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Key Clinical Message Creutzfeldt–Jakob disease is a neurodegenerative disorder caused by brain accumulation of a misfolded form of the cellular prion protein, whose diagnosis is challenging, particularly in early stages, due to the variability and nonspecificity of the clinical and radiological features. 18F‐fluorodeoxyglucose positron‐emitted tomography has the potential to be considered a crucial investigation in these patients, revealing metabolic abnormalities earlier than the conventional neuroimaging analysis. Abstract A 59‐year‐old man, the military officer, was referred to our Units for the onset of neurological symptoms rapidly evolving within a month, characterized by akinetic mutism, constructional apraxia, and disorders of spatial orientation. Brain 18F‐fluorodeoxyglucose (18F‐FDG) positron‐emitted tomography (PET)/CT depicted an asymmetric hypometabolism in the left fronto‐temporo‐parietal cortex, as well as in the left thalamus and the right cerebellar hemisphere, while the glucose metabolism appears to be preserved in the somatosensory cortex and the basal ganglia. Laboratory routine analyses, cerebrospinal fluid routine, infective tests, electroencephalography (EEG), and brain magnetic resonance (MR) were all unremarkable. A positive RT‐QuIC result on cerebro‐spinal fluid (CSF) was subsequently shown, without any pathogenic gene mutations and, therefore, the result was consistent with a diagnosis of sporadic Creutzfeld–Jacob disease. The clinical evolution was quickly unfavorable, and the patient died about 4 months after hospital admission. FDG PET/computed tomography (CT) has the potential to be considered a crucial investigation in these patients, documenting metabolic changes long time before other diagnostic investigations such as CSF, EEG, brain CT, and brain MR, thus suggesting a greater sensitivity of glucose metabolic evaluation in the early stage of the disease in question.

Bacteria employ small regulatory RNAs (sRNA) and/or RNA binding proteins (RBPs) to respond to environmental cues. In Enterobacteriaceae, the FinO-domain containing RBP ProQ associates with numerous sRNAs and mRNAs, impacts sRNA-mediated riboregulation or mRNA stability by binding to 5′- or 3′-untranslated regions as well as to internal stem loop structures. Global RNA-protein interaction studies and sequence comparisons identified a ProQ-like homolog (PA2582/ProQPae) in Pseudomonas aeruginosa (Pae). To address the function of ProQPae, at first a comparative transcriptome analysis of the Pae strains PAO1 and PAO1ΔproQ was performed. This study revealed more than 100 differentially abundant transcripts, affecting a variety of cellular functions. Among these transcripts were pprA and pprB, encoding the PprA/PprB two component system, psrA, encoding a transcriptional activator of pprB, and oprI, encoding the outer membrane protein OprI. RNA co-purification experiments with Strep-tagged Pae ProQ protein corroborated an association of ProQPae with these transcripts. In accordance with the up-regulation of the psrA, pprA, and pprB genes in strain PAO1ΔproQ a phenotypic analysis revealed an increased susceptibility toward the aminoglycosides tobramycin and gentamicin in biofilms. Conversely, the observed down-regulation of the oprI gene in PAO1ΔproQ could be reconciled with a decreased susceptibility toward the synthetic cationic antimicrobial peptide GW-Q6. Taken together, these studies revealed that ProQPae is an RBP that impacts antimicrobial resistance in Pae.

Abstract Background and aims Fabry disease (FD) is an X-linked genetic lysosomal disease, in which a deficit in the alpha-galactosidase A enzyme results in lysosomal build-up of globotriaosylceramide in several organs, causing cardiac, renal and cerebrovascular complications. The aim of this study was to assess the prevalence of papillary muscle hypertrophy (PMH) in patients with FD. Methods A group of 63 patients with FD and a positive genetic diagnosis were studied and were divided into two groups: one included 24 patients with FD and LVH and another group included 39 patients with FD and without LVH. Papillary muscles were measured from the left parasternal short axis view, defining PMH as a diastolic thickness greater than 11 mm in any diameter. Results Patients with FD and LVH had a high prevalence of anterolateral PMH (66.6%), and such prevalence was lower for the posteromedial PMH (33.3%). However, patients who had not yet developed LVH had a high prevalence of anterolateral PMH (33.3%). Conclusions Patients with FD in the pre-clinical stage (without LVH) have a high prevalence of PMH, especially involving the anterolateral papillary muscle. This finding could be an early marker for the development of LVH, allowing to suspect the disease during its early stages, and begin enzyme replacement therapy in the appropriate patients.

