Reduced circulating FABP2 in patients with moderate to severe COVID-19 may indicate enterocyte functional change rather than cell death.

The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and ß-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.

Optimal combinations of ultrasound-based and serum markers of disease severity in patients with chronic hepatitis C.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: metabolite peak-area ratios, relaxation times, and absolute concentrations.

BACKGROUND: Results from cerebral proton (1)H-MR spectroscopy studies of neonates with perinatal hypoxic-ischemic injury have generally been presented as metabolite peak-area ratios, which are T1- and T2-weighted, rather than absolute metabolite concentrations. We hypothesized that compared with (1)H-MR spectroscopy peak-area ratios, calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth (1) would improve prognostic accuracy and (2) enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy. METHODS: Seventeen term infants with neonatal encephalopathy and 10 healthy controls were studied at 2.4T at 1 (1-3) and 2 (2-4) (median [interquartile range]) days after birth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/fatal), according to neurodevelopmental assessments at 1 year. The MR spectroscopy peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), creatine plus phosphocreatine (Cr), N-acetylaspartate (NAA), and choline-containing compounds (Cho) from a voxel centered on the thalami were analyzed according to outcome group. RESULTS: Comparing the severe/fatal group with the controls (significance assumed with P < 0.05), we found that Lac/NAA, Lac/Cho, and Lac/Cr peak-area ratios increased and NAA/Cr and NAA/Cho decreased; Lac, NAA, and Cr T2s were increased; [Lac] was increased and [Cho], [Cr], and [NAA] decreased; and among the concentration ratios, only [Lac]/[NAA] was increased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased [NAA], [Cho], and [Cr] were observed in the infants with normal/mild outcome. Comparison of the normal/mild and severe/fatal groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced [NAA], and increased Lac T2 in the infants with the worse outcome. CONCLUSIONS: Metabolite concentrations, in particular [NAA], enhance the prognostic accuracy of cerebral (1)H-MR spectroscopy-[NAA] was the only measurable to discriminate among all (control, normal/mild, and severe/fatal outcome) groups. However, peak-area ratios are more useful prognostic indicators than concentration ratios because they depend on metabolite concentrations and T2s, both of which are pathologically modulated. Concentration ratios depend only on the concentrations of the constituent metabolites. Increased Cr T2 may provide an indirect marker of impaired cellular energetics, and similarly, NAA T2 may constitute an index of exclusively neuronal energy status. Our recommendation is to collect data that enable calculation of brain metabolite concentrations. However, if time constraints make this impossible, metabolite peak-area ratios provide the next best method of assigning early prognosis in neonatal encephalopathy.

A 31P and 1H-NMR investigation in vitro of normal and abnormal human liver.

Spectral changes in human hepatic tumours and possible systemic effects of tumour on host liver were assessed by 31P and 1H in vitro NMR spectroscopy. The 1H and 31P spectra from liver tumour biopsies showed significant elevation in phosphoethanolamine, phosphocholine, taurine, citrate, alanine, lactate and glycine, and significant reduction in GPE (glycerophosphoethanolamine), GPC (glycerophosphocholine), creatine and threonine compared to histologically normal tissue. 31P-NMR spectra obtained from histologically normal tissue within tumour-bearing livers showed significant elevation in phosphoethanolamine and phosphocholine compared to data from liver biopsies from nontumour-bearing patients (pancreatitis). These results suggest that alterations in membrane metabolism in host liver can be detected by 31P-NMR.

Development and applications of in vivo clinical magnetic resonance spectroscopy.

