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1. Nicola Natsis, MD*,†,‡ 2. Fred Soeprono, MD, JD†,‡ 3. Aislyn Nelson, MD, PhD†,‡ 4. Victoria R. Barrio, MD†,‡ 5. Wynnis L. Tom, MD†,‡ 1. *School of Medicine, University of California, San Diego, San Diego, CA 2. †Division of Pediatric and Adolescent Dermatology, Rady Children’s Hospital, San Diego, CA 3. ‡Department of Dermatology, University of California, San Diego, San Diego, CA A boy is born at 27 weeks’ gestation with generalized erosions of the skin, facial bruising, respiratory distress, hypotension, and poor tone. His fraternal twin brother is without any skin abnormalities. Their 20-year-old Gravida 2 Para 1 mother had no complications during pregnancy and no history of sexually transmitted infections. Prenatal testing from an outside hospital was negative for syphilis, chlamydia, hepatitis B, and hepatitis C. She presented in preterm labor and was treated with steroids, magnesium, and terbutaline. Cesarean delivery was performed prior to rupture of membranes, reportedly because the infants were each in the frank breech position and this twin was having decelerations on the fetal heart tracing. The newborn’s Apgar scores are 3, 5, and 7 at 1, 5, and 10 minutes. Due to his skin erosions and prematurity, he is treated with ampicillin and cefotaxime. On day 3, he is transferred to our facility for a higher level of care. His examination reveals dry, diffuse superficial erosions on the neck, trunk, and extremities (Figs 1 and 2). Many lesions are geometric, with some more linear and angulated on the arms and legs. The back has scattered adherent hemorrhagic crusts. He also has thrombocytopenia at 52,000 platelets/mcL, hyperbilirubinemia (total/direct bilirubin 5.2/2.9 mg/dL), elevated C-reactive protein to 5.9 mg/L, and hypertriglyceridemia to 133 mg/dL. His white blood cell count and differential is normal. Additional testing confirmed the diagnosis. Figure 1. A 3-day-old boy with diffuse erosions with superficial crusting, many geometric or linear. Figure 2. Left leg with diffuse erosions with superficial crusting, many geometric or linear. The differential diagnosis for this rash includes infections such as congenital candidiasis, Staphylococcus aureus , Streptococcus pyogenes , varicella zoster virus (VZV), syphilis, and herpes simplex virus (HSV) infection. Noninfectious etiologies include …

Using amyloid PET imaging as a single primary surrogate efficacy measure in Alzheimer’s disease immunotherapy trials, as happened when the FDA granted accelerated approval of aducanumab, is unjustified. In vivo evidence indicates that PET quantification of amyloid deposition is distorted and misrepresents effects of anti-amyloid treatments due to lack of specificity of the PET imaging probe, effects of amyloid-related imaging abnormalities, spill-over from high white matter signals, and questionable quantification models. Before granting approval to other immunotherapy candidates, the FDA should require rigorous evidence of all imaging claims and irrefutable documentation that proposed treatments are clinically effective and harmless to patients.

A 12-year-old boy presented with a 2-week history of persistent pruritic edematous plaques one day after he received the first dose of the BNT162b2 COVID-19 mRNA vaccine. A skin biopsy showed urticarial dermatitis with tissue eosinophilia consistent with a diagnosis of vaccine-associated eosinophilic cellulitis, with polyethylene glycol as a potential trigger.

Background 2-(4'- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques.

In this work we have successfully hyperdoped germanium with tellurium with a concentration peak of 1021 cm−3. The resulting hyperdoped layers show good crystallinity and sub-bandgap absorption at room temperature which makes the material a good candidate for a new era of complementary metal-oxide-semiconductor-compatible short-wavelength-infrared photodetectors. We obtained absorption coefficients α higher than 4.1 × 10 3 cm−1 at least up to 3 µm. In this study we report the temperature-dependency electrical properties of the hyperdoped layer measured in van der Pauw configuration. The electrical behaviour of this hyperdoped material can be explained with an electrical bilayer coupling/decoupling model and the values for the isolated hyperdoped layer are a resistivity of 4.25 × 10 − 3 Ω ⋅ cm with an electron-mobility around −100 cm2 V−1 s−1.