Abstract Background Neuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood. The 4.1R protein of the erythrocyte membrane is critical for the membrane-associated cytoskeleton structure and in central neurons it regulates the stabilization of AMPA receptors on the neuronal surface at the postsynaptic density. We report clinical, biochemical, and genetic features in four patients from four unrelated families with NA in order to explain the cause of morphological abnormalities and the relationship with neurodegenerative processes. Case presentation All patients were characterised by atypical NA with a novel alteration of the erythrocyte membrane: a 4.1R protein deficiency. The 4.1R protein content was significantly lower in patients (3.40 ± 0.42) than in controls (4.41 ± 0.40, P < 0.0001), reflecting weakened interactions of the cytoskeleton with the membrane. In patients IV:1 (RM23), IV:3 (RM15), and IV:6 (RM16) the 4.1 deficiency seemed to affect the horizontal interactions of spectrin and an impairment of the dimer self-association into tetramers was detected. In patient IV:1 (RM16) the 4.1 deficiency seemed to affect the skeletal attachment to membrane and the protein band 3 was partially reduced. Conclusion A decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA, which might reflect the expression pattern in the central nervous system, especially basal ganglia, and might lead to dysfunction of AMPA-mediated glutamate transmission.

Introduction: In Italy, approximately 80.5% of the population has completed the primary anti-COVID vaccination cycle with approximately 141 million doses administered. With the introduction of new measures to counter the spread of COVID-19, including compulsory vaccination for certain categories of people, the population expressed fears about the safety and adverse effects of SARS-CoV-2 vaccines. Several factors, such as gender and age, could have influenced the outcomes associated with the vaccine. Our single-centre work seeks to provide such evidence with respect to Pfizer/BioNTech’s BNT162b2 (Comirnaty) and AstraZeneca’s AZD1222 (Vaxzevria) vaccines. Materials and Methods: Single-centre descriptive study carried out on a sample of subjects who underwent anti-COVID vaccination at the ‘San Giovanni di Dio e Ruggi d’Aragona’ AOU vaccination centre in Salerno. Patients who reported a suspected adverse reaction after receiving a dose of vaccine were included in the study. The regional vaccine platform SORESA and the VigiFarmaco portal were used to collect the data. Results: During the period covered by the study, 126,928 doses of SARS-CoV-2 vaccine were administered. The Pfizer-BioNTech vaccine group comprised 124,138 administrations. The AstraZeneca vaccine group consisted of 2,790 administrations. 287 post-vaccination adverse reaction reports entered in the National Pharmacovigilance Network were considered. In most of the reactions reported, for both vaccines considered, the symptomatology was attributable to local reactions at the injection site. At the systemic level, however, we noted the prevalence of non-specific events such as fever, headache and diffuse arthromyalgia. Conclusions: Based on our results and comparison with the literature, the data collected on the vaccines considered in the study suggest a favourable safety profile for their large-scale use. The rate of minor adverse events turned out to be low, with similarly reassuring data compared to serious adverse events, such as not to justify hesitation towards vaccination for COVID-19 disease control.

Inflammatory skin diseases include a series of disorders characterized by a strong activation of the innate and adaptive immune system in which proinflammatory cytokines play a fundamental role in supporting inflammation. Skin inflammation is a complex process influenced by various factors, including genetic and environmental factors, characterized by the dysfunction of both immune and non-immune cells. Psoriasis (PS) and atopic dermatitis (AD) are the most common chronic inflammatory conditions of the skin whose pathogeneses are very complex and multifactorial. Both diseases are characterized by an immunological dysfunction involving a predominance of Th1 and Th17 cells in PS and of Th2 cells in AD. Suppressor of cytokine signaling (SOCS) proteins are intracellular proteins that control inflammatory responses by regulating various signaling pathways activated by proinflammatory cytokines. SOCS signaling is involved in the regulation and progression of inflammatory responses in skin-resident and non-resident immune cells, and recent data suggest that these negative modulators are dysregulated in inflammatory skin diseases such as PS and AD. This review focuses on the current understanding about the role of SOCS proteins in modulating the activity of inflammatory mediators implicated in the pathogenesis of inflammatory skin diseases such as PS and AD.