4.1 CURRENT STATUS. While an extensive clinical literature of MRS of muscle, brain, heart and liver has been achieved, the MRS technique is not considered essential for routine diagnosis because it is inherently insensitive and metabolic changes tend to be small. However, MRS techniques have proven to be of considerable value for prognosis in some circumstances, notably for predicting outcome following hypoxic-ischaemic injury in the newborn and also in predicting graft viability following organ transplantation. The chemical specificity of MRS has been illustrated, and exploiting the non-invasive nature of the technique, metabolic fingerprinting of pathophysiological processes throughout the natural history of a wide variety of diseases is now being accomplished. Particularly exciting are the applications of 13C MRS for measuring hepatic and muscle glycogen levels, for example in diabetics, and the use of hepatic 31P MRS for assessing liver function in cirrhosis. Other areas of excitement are the applications of 1H MRS in assessing neuronal function in epilepsy and stroke, and for measuring the evolution of lactate in stroke and hypoxic-ischaemic encephalopathy. Emphasis on technique development continues, and applications still tend to be technology-led. The availability of routine clinical MRI systems with spectroscopy capabilities has given MRS studies wider applicability. The recent improvements in spatial resolution have been impressive and the technique is slowly becoming more quantitative. 4.2. FUTURE PERSPECTIVES. Given the flexibility of clinical magnetic resonance techniques, particularly magnetic resonance imaging, it is likely that MRI will be the diagnostic tool of choice in a wider range of diseases, such as multiple sclerosis, stroke, neurodegenerative conditions, sports injuries and in staging malignancies. Since proton magnetic resonance spectroscopy packages have become a routine addition to many MRI systems, it is feasible to select the MRI sequences of most value in highlighting anatomical and pathological abnormalities and to incorporate specifically selected MRS sequences to emphasize biochemical differences. Improvements in technical methodologies are central to further developments. For example, use of internal coils, such as implantable or endoscopic coils, will enable small regions of tissue to be studied in considerable detail, which may otherwise be inaccessible to measurement. Chemical MRS studies have benefited from the use of higher magnetic fields, and the same may be expected for clinical MRS studies. Whole-body magnets up to 4 T have been used in a few centres, and certainly 3 T systems are becoming more widely available with the recent tremendous interest in functional imaging. Certainly, better control of artefacts can be expected; for example, improved definition of spectral changes due to voluntary or involuntary movements. Wider use of proton decoupling methods will improve the specificity of the spectra, by allowing definitive assignments of overlapping resonances, as well as the sensitivity. Comparing PET and MRS studies, it is becoming increasingly obvious that both will be required in parallel to explore parameters of brain metabolism and function. The ability to measure 13C MR signals in the brain has been demonstrated, which allows measurements of glutamate and glucose turnover. MRS measurements have the advantage of not requiring a radioactive isotope, as well as being insensitive to activity-related changes in regional cerebral blood flow. Also the study of cerebral glucose metabolism by MRS is very promising, allowing a resolution and sensitivity comparable to PET. A combination of MRS and PET studies will allow the pathogenesis of neuropsychiatric disorders to be better understood. (ABSTRACT TRUNCATED)

Characterization of cerebral white matter damage in preterm infants using 1H and 31P magnetic resonance spectroscopy.

The biochemical characteristics of white matter damage (WMD) in preterm infants were assessed using magnetic resonance spectroscopy (MRS). The authors hypothesized that preterm infants with WMD at term had a persisting cerebral lactic alkalosis and reduced N-acetyl aspartate (NAA)/ creatine plus phosphocreatine (Cr), similar to that previously documented in term infants weeks after perinatal hypoxiaischemia (HI). Thirty infants (gestational age 27.9 +/- 3.1 weeks, birth weight 1,122 +/- 445 g) were studied at postnatal age of 9.8 +/- 4.1 weeks (corrected age 40.3 +/- 3.9 weeks). Infants were grouped according to the presence or absence of WMD on magnetic resonance (MR) images. The peak area ratios of lactate/Cr, NAA/Cr, myo-inositol/Cr, and choline (Cho)/Cr were measured from an 8-cm3 voxel in the posterior periventricular white matter (WM) using proton MRS. Intracellular pH (pHi) was calculated using phosphorus MRS. Eighteen infants had normal WM on MR imaging; 12 had WMD. For infants with WMD, lactate/Cr and myo-inositol/Cr were related (P < 0.01); lactate/Cr and pHi were not (P = 0.8). In the WMD group, mean lactate/Cr and myo-inositol/Cr were higher (P < 0.001, P < 0.05, respectively) than the normal WM group. There was no difference in the NAA/Cr, Cho/Cr, or pHi between the two groups, although pHi was not measured in all infants. These findings suggest that WMD in the preterm infant at term has a different biochemical profile compared with the term infant after perinatal HI.

