines has been investigated using normal, reserpinized and guanethidine treated animals. Both reserpine and guanethidine treatment produces supersensitivity to adrenaline, noradrenaline and to a greater extent to isoprenaline.

Comparative study of beta andreoceptor antagonists on the isolated atria of control and of the reserpine treated rabbits.

The effect of four adrenoceptor antagonists, chosen because of reported differences in their selectivities, were compared using the positive chronotropic response to isoprenaline on isolated rabbit atria. Oxprenolol was the most potent antagonist of the isoprenaline induced cardiac arrhythmias. Alprenolol, practolol and propranolol also blocked the positive chronotropic responses to isoprenaline effectively. All the antagonists lowered the resting heart rate. The effects of all four selected antagonists on heart rate probably result from cardiac beta adrenoceptor blockade. Atria isolated from reserpine treated rabbits, showed a reduced percentage of increase in the heart rate in response to addition of isoprenaline. This decreased response has been related in some cases to direct myocardial inhibition.

Effects of reserpine on the responses of the isolated rat fundus strip to catecholamines and specific adrenoceptor antagonists.

The effects of reserpine on the sensitivity to catecholamines and adrenoceptor antagonists propranolol and azapetine were studied on the fundus strips of the rat. The results obtained in this study would support the view that reserpine may increase the sensitivity of beta receptor to isoprenaline and adrenaline by the mechanism which may be independent of the uptake of catecholamines in the sympathetic nervous system.