The lengthy debate on the validity of the amyloid hypothesis and the usefulness of amyloid imaging and anti-amyloid therapeutic interventions in dementia continues unabated, even though none of them have been able to convince the medical world of their correctness and clinical value. There are huge financial interests associated with promoting both, but in spite of the large sums of money in their support, no effective anti-amyloid treatments or diagnostic use of amyloid imaging have emerged. There are solid scientific reasons that explain these negative results, and it is time to move forward to other promising options for the benefit of the patients.

Objectives:Geriatric depression often presents with memory and cognitive complaints that are associated with increased risk for Alzheimer’s disease (AD). In a parent clinical trial of escitalopram combined with memantine or placebo for geriatric depression and subjective memory complaints, we found that memantine improved executive function and delayed recall performance at 12 months (NCT01902004). In this report, we used positron emission tomography (PET) to assess the relationship between in-vivo amyloid and tau brain biomarkers and clinical and cognitive treatment response.Design:In a randomized double-blind placebo-controlled trial, we measured 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) binding at baseline and assessed mood and cognitive performance at baseline, posttreatment (6 months), and naturalistic follow-up (12 months).Participants:Twenty-two older adults with major depressive disorder and subjective memory complaints completed PET scans and were included in this report.Results:Across both treatment groups, higher frontal lobe [18F]FDDNP binding at baseline was associated with improvement in executive function at 6 months (corrected p = .045). This effect was no longer significant at 12 months (corrected p = .12). There was no association of regional [18F]FDDNP binding with change in mood symptoms (corrected p = .2).Conclusions:[18F]FDDNP binding may predict cognitive response to antidepressant treatment. Larger trials are required to further test the value of [18F]FDDNP binding as a biomarker for cognitive improvement with antidepressant treatment in geriatric depression.

Background and Objective Health care costs represent a substantial an increasing percentage of global expenditures. One key component is treatment of respiratory diseases, which account for one in twelve deaths in Europe. Computational simulations of lung airflow have potential to provide considerable cost reduction and improved outcomes. Such simulations require accurate in silico modeling of the lung airway. The geometry of the lung is extremely complex and for this reason very simple morphologies have primarily been used to date. The objective of this work is to develop an effective methodology for the creation of hybrid pulmonary geometries combining patient-specific models obtained from CT images and idealized pulmonary models, for the purpose of carrying out experimental and numerical studies on aerosol/particle transport and deposition in inhaled drug delivery. Methods For the construction of the hybrid numerical model, lung images obtained from computed tomography were exported to the DICOM format to be treated with a commercial software to build the patient-specific part of the model. At the distal terminus of each airway of this portion of the model, an idealization of a single airway path is connected, extending to the sixteenth generation. Because these two parts have different endings, it is necessary to create an intermediate solid to link them together. Physically realistic treatment of truncated airway boundaries in the model was accomplished by mapping of the flow velocity distribution from corresponding conducting airway segments. Results The model was verified using two sets of simulations, steady inspiration/expiration and transient simulation of forced spirometry. The results showed that the hybrid model is capable of providing a realistic description of air flow dynamics in the lung while substantially reducing computational costs relative to models of the full airway tree. Conclusions The model development outlined here represents an important step toward computational simulation of lung dynamics for patient-specific applications. Further research work may consist of investigating specific diseases, such as chronic bronchitis and pulmonary emphysema, as well as the study of the deposition of pollutants or drugs in the airways.