In the opportunistic human pathogen Pseudomonas aeruginosa (Pae), carbon catabolite repression (CCR) orchestrates the hierarchical utilization of N and C sources, and impacts virulence, antibiotic resistance and biofilm development. During CCR, the RNA chaperone Hfq and the catabolite repression control protein Crc form assemblies on target mRNAs that impede translation of proteins involved in uptake and catabolism of less preferred C sources. After exhaustion of the preferred C-source, translational repression of target genes is relieved by the regulatory RNA CrcZ, which binds to and acts as a decoy for Hfq. Here, we asked whether Crc action can be modulated to relieve CCR after exhaustion of a preferred carbon source. As Crc does not bind to RNA per se, we endeavored to identify an interacting protein. In vivo co-purification studies, co-immunoprecipitation and biophysical assays revealed that Crc binds to Pae strain O1 protein PA1677. Our structural studies support bioinformatics analyzes showing that PA1677 belongs to the isochorismatase-like superfamily. Ectopic expression of PA1677 resulted in de-repression of Hfq/Crc controlled target genes, while in the absence of the protein, an extended lag phase is observed during diauxic growth on a preferred and a non-preferred carbon source. This observations indicate that PA1677 acts as an antagonist of Crc that favors synthesis of proteins required to metabolize non-preferred carbon sources. We present a working model wherein PA1677 diminishes the formation of productive Hfq/Crc repressive complexes on target mRNAs by titrating Crc. Accordingly, we propose the name CrcA (catabolite repression control protein antagonist) for PA1677.

The exponential growth of currently available evidence has made it necessary to collect, filter, critically appraise, and synthesize biomedical information to keep up to date. In this sense, systematic reviews are a helpful tool and can be reliable sources to assist in evidence-based decision-making. Systematic reviews are defined as secondary research or syntheses of evidence focused on a specific question that -- based on a structured methodology -- make it possible to identify, select, critically appraise, and summarize findings from relevant studies. Systematic reviews have several potential advantages, such as minimizing biases or obtaining more accurate results. The reliability of the evidence presented in systematic reviews is determined, amongst other factors, by the quality of their methodology and the included studies. To conduct a systematic review, a series of steps must be followed: the formulation of a research question using the participants, interventions, comparisons, outcomes (PICO) format; an exhaustive literature search; the selection of relevant studies; the critical appraisal of the data obtained from the included studies; the synthesis of results, often using statistical methods (meta-analysis); and finally, estimating the certainty of the evidence for each outcome. In this methodological note, we will define the basic concepts of systematic reviews, their methods, and their limitations.

Abstract Encasing an OLED between two planar metallic electrodes creates a Fabry–Pérot microcavity, resulting in significant narrowing of the emission bandwidth. The emission from such microcavity OLEDs depends on the overlap of the resonant cavity modes and the comparatively broadband electroluminescence spectrum of the organic molecular emitter. Varying the thickness of the microcavity changes the mode structure, resulting in a controlled change in the peak emission wavelength. Employing a silicon wafer substrate with high thermal conductivity to dissipate excess heat in thicker cavities allows cavity thicknesses from 100 to 350 nm to be driven at high current densities. Three resonant modes, the fundamental and first two higher harmonics, are characterized, resulting in tunable emission peaks throughout the visible range with increasingly narrow bandwidth in the higher modes. Angle resolved electroluminescence spectroscopy reveals the outcoupling of the TE and TM waveguide modes which blue-shift with respect to the normal emission at higher angles. Simultaneous stimulation of two resonant modes can produce dual peaks in the violet and red, resulting in purple emission. These microcavity-based OLEDs employ a single green molecular emitter and can be tuned to span the entire color gamut, including both the monochromatic visible range and the purple line.