Osteosarcoma and other neoplasms of bone. Magnetic resonance spectroscopy to monitor therapy.

Fourteen patients with malignant tumors of bone (ten osteogenic sarcomas, one Ewing's tumor, one giant-cell tumor, two non-Hodgkin's lymphomas), plus one patient with a synovial cell sarcoma, who had been treated by standard extremity-conserving chemotherapy regimens, were examined before treatment by means of localized phosphorus 31 magnetic resonance spectroscopy. Thirteen (86%) of 15 examinations were successful, and 100% of successful examinations showed metabolic abnormality in the tumor. Tumors contained excess adenosine triphosphate and inorganic phosphate, an unusual peak of phosphomonoester, consistent with excessive glycolysis in tumors. The intratumor pH was normal in the 12 bone tumors, but acidic in the single soft-tissue sarcoma (pH 6.8). Metabolic response was observed in all seven patients monitored during chemotherapy, with the earliest examinations being performed two days after first treatment. An increase in the inorganic phosphate level, loss of adenosine triphosphate, and loss of phosphomonoester indicated tumor response; loss of all abnormal metabolites (two of seven patients) indicated regression of the tumor. Tumor relapse was accompanied by reappearance of abnormalities in the magnetic resonance spectrum. Phosphorus 31 magnetic resonance spectroscopy offers a unique means of determining the early response of these malignant tumors to therapy as well as predicting their relapse.

In vivo MR spectroscopy in diagnosis and research of neuropsychiatric disorders.

Magnetic resonance spectroscopy is one of the most important tools for quantitative analysis of chemical composition and structure, and this non-invasive technique is now being applied in vivo to study biochemical processes in those neuropsychiatric disorders that are part of the phospholipid spectrum. Interpretation of a clinical magnetic resonance spectrum can provide information about membrane phospholipid turnover, cellular energetics, neuronal function, selected neurotransmitter activity and intracellular pH. Cerebral proton and phosphorus magnetic resonance spectroscopy findings are summarized in relation to schizophrenia, dyslexia and chronic fatigue syndrome.

Associations between central and peripheral measures of phospholipid breakdown revealed by cerebral 31-phosphorus magnetic resonance spectroscopy and fatty acid composition of erythrocyte membranes.

1. Abnormal neuronal membrane phospholipid metabolism is increasingly recognized as being of central importance to a number of neuropsychiatric disorders. Currently, two important indices of membrane phospholipid metabolism tend to be measured: the ratio of the areas of the phosphomonoester (PME) and phosphodiester (PDE) peaks from in vivo cerebral phosphorus magnetic resonance spectroscopy (31P MRS) studies; and erythrocyte membrane fatty acid concentrations. Thus far, there have been no studies comparing these two indices to ascertain the extent to which they agree. 2. The authors measured these indices in nine normal adults. Spectral localization was achieved using four-dimensional chemical shift imaging methods and erythrocyte membrane fatty acid concentrations (from blood samples taken at the time of scanning) were measured using gas liquid chromatography. 3. Levels of PDE (an index of phospholipid catabolism), measured using cerebral 31P MRS, were significantly correlated with reduced concentrations of the highly unsaturated fatty acids docosahexaenoic acid (DHA) (r = -0.68, p < 0.05) and eicosapentaenoic acid (EPA) (r -0.78, p < 0.02). No significant correlations were found between peripheral concentrations of any highly unsaturated fatty acids and PME levels, nor between their essential fatty acid precursors and either PDE or PME levels. Other 31-phosphorus metabolites also showed no significant correlations with the blood fatty acid measures. 4. The correlations between central measures of PDE and peripheral measures of DHA and EPA provide validation of cerebral 31P MRS as a non-invasive technique for the study of membrane phospholipid metabolism in vivo.