This article studies the physical and electrical behavior of indium tin oxide layers (ITO) grown by an unconventional technique: High Pressure Sputtering (HPS), from a ceramic ITO target in a pure Ar atmosphere. This technique has the potential to reduce plasma induced damage to the samples. The aim is to obtain, at low temperature via HPS, good quality transparent conductive oxide layers for experimental photovoltaic cells with emerging selective contacts such as transition metal oxides, alkaline metal fluorides, etc. We found that the resistivity of the films was strongly dependent on Ar pressure. To obtain device-quality resistivity without intentional heating during deposition a pressure higher than 1.0 mbar was needed. These films deposited on glass were amorphous, presented a high electron mobility (up to 45 cm2V−1s−1) and a high carrier density (2.9 × 1020 cm−3 for the sample with the highest mobility). The optimum Ar pressure range was found at 1.5–2.3 mbar. However, the resistivity degraded with a moderate annealing temperature in air. Finally, the feasibility of the integration with photovoltaic cells was assessed by depositing on Si substrates passivated by a-Si:H. The film deposited at 1.5 mbar was uniform and amorphous, and the carrier lifetime obtained was 1.22 ms with an implied open circuit voltage of 719 mV after a 215 °C air anneal. The antireflective properties of HPS ITO were also demonstrated. These results show that ITO deposited by HPS is adequate for the research of solar cells with emerging selective contacts.

Author(s): Sala-Rabanal, Monica; Ghezzi, Chiara; Hirayama, Bruce A; Kepe, Vladimir; Liu, Jie; Barrio, Jorge R; Wright, Ernest M | Abstract: KEY POINTS:The goal was to determine the importance of the sodium-glucose cotransporter SGLT1 and the glucose uniporter GLUT2 in intestinal glucose absorption during oral glucose tolerance tests (OGTTs) in mice. Glucose absorption was determined in mice using positron emission tomography and three non-metabolizable glucose probes: one specific for SGLTs, one specific for GLUTs, and one a substrate for both SGLTs and GLUTs. Absorption was determined in wild-type, Sglt1-/- and Glut2-/- mice. Gastric emptying was a rate-limiting step in absorption. SGLT1, but not GLUT2, was important in fast glucose absorption. In the absence of SGLT1 or GLUT2, the oral glucose load delivered to the small intestine was slowly absorbed. Oral phlorizin only inhibited the fast component of glucose absorption, but it contributed to decreasing blood glucose levels by inhibiting renal reabsorption. ABSTRACT:The current model of intestinal absorption is that SGLT1 is responsible for transport of glucose from the lumen into enterocytes across the brush border membrane, and GLUT2 for the downhill transport from the epithelium into blood across the basolateral membrane. Nevertheless, questions remain about the importance of these transporters in vivo. To address these questions, we have developed a non-invasive imaging method, positron emission tomography (PET), to monitor intestinal absorption of three non-metabolized glucose tracers during standard oral glucose tolerance tests (OGTTs) in mice. One tracer is specific for SGLTs (α-methyl-4-[18 F]fluoro-4-deoxy-d-glucopyranoside; Me-4FDG), one is specific for GLUTs (2-deoxy-2-[18 F]fluoro-d-glucose; 2-FDG), and one is a substrate for both SGLTs and GLUTs (4-deoxy-4-[18 F]fluoro-d-glucose; 4-FDG). OGTTs were conducted on adult wild-type, Sglt1-/- and Glut2-/- mice. In conscious mice, OGTTs resulted in the predictable increase in blood glucose that was blocked by phlorizin in both wild-type and Glut2-/- animals. The blood activity of both Me-4FDG and 4-FDG, but not 2-FDG, accompanied the changes in glucose concentration. PET imaging during OGTTs further shows that: (i) intestinal absorption of the glucose load depends on gastric emptying; (ii) SGLT1 is important for the fast absorption; (iii) GLUT2 is not important in absorption; and (iv) oral phlorizin reduces absorption by SGLT1, but is absorbed and blocks glucose reabsorption in the kidney. We conclude that in standard OGTTs in mice, SGLT1 is essential in fast absorption, GLUT2 does not play a significant role, and in the absence of SGLT1 the total load of glucose is slowly absorbed.