Microglia, the resident macrophage-like population in the central nervous system, play a crucial role in the pathogenesis of many neurodegenerative disorders by triggering an inflammatory response that leads to neuronal death. Neuroprotective compounds to treat or prevent neurodegenerative diseases are a new field of study in modern medicine. Microglia are activated in response to inflammatory stimuli. The pathogenesis of various neurodegenerative diseases is closely related to the constant activation of microglia due to their fundamental role as a mediator of inflammation in the brain environment. α-Tocopherol, also known as vitamin E, is reported to possess potent neuroprotective effects. The goal of this study was to investigate the biological effects of vitamin E on BV2 microglial cells, as a possible neuroprotective and anti-inflammatory agent, following stimulation with lipopolysaccharide (LPS). The results showed that the pre-incubation of microglia with α-tocopherol can guarantee neuroprotective effects during microglial activation induced by LPS. α-Tocopherol preserved the branched morphology typical of microglia in a physiological state. It also reduced the migratory capacity; the production of pro-inflammatory and anti-inflammatory cytokines such as TNF-α and IL-10; and the activation of receptors such as TRL4 and CD40, which modulate the PI3K-Akt signaling pathway. The results of this study require further insights and research, but they present new scenarios for the application of vitamin E as an antioxidant for the purpose of greater neuroprotection in vivo for the prevention of possible neurodegenerative diseases.

Presentado en sesión de 24 de seteimbre de 1937

Resveratrol is a polyphenol that acts as antioxidants do, protecting the body against diseases, such as diabetes, cancer, heart disease, and neurodegenerative disorders, such as Alzheimer’s (AD) and Parkinson’s diseases (PD). In the present study, we report that the treatment of activated microglia with resveratrol after prolonged exposure to lipopolysaccharide is not only able to modulate pro-inflammatory responses, but it also up-regulates the expression of decoy receptors, IL-1R2 and ACKR2 (atypical chemokine receptors), also known as negative regulatory receptors, which are able to reduce the functional responses promoting the resolution of inflammation. This result might constitute a hitherto unknown anti-inflammatory mechanism exerted by resveratrol on activated microglia.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect in which the right ventricle and associated tricuspid valve (TV) alone support the circulation. TV failure is thus associated with heart failure, and the outcome of TV valve repair are currently poor. 3D echocardiography (3DE) can generate high-quality images of the valve, but segmentation is necessary for precise modeling and quantification. There is currently no robust methodology for rapid TV segmentation, limiting the clinical application of these technologies to this challenging population. We utilized a Fully Convolutional Network (FCN) to segment tricuspid valves from transthoracic 3DE. We trained on 133 3DE image-segmentation pairs and validated on 28 images. We then assessed the effect of varying inputs to the FCN using Mean Boundary Distance (MBD) and Dice Similarity Coefficient (DSC). The FCN with the input of an annular curve achieved a median DSC of 0.86 [IQR: 0.81–0.88] and MBD of 0.35 [0.23–0.4] mm for the merged segmentation and an average DSC of 0.77 [0.73–0.81] and MBD of 0.6 [0.44–0.74] mm for individual TV leaflet segmentation. The addition of commissural landmarks improved individual leaflet segmentation accuracy to an MBD of 0.38 [0.3–0.46] mm. FCN-based segmentation of the tricuspid valve from transthoracic 3DE is feasible and accurate. The addition of an annular curve and commissural landmarks improved the quality of the segmentations with MBD and DSC within the range of human inter-user variability. Fast and accurate FCN-based segmentation of the tricuspid valve in HLHS may enable rapid modeling and quantification, which in the future may inform surgical planning. We are now working to deploy this network for public use.

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Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures derived from cells that are released by all cell types, including brain cells. EVs are now thought to be an additional mechanism of intercellular communication. Both under normal circumstances and following the addition of proinflammatory stimuli, microglia release EVs, but the contents of these two types of EVs are different. Microglia are considered the brain-resident immune cells that are involved in immune surveillance and inflammatory responses in the central nervous system. In this research, we have analyzed the effects of EVs isolated from microglia in response to LPS (Lipopolysaccharide) on microglia activation. The EVs produced as result of LPS stimulation, knows as EVs-LPS, were then used as stimuli on microglia BV2 resting cells in order to investigate their ability to induce microglia to polarize towards an inflammatory state. After EVs-LPS stimulation, we analyzed the change to BV2 cells’ morphology, proliferation, and migration, and investigated the expression and the release of pro-inflammatory cytokines. The encouraging findings of this study showed that EVs-LPS can activate microglia in a manner similar to that of LPS alone and that EVs derived from control cells cannot polarize microglia towards a pro-inflammatory state. This study has confirmed the critical role of EVs in communication and shown how EVs produced in an inflammatory environment can exacerbate the inflammatory process by activating microglia, which may have an impact on all brain cells.