The benefits of increasing spatial resolution as a means of reducing artifacts due to field inhomogeneities.

All users of NMR equipment are familiar with the desirability of achieving as high a quality of field as possible. On the other hand, it is easy to forget that the field quality of relevance in both imaging and spectroscopy is that over individual voxels, and not the whole volume. This note demonstrates in practice how performance in poor fields is improved substantially by reducing voxel size (or increasing spatial resolution), offering a potential alternative to additional shimming under appropriate circumstances. It argues that the best criterion for assessing magnet quality in spatially localized systems is the maximum field error gradient in the volume of usable field, rather than the maximum deviation in the field.

Secure spread spectrum watermarking for multimedia.

This paper presents a secure (tamper-resistant) algorithm for watermarking images, and a methodology for digital watermarking that may be generalized to audio, video, and multimedia data. We advocate that a watermark should be constructed as an independent and identically distributed (i.i.d.) Gaussian random vector that is imperceptibly inserted in a spread-spectrum-like fashion into the perceptually most significant spectral components of the data. We argue that insertion of a watermark under this regime makes the watermark robust to signal processing operations (such as lossy compression, filtering, digital-analog and analog-digital conversion, requantization, etc.), and common geometric transformations (such as cropping, scaling, translation, and rotation) provided that the original image is available and that it can be successfully registered against the transformed watermarked image. In these cases, the watermark detector unambiguously identifies the owner. Further, the use of Gaussian noise, ensures strong resilience to multiple-document, or collusional, attacks. Experimental results are provided to support these claims, along with an exposition of pending open problems.

The Bayesian image retrieval system, PicHunter: theory, implementation, and psychophysical experiments.

This paper presents the theory, design principles, implementation and performance results of PicHunter, a prototype content-based image retrieval (CBIR) system. In addition, this document presents the rationale, design and results of psychophysical experiments that were conducted to address some key issues that arose during PicHunter's development. The PicHunter project makes four primary contributions to research on CBIR. First, PicHunter represents a simple instance of a general Bayesian framework which we describe for using relevance feedback to direct a search. With an explicit model of what users would do, given the target image they want, PicHunter uses Bayes's rule to predict the target they want, given their actions. This is done via a probability distribution over possible image targets, rather than by refining a query. Second, an entropy-minimizing display algorithm is described that attempts to maximize the information obtained from a user at each iteration of the search. Third, PicHunter makes use of hidden annotation rather than a possibly inaccurate/inconsistent annotation structure that the user must learn and make queries in. Finally, PicHunter introduces two experimental paradigms to quantitatively evaluate the performance of the system, and psychophysical experiments are presented that support the theoretical claims.

Rotation, scale, and translation resilient watermarking for images.

Many electronic watermarks for still images and video content are sensitive to geometric distortions. For example, simple rotation, scaling, and/or translation (RST) of an image can prevent blind detection of a public watermark. In this paper, we propose a watermarking algorithm that is robust to RST distortions. The watermark is embedded into a one-dimensional (1-D) signal obtained by taking the Fourier transform of the image, resampling the Fourier magnitudes into log-polar coordinates, and then summing a function of those magnitudes along the log-radius axis. Rotation of the image results in a cyclical shift of the extracted signal. Scaling of the image results in amplification of the extracted signal, and translation of the image has no effect on the extracted signal. We can therefore compensate for rotation with a simple search, and compensate for scaling by using the correlation coefficient as the detection measure. False positive results on a database of 10,000 images are reported. Robustness results on a database of 2000 images are described. It is shown that the watermark is robust to rotation, scale, and translation. In addition, we describe tests examining the watermarks resistance to cropping and JPEG compression.