Caution is warranted when in vitro results of biomarkers labeled with tritium were perfunctorily used to criticize in vivo data and conclusions derived with the same tracers labeled with positron emitters and positron emission tomography (PET). This concept is illustrated herein with the PET utilization of [18F]FDDNP, a biomarker used for in vivo visualization of β-amyloid and tau protein neuroaggregates in humans, later contradicted by in vitro data reported with [3H]FDDNP. In this investigation, we analyze the multiple factors involved in the experimental design of the [3H]FDDNP in vitro study that led to the erroneous interpretation of results. The present work describes full details on the synthesis, characterization, purity, and kinetics of radiolytic stability of [3H]FDDNP. The optimal in vitro conditions for detecting tau and β-amyloid protein aggregates using macroscopic and microscopic autoradiography with both [18F]FDDNP and [3H]FDDNP are also presented. Macroscopic autoradiography determinations were performed with [3H]FDDNP of verified purity using established methods described previously in the literature. The autoradiographic results using phosphate buffered saline (PBS) with less than 1 % EtOH and pure, freshly prepared [3H]FDDNP compared with the earlier reported data using [3H]FDDNP of undetermined purity and PBS in 10 % EtOH demonstrate the critical importance of rigorous experimental design for meaningful in vitro determinations. [18F]FDDNP binding to both amyloid plaques and neurofibrillary tangles was confirmed by amyloid and tau immunohistochemical stains of adjacent tissues. This work illustrates the sensitivity of in vitro techniques to various experimental conditions and underscores that conclusions obtained from translational in vitro to in vivo determinations must always be performed with extreme care to avoid wrong interpretations that can be perpetuated and assumed without further analysis.

Primary cutaneous aspergillosis is a rare but potentially life-threatening disease. We present the case of a premature infant who developed primary cutaneous aspergillosis with Aspergillus niger at the site of a skin abrasion that had been treated with a purple-colored cyanoacrylate product. The infection was treated successfully with gentle debridement of the cyanoacrylate product, followed by intravenous voriconazole and topical fluconazole. To our knowledge, this is the first reported case of primary cutaneous aspergillosis occurring at the site of cyanoacrylate-based skin adhesive.

Referring to recent international articles stating that amyloid imaging or detection has a high additive value in making a diagnosis of Alzheimer's disease (AD) when previous investigations are inconclusive, the authors of this editorial argue that this statement is based on circular reasoning and, hence, misleading. Since autopsy findings and other potential indicators fit poorly with amyloid PET, they conclude that this examination has no role in the diagnosis of AD.

A novel glucose transporter, the sodium glucose cotransporter 2 (SGLT2), has been demonstrated to contribute to the demand for glucose by pancreatic and prostate tumors, and its functional activity has been imaged using a SGLT specific PET imaging probe, α-methyl-4-[F-18]fluoro-4-deoxy-d-glucopyaranoside (Me-4FDG). In this study, Me-4FDG PET was extended to evaluate patients with high-grade astrocytic tumors. Me-4FDG PET scans were performed in four patients diagnosed with WHO Grade III or IV astrocytomas and control subjects, and compared with 2-deoxy-2-[F-18]fluoro-d-glucose (2-FDG) PET and magnetic resonance imaging (MRI) of the same subjects. Immunocytochemistry was carried out on Grade IV astrocytomas to determine the cellular location of SGLT proteins within the tumors. Me-4FDG retention was pronounced in astrocytomas in dramatic contrast to the lack of uptake into the normal brain, resulting in a high signal-to-noise ratio. Macroscopically, the distribution of Me-4FDG within the tumors overlapped with that of 2-FDG uptake and tumor definition using contrast-enhanced MRI images. Microscopically, the SGLT2 protein was found to be expressed in neoplastic glioblastoma cells and endothelial cells of the proliferating microvasculature. This preliminary study shows that Me-4FDG is a highly sensitive probe for visualization of high-grade astrocytomas by PET. The distribution of Me-4FDG within tumors overlapped that for 2-FDG, but the absence of background brain Me-4FDG resulted in superior imaging sensitivity. Furthermore, the presence of SGLT2 protein in astrocytoma cells and the proliferating microvasculature may offer a novel therapy using the SGLT2 inhibitors already approved by the FDA to treat type 2 diabetes mellitus.

Objective Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. Methods Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. Results Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η 2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. Conclusions By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.