Pseudomonas aeruginosa (Pae) is notorious for its high-level resistance toward clinically used antibiotics. In fact, Pae has rendered most antimicrobials ineffective, leaving polymyxins and aminoglycosides as last resort antibiotics. Although several resistance mechanisms of Pae are known toward these drugs, a profounder knowledge of hitherto unidentified factors and pathways appears crucial to develop novel strategies to increase their efficacy. Here, we have performed for the first time transcriptome analyses and ribosome profiling in parallel with strain PA14 grown in synthetic cystic fibrosis medium upon exposure to polymyxin E (colistin) and tobramycin. This approach did not only confirm known mechanisms involved in colistin and tobramycin susceptibility but revealed also as yet unknown functions/pathways. Colistin treatment resulted primarily in an anti-oxidative stress response and in the de-regulation of the MexT and AlgU regulons, whereas exposure to tobramycin led predominantly to a rewiring of the expression of multiple amino acid catabolic genes, lower tricarboxylic acid (TCA) cycle genes, type II and VI secretion system genes and genes involved in bacterial motility and attachment, which could potentially lead to a decrease in drug uptake. Moreover, we report that the adverse effects of tobramycin on translation are countered with enhanced expression of genes involved in stalled ribosome rescue, tRNA methylation and type II toxin-antitoxin (TA) systems.

Abstract INTRODUCTION: Chagas disease is one of the most common diseases in Latin America and heart involvement is the main cause of death. This study aimed to determine differences in tissue Doppler imaging (TDI) parameters in the assessment left and right ventricular function in patients with the indeterminate form of Chagas disease compared to those in healthy controls. METHODS: We compared 194 patients with the indeterminate form of Chagas disease to 72 age-matched healthy individuals. We considered p-values

Inflammaging is a term used to describe the tight relationship between low-grade chronic inflammation and aging that occurs during physiological aging in the absence of evident infection. This condition has been linked to a broad spectrum of age-related disorders in various organs including the brain. Inflammaging represents a highly significant risk factor for the development and progression of age-related conditions, including neurodegenerative diseases which are characterized by the progressive dysfunction and degeneration of neurons in the brain and peripheral nervous system. Curcumin is a widely studied polyphenol isolated from Curcuma longa with a variety of pharmacologic properties. It is well-known for its healing properties and has been extensively used in Asian medicine to treat a variety of illness conditions. The number of studies that suggest beneficial effects of curcumin on brain pathologies and age-related diseases is increasing. Curcumin is able to inhibit the formation of reactive-oxygen species and other pro-inflammatory mediators that are believed to play a pivotal role in many age-related diseases. Curcumin has been recently proposed as a potential useful remedy against neurodegenerative disorders and brain ageing. In light of this, our current review aims to discuss the potential positive effects of Curcumin on the possibility to control inflammaging emphasizing the possible modulation of inflammaging processes in neurodegenerative diseases.

Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-β, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection.

OBJECTIVE: Prostate Specific Antigen (PSA) is a commonly used marker for the diagnosis and follow-up of Prostate Cancer (PC) and Prostatic Intraepithelial Neoplasia (PIN). Furthermore, in order to ensure early detection of the patients at risk of PC and PIN, there is a growing need for new tools able to early identify this subject. Molecular analysis of neoplastic prostate tissues showed the inactivation of the Glutathione-S-Transferase gene (GSTP1) due to the hypermethylation. The aim of this study is the validation of the specific and sensitive detection of the methylation status of the GSTP1 gene for potential biomarker to assess early detection of PIN. PATIENTS AND METHODS: The methylation status of 5’ promoter region of the GSTP1 gene was obtained by Methylation Sensitivity-PCR (MS-PCR). The test was optimized in terms of the specificity and sensitivity. The cost-efficacy of the test was tested on the DNA from 20 donors healthy subject, 57 benign prostatic hypertrophy (BPH), and 57 PC patients. RESULTS: GSTP1 promoter gene methylation was detected in 0% of healthy subjects (20/20, median age 32,7 years), in 43,9% of patients with BPH (25/57 mean age 60,5 years) and in 57,6% of patients with PC (34/57 mean age 67,8 years). Significantly, the 81,8% of patients with PC, age >65 years and total PSA≤ 4 ng/ml were positive for the methylation status of GSTP1 gene. CONCLUSIONS: In this way, specific evaluation of the methylation status of the GSTP1 gene may be a useful tool for the prediction of patients at risk of PC. In addition, the test is cost-effectiveness and could be used extensively for cancer prevention.

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)