Risk factors for lamb mortality on UK sheep farms.

Data on neonatal-lamb mortality and flock history were recorded by veterinary students working on 108 sheep farms in the UK in Spring 1997. The mean reported mortality incidence risk was 10.0% (median 9%; inter-quartile range 5.9-12.3%). The outcomes were incidence risks of stillbirth, perinatal (within 24h of birth) mortality and postnatal (>24h after birth) mortality. Exposures were screened for univariable associations with mortality risk. Logistic binomial multiple regressions adjusted for confounding, with farm as a random effect. This study has raised hypotheses for management factors associated with lamb mortality that warrant further study. Intensive rearing systems appear to be associated with increased perinatal and postnatal mortality, although housing ewes at lambing was associated with a decreased risk of stillbirth. High perinatal mortality also was associated with poor mothering-pen hygiene, flocks that foster more lambs, and failure to provide appropriate nursing for sick lambs. Larger flocks, poor ewe condition at breeding, and flocks with higher ewe-replacement rates were associated with higher postnatal mortality.

Scanning optical fluorescence microscopy.

A scanning optical fluorescence microscope is described which possesses several advantages over a conventional fluorescence microscope. These include improved resolution, a reduction in background- and auto-fluorescence, an increase in the available fluorescence spectrum and simple modification for automated fluorescence studies. Experimental results are included.

Improvement in resolution by nearly confocal microscopy.

In a conventional confocal microscope the resolution is improved over that attainable in a conventional instrument. A further improvement in resolution is produced when the detector pinhole is offset resulting in nearly confocal operation. For the case where the pinhole is placed over the first dark ring in the Airy disk in the detector plane, dark-field conditions are produced by a very simple method.

Four-dimensional phosphorus-31 chemical shift imaging of carcinoid metastases in the liver.

Four-dimensional chemical shift imaging was used to map spatial variations in phosphorus metabolites in a patient with carcinoid metastases in the liver. The results were compared to those from an age and sex matched volunteer, with no known previous history of liver disease. In the patient local abnormalities were observed. These included elevated phosphomonoester and decreased phosphodiester concentrations relative to adenosine triphosphate. The regions of abnormality corresponded to regions containing metastases identified with x-ray computed tomography and magnetic resonance imaging.

Some considerations concerning susceptibility, longitudinal relaxation time constants and motion artifacts in vivo human spectroscopy.

Artifacts due to localized susceptibility effects, variations in the spin-lattice relaxation time constants of signals and a mixing of signals arising from tissue motions can contaminate otherwise credible results. The sources and magnitude of some of these are discussed and their likely impact assessed, so that the necessity of incorporating additional measurements in an individual study can be demonstrated.

Abnormal cerebral phospholipid metabolism in dyslexia indicated by phosphorus-31 magnetic resonance spectroscopy.

It has recently been suggested that many of the features of dyslexia may be explicable in terms of an abnormality of membrane phospholipid metabolism. To investigate this we studied 12 dyslexic and 10 non-dyslexic adults using in vivo cerebral phosphorus-31 magnetic resonance spectroscopy (31P MRS), as the phosphomonoester (PME) and phosphodiester (PDE) peaks include indices of membrane phospholipid turnover. Spectral localization was achieved using four-dimensional chemical shift imaging methods. The PME peak area was significantly elevated in the dyslexic group, as evidenced by higher ratios of PME/total phosphorus (F = 9.5, p < 0.006), PME/beta NTP (F = 17.5, p < 0.001) and PME/PDE (F = 6.9, p < 0.02). No other spectral measurements differed significantly between the groups. These findings are consistent with the hypothesis that membrane phospholipid metabolism is abnormal in dyslexia. The PME peak is multicomponent, but predominantly consists of phosphoethanolamine (PE) and phosphocholine (PC), which are precursors of membrane phospholipids. Our finding of raised PME in dyslexia could therefore reflect reduced incorporation of phospholipids into cell membranes, although definitive interpretation must await further evidence.