A new, high radiochemical yield synthesis of [18F]FHBG and [18F]FHPG, the most popular imaging agents currently in use for monitoring gene therapy using positron emission tomography (PET), is reported in this work. Protection of sensitive sites in the precursors generally utilized for the preparation of [18F]FHBG and [18F]FHPG using the nucleophilic 18F-fluorination reaction was found to be critical for good radiochemical yields, reliability and reproducibility of the synthetic process. As an initial approach, protection at O6-oxygen in the guanine moiety of the currently used monomethoxytrityl-protected penciclovir tosylate derivative 9 with carbamoyl groups was carried out. Subsequently, full protection of both O6-oxygen and N2-nitrogen in the monomethoxytrityl-protected penciclovir and ganciclovir tosylate analogs 9 and 10 were achieved by their reaction with di-tert-butyl dicarbonate, which resulted in O6-tert-butyl-N2-Boc-monomethoxytrityl-protected penciclovir tosylate 18 and O6-tert-butyl-N2-Boc-monomethoxytrityl-protected ganciclovir tosylate 19, respectively. The newly synthesized carbamoyl- and the Boc- protected precursors were first reacted with non-radioactive KF complexed with Kryptofix 222 to isolate the fluorinated products. Acid hydrolysis of the purified fluorinated intermediates provided the nucleosides FHBG and FHPG. Full characterization of the new precursors as well as the products obtained by fluorination and hydrolysis reactions were carried out by one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Single crystal X-ray crystallographic analysis of a model ganciclovir analog 22 confirmed the structural characterization of the new Boc-protected tosylate precursors 18 and 19 by NMR spectroscopy. The carbamoyl- and the Boc-protected precursors were further subjected to radiofluorination followed by acid hydrolysis reactions to furnish [18F]FHBG and [18F]FHPG reliably and reproducibly in excellent radiochemical yields (>65%), much higher than those previously achieved.

Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late-life depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross-sectional pilot study, we performed positron emission tomography scans after injection of 2-(1-{6-[(2-[18 F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([18 F]FDDNP), an in vivo amyloid and tau neuroimaging study, in patients with LLD to explore neural correlates of apathy.Sixteen depressed elderly volunteers received clinical assessments and [18 F]FDDNP positron emission tomography scans. The cross-sectional relationship of [18 F]FDDNP binding levels with depression (Hamilton Depression Rating Scale) and apathy (Apathy Evaluation Scale) were studied using Spearman's correlation analyses because of the relatively small sample size. Age, sex, and years of education were partialed out. Significance levels were set at P ≤ 0.05.[18 F]FDDNP binding in the anterior cingulate cortex was negatively associated with the Apathy Evaluation Scale total (r = -0.62, P = 0.02; where low Apathy Evaluation Scale score equals greater severity of apathy). This suggests that apathy in LLD is associated with higher amyloid and/or tau levels in the anterior cingulate cortex. None of the regional [18 F]FDDNP binding levels was significantly associated with the Hamilton Depression Rating Scale total.This pilot study suggests that increased apathy in subjects with LLD may be associated with greater amyloid and/or tau burden in certain brain regions. Future studies in larger samples would elucidate the generalizability of these results, which eventually could lead to improved diagnostic and treatment methods in LLD.

Overexpression of the amyloid precursor protein (APP)gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer’s disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66–72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma Amyloid-β(Aβ)measurements and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17–28% per year. No dementia was detected on neurological examinations. On both PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non -demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APPin the clinical, biochemical and neuropathological findings of AD in DS.

Thermoplastic masks made of polyester resin are used to immobilize patients receiving radiation therapy. We describe a case of allergic contact dermatitis (ACD) to a thermoplastic mask worn by a child receiving proton beam therapy for treatment of medulloblastoma. ACD to a thermoplastic mask in an adult was first reported in 2018. (J Med Case Rep. 2018;12:181) To our knowledge, ACD to a thermoplastic mask has not been reported previously in the pediatric population.

2-Deoxy-2-(18)F-fluoro-d-glucose (2-FDG) with PET is undeniably useful in the clinic, being able, among other uses, to monitor change over time using the 2-FDG SUV metric. This report suggests some potentially serious caveats for this and related roles for 2-FDG PET. Most critical is the assumption that there is an exact proportionality between glucose metabolism and 2-FDG metabolism, called the lumped constant, or LC. This report describes that LC is not constant for a specific tissue and may be variable before and after disease treatment. The purpose of this work is not to deny the clinical value of 2-FDG PET; it is a reminder that when one extends the use of an appropriately qualified imaging method, new observations may arise and further validation would be necessary. The current understanding of glucose-based energetics in vivo is based on the quantification of glucose metabolic rates with 2-FDG PET, a method that permits the noninvasive assessment of various human disorders. However, 2-FDG is a good substrate only for facilitated-glucose transporters (GLUTs), not for sodium-dependent glucose cotransporters (SGLTs), which have recently been shown to be distributed in multiple human tissues. Thus, the GLUT-mediated in vivo glucose utilization measured by 2-FDG PET would be masked to the potentially substantial role of functional SGLTs in glucose transport and use. Therefore, under these circumstances, the 2-FDG LC used to quantify in vivo glucose utilization should not be expected to remain constant. 2-FDG LC variations have been especially significant in tumors, particularly at different stages of cancer development, affecting the accuracy of quantitative glucose measures and potentially limiting the prognostic value of 2-FDG, as well as its accuracy in monitoring treatments. SGLT-mediated glucose transport can be estimated using α-methyl-4-deoxy-4-(18)F-fluoro-d-glucopyranoside (Me-4FDG). Using both 2-FDG and Me-4FDG should provide a more complete picture of glucose utilization via both GLUT and SGLT transporters in health and disease states. Given the widespread use of 2-FDG PET to infer glucose metabolism, it is relevant to appreciate the potential limitations of 2-FDG as a surrogate for glucose metabolic rate and the potential reasons for variability in LC. Even when the readout for the 2-FDG PET study is only an SUV parameter, variability in LC is important, particularly if it changes over the course of disease progression (e.g., an evolving tumor).

In this paper, a deterministic stress decomposition is applied over the numerical three-dimensional flow solution available for a single volute centrifugal pump. The numerical model has proven in previous publications its robustness to obtain the impeller to volute-tongue flow interaction, and it is now used as starting point for the current research. The main objective has been oriented toward a detailed analysis of the lack of uniformity in the flow that the volute tongue promotes on the blade-to-blade axisymmetric pattern. Through this analysis, the fluctuation field may be retrieved and main interaction sources have been pinpointed. The results obtained with the deterministic analysis become of paramount interest to understand the different flow features found in a typical centrifugal pump as a function of the flow rate. Moreover, this postprocessing tool provides an economic and easy procedure for designers to compare the different deterministic terms, also giving relevant information on the unresolved turbulence intensity scales. Complementarily, a way to model the turbulent effects in a systematic way is also presented, comparing their impact on the performance with respect to deterministic sources in a useful framework, that may be applied for similar kinds of pumps.

CFD modeling research about the lung airflow with a complete resolution and an adequate accuracy at all scales requires a great amount of computational resources due to the vast number of necessary grid elements. As a result, a common practice is to conduct simplifications that allows to manage it with ordinary computational power. In this study, the implementation of a special boundary condition in order to develop a simplified single conductive lung airway model, which exactly represents the effect of the removed airways, is presented. The boundary condition is programmed in the open-source software OpenFOAM®, and the developed source code is presented in the proper syntax. After this description, modeling accuracy is evaluated under different flow rate conditions typical of human breathing processes, including both inspiration and expiration movements. Afterward, a validation process is conducted using results of a Weibel's model (0-4 generations) simulation for a medium flow rate of 50 L/min. Finally, a comparison against the proposed boundary condition implemented in the commercial code ANSYS Fluent is made, which highlights the benefits of using the free code toolbox. The specific contribution of this paper will be to show that OpenFOAM® developed model can perform even better than other commercial codes due to a precise implementation and coupling of the default solver with the in-house functions by virtue of the open-source nature of the code.

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

Glucose transporters are central players in glucose homeostasis. There are two major classes of glucose transporters in the body, the passive facilitative glucose transporters (GLUTs) and the secondary active sodium-coupled glucose transporters (SGLTs). In the present study, we report the use of a non-invasive imaging technique, positron emission tomography, in mice aiming to evaluate the role of GLUTs and SGLTs in controlling glucose distribution and utilization. We show that GLUTs are most significant for glucose uptake into the brain and liver, whereas SGLTs are important in glucose recovery in the kidney. This work provides further support for the use of SGLT imaging in the investigation of the role of SGLT transporters in human physiology and diseases such as diabetes and cancer. The importance of sodium-coupled glucose transporters (SGLTs) and facilitative glucose transporters (GLUTs) in glucose homeostasis was studied in mice using fluorine-18 labelled glucose molecular imaging probes and non-invasive positron emission tomography (PET) imaging. The probes were: α-methyl-4-[F-18]-fluoro-4-deoxy-d-glucopyranoside (Me-4FDG), a substrate for SGLTs; 4-deoxy-4-[F-18]-fluoro-d-glucose (4-FDG), a substrate for SGLTs and GLUTs; and 2-deoxy-2-[F-18]-fluoro-d-glucose (2-FDG), a substrate for GLUTs. These radiolabelled imaging probes were injected i.v. into wild-type, Sglt1(-/-) , Sglt2(-/-) and Glut2(-/-) mice and their dynamic whole-body distribution was determined using microPET. The distribution of 2-FDG was similar to that reported earlier (i.e. it accumulated in the brain, heart, liver and kidney, and was excreted into the urinary bladder). There was little change in the distribution of 2-FDG in Glut2(-/-) mice, apart from a reduction in the rate of uptake into liver. The major differences between Me-4FDG and 2-FDG were that Me-4FDG did not enter the brain and was not excreted into the urinary bladder. There was urinary excretion of Me-4FDG in Sglt1(-/-) and Sglt2(-/-) mice. However, Me-4FDG was not reabsorbed in the kidney in Glut2(-/-) mice. There were no differences in Me-4FDG uptake into the heart of wild-type, Sglt1(-/-) and Sglt2(-/-) mice. We conclude that GLUT2 is important in glucose liver transport and reabsorption of glucose in the kidney along with SGLT2 and SGLT1. Complete reabsorption of Me-4FDG from the glomerular filtrate in wild-type mice and the absence of reabsorption in the kidney in Glut2(-/-) mice confirm the importance of GLUT2 in glucose absorption across the proximal tubule.

Background: Lung cancer is the number one cause of cancer-related death, and lung adenocarcinoma (LUAD) is the most frequent type. Lung screening with computed tomography has allowed detection of early nodules that need diagnostic definition. We have identified the sodium-dependent glucose transporter 2 (SGLT2) as a novel diagnostic and therapeutic target that may aid the identification and the treatment of early LUAD. However, a limitation of these studies is the lack of experimental models of early cancer. Patient-derived xenografts (PDXs) are a reliable tool of translational oncology. However, the establishment of PDXs from early-stage, low-grade LUAD is characterized by low efficiency and extremely long experimental times. To study the predictive value of SGLT2 activity in early LUAD, we have established an alternative model based on a double culture system: 1) implantation of tumor tissue on the chorioallantoic membrane (CAM) of the chicken egg (in ovo system), which can be imaged only 1 week after the patient surgery; 2) growth of tumor spheroids in 3D in vitro culture, to test response to treatments. Methods: Each PDX of LUAD is divided in two specimens: one for in ovo growth in the CAM assay and one for the 3D culture as tumor spheroids. The CAM xenografts are imaged with two different tracers to characterize glucose uptake: [18F] fluorodeoxyglucose (FDG), to measure GLUT activity, and 4-[18F] fluorodeoxyglucose (Me4FDG), to assess sodium-dependent glucose transport (SGLT). The PD-tumor spheroids are cultured in 96-well plates and used for treatment with SGLT2 inhibitors as well as other drugs. Results: PET imaging of LUADs with FDG and Me4FDG revealed the presence of both glucose transporters, GLUT1 and SGLT2. Treatment of the tumor spheroids with SGLT2 inhibitors reduced cell viability and caused integrity loss in a dose-dependent manner. Conclusion: The CAM xenograft model is a useful model for implanting PD tumor fragments and studying glucose metabolism in ovo by PET imaging with very short experimental times. Tumor fragments connect to the chicken embryo vasculature within 3-5 days, so that PD material can be analyzed soon after surgery. The Me4FDG uptake in the CAM system predicts the treatment response of tumor spheroids cultured in vitro from the same PD samples. Citation Format: Eva J. Koziolek, Desiree Martin, Jie Liu, Jorge R. Barrio, W. Dean Wallace, David B. Shackelford, Jane Yanagawa, Steven Dubinett, Claudio Scafoglio. A novel patient-derived approach for preclinical evaluation of predictive imaging biomarkers in early lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A46.

The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions and well-differentiated adenocarcinomas. SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl 4-deoxy-4-[18F] fluoro-alpha-d-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mouse models and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors.

Author(s): Chen, Stephen T; Siddarth, Prabha; Merrill, David A; Martinez, Jacqueline; Emerson, Natacha D; Liu, Jie; Wong, Koon-Pong; Satyamurthy, Nagichettiar; Giza, Christopher C; Huang, Sung-Cheng; Fitzsimmons, Robert P; Bailes, Julian; Omalu, Bennet; Barrio, Jorge R; Small, Gary W | Abstract: BackgroundOur group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls.ObjectiveTo compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI).MethodsFDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups.ResultsFDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p l 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02).ConclusionThis first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Caution is warranted when in vitro results of biomarkers labeled with tritium were perfunctorily used to criticize in vivo data and conclusions derived with the same tracers labeled with positron emitters and positron emission tomography (PET). This concept is illustrated herein with the PET utilization of [The present work describes full details on the synthesis, characterization, purity, and kinetics of radiolytic stability of [The autoradiographic results using phosphate buffered saline (PBS) with less than 1 % EtOH and pure, freshly prepared [This work illustrates the sensitivity of in vitro techniques to various experimental conditions and underscores that conclusions obtained from translational in vitro to in vivo determinations must always be performed with extreme care to avoid wrong interpretations that can be perpetuated and assumed without further analysis.

© 2017 The Authors Objective: Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). Methods: Forty subjects (age 51–84 years) were randomized to a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated. Results: SRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = −0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = −0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). Conclusions: Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory.

Objectives: To analyse the prevalence, evolution of cardiovascular risk factors (CVRF) and their relationship with follow-up of metabolic control in paediatric patients with Type 1 Diabetes (T1DM). Patients and methods: A longitudinal ambispective study was conducted including 75 children and adolescents with T1DM diagnosed from 1996 to 2003 and followed-up for nine years. Family history of CVRF was registered. Data from the second, sixth and ninth year after diagnosis were analysed. Results: Family history of CVRF was found in 46.6% of the patients. The prevalence of HbA1c > 7.5% in the second, sixth and ninth year after diagnosis was 45.3%, 53.3% and 56%, respectively. The prevalence of obesity (BMI > 2SDS) in the three visits was 5.3%, 5.3% and 6.7%, respectively. Hypertension (BP > p90) was found in 14.6%, 8% and 13.3% of the patients in the three visits, respectively. The levels of various parameters were the following: Total cholesterol > 200 mg/dL: 25.3%, 13.3% and 16%; high density cholesterol lipoprotein 100 mg/dL: 38.6%, 34.6% and 38.6%; triglyceride > 150 mg/dL: 0%, 1.3% and 2.6%, respectively. There was a significant increase in the prevalence of TG/HDL-C ≥ 2 between the sixth and the ninth year after diagnosis (1.3% and 9.3%, P 7,5% del 45,3, el 53,3 y el 56%, respectivamente; de obesidad (índice de masa corporal > 2 desviaciones estándar) del 5,3, el 5,3 y el 6,7%, y de HTA (presión arterial > p90) del 14,6, el 8 y el 13,3%. Colesterol total > 200 mg/dl en el 25,3, el 13,3 y el 16%; lipoproteína de alta densidad del colesterol (HDL-c) 100 mg/dl en el 38,6, el 34,6 y el 38,6%; triglicéridos (TG) > 150 mg/dl en el 0, el 1,3 y el 2,6%, respectivamente. Encontramos un aumento significativo en la prevalencia de TG/HDL-c ≥ 2 entre el sexto y el noveno años de evolución de la enfermedad (1,3% y 9,3%, p